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1
Nguyen, Thanh Phuong T., Caroline P. Kerr, Joseph J. Grudzinski, Carolina A. Ferreira, Julia Sheehan-Klenk, Ohyun Kwon, Maria Powers, et al. "Abstract 6407: Radionuclide-specific effects of90Y-,177Lu-, or225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhanced immunotherapy response in syngeneic murine tumors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6407. http://dx.doi.org/10.1158/1538-7445.am2023-6407.
Анотація:
Abstract Background: Targeted radionuclide therapy (TRT) delivers radiation treatment systemically to tumor sites via a therapeutic radionuclide-linked tumor-selective targeting vector. NM600 is an alkylphosphocholine analog selectively taken up and retained in murine and human tumor cells. We previously showed that low dose radiation delivery with 90Y-NM600 improves tumor response to immune checkpoint inhibitors (ICIs). Understanding the effect of different radionuclide physical properties (emission type, linear energy transfer (LET), half-life, and tissue range) on immunomodulation of metastatic cancers may guide therapy development. Here, we evaluated the type 1 interferon (IFN1) response elicited by 90Y-, 177Lu-, and 225Ac-NM600 in an immunologically cold syngeneic murine tumor model, B78 melanoma. We hypothesized that the unique physical properties of radionuclides will differentially impact immunomodulation by TRT. Methods: Mice bearing B78 WT or Tmem173 -/- CRISPR deletion B78 (STING KO) tumors were randomized to receive 1.5 Gy external beam radiation (EBRT), an equivalent tumor dose of 90Y-, 177Lu-, or 225Ac-NM600 determined by the Monte Carlo-based RAPID platform, or no radiation on day 1. Tumors were harvested on days 4, 7, and 10 for RT-qPCR. Mice bearing two B78 WT or Tmem173 -/- CRISPR deletion B78 (STING KO) tumors were randomized to receive 4 Gy external beam radiation therapy (EBRT), an equivalent tumor dose of 90Y- or 177Lu-NM600, 0.5 μCi 225Ac-NM600, or no radiation +/- dual ICI (anti-CTLA4 and anti-PDL1). Mice were monitored for tumor growth and survival following these treatments. Results: Both EBRT and TRT upregulated expression of IFN1 response-associated genes (Ifnβ1, Mx1) in B78 WT tumors. Only TRT induced upregulation of Ifnβ1 and Mx1 in STING KO B78 tumors. Ddx58, which encodes RIG-I, integral to an alternative IFN1 pathway, was upregulated in both B78 WT and STING KO tumors following 225Ac-NM600, but not other treatments. TRT in B78 STING KO tumors had earlier expression of IFN1 response-associated genes than B78 WT, 225Ac-NM600 in combination with dual ICI improved overall survival over 90Y- or 177Lu-NM600 + ICI and 225Ac-NM600 monotherapy. Conclusions: The distinct physical properties of TRT radiation, γ, β or α, affect the timing, magnitude, and molecular pathways leading to this IFN1 response. Understanding TRT effects on the tumor microenvironment may optimize TRT and immunotherapy. Citation Format: Thanh Phuong T. Nguyen, Caroline P. Kerr, Joseph J. Grudzinski, Carolina A. Ferreira, Julia Sheehan-Klenk, Ohyun Kwon, Maria Powers, Paul A. Clark, Raghava N. Sriramaneni, Reinier Hernandez, Bryan Bednarz, Jamey P. Weichert, Zachary S. Morris. Radionuclide-specific effects of90Y-,177Lu-, or225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhanced immunotherapy response in syngeneic murine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6407.
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Kerr, Caroline P., Joseph J. Grudzinski, Carolina A. Ferreira, David Adam, Julia Sheehan-Klenk, Amber M. Bates, Won Jong Jin, et al. "Abstract 2828: Impact of sequencing of immune checkpoint blockade and targeted radionuclide therapy on murine tumor response." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2828. http://dx.doi.org/10.1158/1538-7445.am2023-2828.
Анотація:
Abstract Background: Sequencing of immune checkpoint inhibitors (ICI) and external beam radiation therapy (EBRT) for cancer treatment has been studied, but the optimal sequencing has yet to be determined. While some studies have noted therapeutic advantages of priming the tumor immune microenvironment with EBRT prior to ICI, others have described the benefit of modulating the tumor infiltrating lymphocyte (TIL) population with ICI before EBRT. Targeted radionuclide therapy (TRT) approaches allow investigation of how irradiation by a tumor-targeted radionuclide and differences in emission type, linear energy transfer, and dose rate affect optimal timing of ICI administration. NM600 is an alkylphosphocholine analog selectively taken up by tumors capable of chelating numerous radionuclides for comparative studies. Objective: We use two immunologically cold tumor models, MOC2 head and neck squamous cell carcinoma and B78 melanoma, to describe the influence of dose rate on type I interferon (IFN1) signaling and the effect of ICI and 90Y-, 177Lu-, and 225Ac-NM600 TRT sequences on tumor response. Methods: 90Y, 177Lu, or 225Ac were added to culture media in activities estimated using GEANT4 Monte Carlo to deliver 12 Gy to the cell monolayer. qPCR was performed on cDNA from cells irradiated with EBRT, 90Y, 177Lu, or 225Ac, and harvested on days 1, 3, or 7. In vivo dosimetry was performed using the Monte Carlo-based RAPID platform utilizing serial PET/CT or SPECT/CT imaging and/or longitudinal biodistribution. Differences over time (days 4, 7, 14, 21, 28 after RT) in TIL and systemic immune cell populations were measured by flow cytometry following no treatment, 12 Gy EBRT, or 90Y-, 177Lu-, or 225Ac-NM600 in MOC2 tumors. Mice bearing B78 tumors received 1.5 Gy 90Y-, 177Lu-, or 225Ac-NM600, or no radiation on day 1 +/- ICI (anti-CTLA4 + anti-PDL1) on days -3/0/3 (early), 4/7/10 (middle), or 11/14/17 (late). Mice were monitored for tumor growth and survival. Results: TRT and EBRT induced IFN1 responses in MOC2 cells. MOC2 cells treated every 24h with EBRT-matched 90Y/225Ac dose rates led to upregulation of IFN1-associated Ifnb1 and Mx1, mimicking radionuclide-induced responses. Increased tumor CD8/Treg ratios and decreased Tregs were observed at day 7 following all RT forms in MOC2 tumors. Long half-life 225Ac-NM600 (90Y: 65h; 177Lu: 161h; 225Ac: 240h) induced similar TIL changes at day 21. For 1.5 Gy 90Y-, 177Lu-, and 225Ac-NM600, B78 tumor growth delay and statistically significant overall survival benefit over respective TRT monotherapy and control groups was observed with early (day -3/0/3) dual ICI administration. Conclusions: These studies demonstrate novel immunomodulatory effects of α- and β- emitting TRT and the capacity to achieve substantial antitumor responses with appropriate TRT + ICI sequencing. These results may inform clinical trial design of TRT + ICI regimens for patients with metastatic cancers. Citation Format: Caroline P. Kerr, Joseph J. Grudzinski, Carolina A. Ferreira, David Adam, Julia Sheehan-Klenk, Amber M. Bates, Won Jong Jin, Ohyun Kwon, Justin C. Jagodinsky, Maria Powers, Raghava N. Sriramaneni, Paul A. Clark, Luke Zangl, Thanh Phuong T. Nguyen, Anatoly N. Pinchuk, Cynthia Choi, Christopher F. Massey, Reinier Hernandez, Bryan Bednarz, Jamey P. Weichert, Zachary S. Morris. Impact of sequencing of immune checkpoint blockade and targeted radionuclide therapy on murine tumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2828.
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Pal, Debjani, Miguel Toro Gonzáleza, Amber N. Bibleb, Brian Sanders, Anna Plechaty, Owee Kirpekar, Mircea Podar, and Sandra M. Davern. "Abstract 480: Nanotherapeutic strategies to improve targeted radionuclide therapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 480. http://dx.doi.org/10.1158/1538-7445.am2024-480.
Анотація:
Abstract Cancer is a leading cause of death worldwide. Several multidisciplinary approaches exist for cancer treatment, including radiotherapy and chemotherapy. Radiotherapy uses high-energy radiation to kill cancer cells; chemotherapy inhibits cancer cell proliferation and often kills cells by targeting the cell cycle. Resistance to radiotherapy and chemotherapy is a key determining factor in the outcome of therapeutic efficacy. Conventional nontargeted radiotherapy also affects distant nonirradiated cells, leading to DNA damage and changes in the cell cycle that are often linked to secondary carcinogenesis in patients. In recent years, targeted radionuclide therapy (TRT) has emerged as a promising personalized treatment strategy that delivers cytotoxic levels of radiation directly and specifically to cancer cells. Among radioisotopes,225Ac exhibits desirable properties for TRT: multiple α-particle emission and high cytotoxicity. One of the challenges with 225Ac is the nonspecific toxicity caused by the release and relocation of its decay daughters. Different approaches have been proposed to prevent the relocation of decay daughters, including nanoparticles. Nanoparticles have been pursued as a promising delivery vehicle of α-emitting radioisotopes to the tumor site. Here, we show specific targeting of Her2-positive breast cancer cells with 225Ac-radiolabeled lanthanum orthovanadate (LaVO4) nanoparticles. Nanoparticles’ surfaces were functionalized to improve biocompatibility and conjugated to target cancer cells, respectively. Cellular uptake and localization of these engineered nanoparticles were analyzed by a Confocal microscope and IncuCyte live cell analysis system. Results confirm its localization in the nucleus following the endolysosomal path, enhancing the nanoparticles’ effectiveness as a delivery vehicle for α-emitting radioisotopes with the potential of increased treatment efficacy. Upon addition of cancer-targeting ligands, these nanoparticles can achieve higher efficiency by delivering the radioisotope to the tumor cells with a potential of safe encapsulation of all α-emitters in the decay chain. The anticancer efficiency of 225Ac-radiolabeled nanoparticles was demonstrated by a dose-dependent effective killing of 3D breast cancer spheroids using both IncuCyte live imaging and the cell survival assays. Ultimately, the results of this study will be crucial in determining the future use of targeted radiolabeled nanoparticle-based delivery systems as an approach for more efficacious cancer treatment. Citation Format: Debjani Pal, Miguel Toro Gonzáleza, Amber N. Bibleb, Brian Sanders, Anna Plechaty, Owee Kirpekar, Mircea Podar, Sandra M. Davern. Nanotherapeutic strategies to improve targeted radionuclide therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 480.
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Adhikarla, Vikram, Dennis Awuah, Alexander B. Brummer, Enrico Caserta, Amrita Krishnan, Flavia Pichiorri, Megan M. Minnix, et al. "Abstract 2732: A mathematical model for optimization of combination therapy involving targeted radionuclide and CAR-T cell therapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2732. http://dx.doi.org/10.1158/1538-7445.am2022-2732.
Анотація:
Abstract Background: Immunotherapy with chimeric antigen receptor - T (CAR-T) cells and targeted radionuclide therapy (TRT) are two highly promising therapies in cancer treatment. Often, these therapies show limited efficacy in complete eradication of cancer cells making the combination of these two therapies an attractive cancer treatment option. The complications involved in dosing and scheduling of these therapies make mathematical modeling an appropriate method for analyzing and predicting disease response to these therapies. Here we propose a mathematical model evaluating disease response to the combination of these two therapies and explore the optimization of their dosing and scheduling. Methods: An ordinary differential equation-based formalism is proposed for simulation of tumor response to CAR-T cell therapy as well as TRT. CAR-T cell dose and injected radioactivity was input to the model. Among others, key model parameters included tumor proliferation rate, tumor cell and CAR-T cell radiosensitivity, CAR-T cell killing rate, CAR-T cell decay rate indicating persistence. Preclinical experiments involving CS1- CAR-T cell therapy and 225Ac-DOTA-Daratumumab TRT in a multiple myeloma mice model were used to parameterize the model. Sensitivity study of the model parameters using overall survival (OS) and progression-free survival (PFS) as evaluation metrics, was performed to elucidate the parameters with highest impact. Results: OS and PFS were 97 and 55 days when CAR-T cell therapy was given prior to TRT as compared to OS of 43 days for untreated control mice. Sensitivity study of model parameters showed that tumor proliferation has the highest impact on survival metrics. For a ±50% change in tumor proliferation rate, OS changed by -41%/+111% and PFS changed by -62%/+147%. Similar changes in TRT injected activity and CAR-T cell dose changed OS by ± 15% and ±21% respectively. Accordingly, PFS changed by roughly ±32% and ±45% respectively. A variation of the interval between the therapies showed that faster growing tumors required a shorter interval between the two therapies. The sequence of therapies was also changed and TRT prior to CAR-T cell therapy demonstrated shorter PFS (43 days) due to the adverse effects of radiation on CAR-T cells. Conclusion: For a fixed dose of TRT and CAR-T cells, tumor proliferation rate was found to be the prime factor impacting therapy interval. The presented work shows the key parameters required for planning and optimizing preclinical experiments and clinical trials. Using disease, CAR-T cell and radionuclide-specific parameters as shown in this work as well as incorporating immune stimulating effects of radiation would make it an extremely potent tool for optimizing combination therapies. Citation Format: Vikram Adhikarla, Dennis Awuah, Alexander B. Brummer, Enrico Caserta, Amrita Krishnan, Flavia Pichiorri, Megan M. Minnix, John E. Shively, Jeffrey Y.C. Wong, Xiuli Wang, Russell C. Rockne. A mathematical model for optimization of combination therapy involving targeted radionuclide and CAR-T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2732.
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Kerr, Caroline P., Amber M. Bates, Joseph J. Grudzinski, Carolina A. Ferreira, Julia Sheehan-Klenk, David Adam, Maria Powers, et al. "Abstract 1306: Radionuclide-specific effects of 90Y-, 177Lu-, or 225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhancing immunotherapy response in murine tumor models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1306. http://dx.doi.org/10.1158/1538-7445.am2022-1306.
Анотація:
Abstract Purpose: In preclinical studies, we have demonstrated that delivering low dose radiation to all tumor sites utilizing 90Y-NM600 improves the response to immune checkpoint inhibitors (ICIs). NM600 is an alkylphosphocholine analog that is selectively taken up and retained in murine and human tumors. In this study, the immunomodulatory capacities of three distinct radionuclides (90Y, 177Lu, 225Ac) were compared using immunologically cold syngeneic murine tumor models: MOC2 head and neck squamous cell carcinoma (HNSCC) and B78 melanoma. We hypothesized that physical properties of radionuclides (e.g. emission type, linear energy transfer (LET), half-life, dose rate) would differentially impact immunomodulation by TRT and ICI treatment response. Methods: Dosimetry performed using the Monte Carlo-based RAPID platform utilizing serial 86Y-NM600 PET/CT imaging determined that 100 μCi 90Y-NM600 or 200 μCi 177Lu-NM600 delivered ~12Gy to the MOC2 tumor and ~4Gy to the B78 tumor. 225Ac-NM600 was dosed at activities ≤0.5 μCi, as determined to be safe and effective previously. Mice bearing two MOC2, B78 WT, or Tmem173 -/- CRISPR deletion B78 (STING KO) tumors were randomized to receive external beam radiation therapy (EBRT), an equivalent tumor dose of 90Y- or 177Lu-NM600, 0.25 μCi 225Ac-NM600, or no radiation +/- dual ICI (anti-CTLA4 and anti-PDL1). Tumors, blood, bone marrow, and spleen were harvested at days 4, 7, 14, and 21 post-treatment for flow cytometry and RT-qPCR. Additional mice were monitored for tumor growth and survival following these treatments. Results: TRT and EBRT induced favorable tumor-specific immune cell infiltration (increased CD8/Treg ratio) at day 7. 225Ac-NM600 additionally induced similar changes at day 21, consistent with the longer half-life radioisotope (90Y: 65h; 177Lu: 161h; 225Ac: 240h). Expression of immune susceptibility markers (Mhc1, Pdl1) and type I interferon (IFN1) response-associated genes (Ifnβ1, Mx1) was upregulated following 12 Gy EBRT or TRT both in vitro and in vivo compared to non-irradiated controls in MOC2 cells and tumors. The timing and magnitude of these effects correlated with radionuclide half-life and LET. 225Ac-NM600 + ICI improved overall survival in B78 WT mice over 90Y- or 177Lu-NM600 + ICI, 225Ac-NM600 or ICI monotherapy, and non-irradiated controls. In the B78 STING KO melanoma cell line, this 225Ac-NM600 + ICI survival benefit was decreased. Conclusions: These studies demonstrate the capacity to deliver immunomodulatory radiation to tumors using gamma-, beta- or alpha-emitting TRT. The physical properties of the delivered radionuclide dictate timing and magnitude of the IFN1 response stimulated by TRT. Understanding these effects may be critical to safely and effectively integrating TRT and immunotherapies to enhance anti-tumor immunity in cancer patients. Citation Format: Caroline P. Kerr, Amber M. Bates, Joseph J. Grudzinski, Carolina A. Ferreira, Julia Sheehan-Klenk, David Adam, Maria Powers, Wonjong Jin, Justin C. Jagodinsky, Raghava N. Sriramaneni, Paul A. Clark, Luke Zangl, Anatoly N. Pinchuk, Alejandro J. Onate, Ria Kumari, Cynthia Choi, Christopher F. Massey, Bryan Bednarz, Reinier Hernandez, Jamey P. Weichert, Zachary S. Morris. Radionuclide-specific effects of 90Y-, 177Lu-, or 225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhancing immunotherapy response in murine tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1306.
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Adhikarla, Vikram, Dennis Awuah, Enrico Caserta, Megan Minnix, Maxim Kuznetsov, Amrita Krishnan, Jeffrey Y. Wong, et al. "Abstract 7374: Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7374. http://dx.doi.org/10.1158/1538-7445.am2024-7374.
Анотація:
Abstract Background: Resistance of cancer cells to monotherapies has led to the development of sequential or combination therapy regimens. However, dosing and scheduling of these therapies is challenging due to the numerous dosing and scheduling combinations that can be given. Mathematical models are thus critical tools for addressing this challenge as multiple therapy combinations can be tested in silico to finalize a patient-specific therapeutic regimen in vivo. Here we develop a mathematical framework for combining targeted radiation therapy (TRT) with Chimeric Antigen Receptor (CAR)-T cell immunotherapy and demonstrate the use of in silico techniques to schedule these therapies for maximizing survival. Methods: In the mathematical framework tumor growth is assumed to be exponential and the effect of radiation on both tumor cells and CAR-T cells is modeled using the linear-quadratic model of cell survival to radiation. A predator-prey model is used to characterize the dynamics of tumor and CAR-T cells. Using a preclinical disseminated mouse model of multiple myeloma (MM1S), we evaluate tumor response to 200 nCi of 225Ac-DOTA-Daratumumab (TRT) and 1 million cells of CS1 CAR-T cell therapy both as monotherapies as well as in combination. Tumor burden tracked using bioluminescence imaging from six groups of mice is used to calibrate model parameters: (a) No treatment. (b) Day 7 TRT. (c) Day 7 CAR-T cell therapy. (d) Day 7 TRT + Day 18 CAR-T cell therapy. (e) Day 7 TRT + Day 25 CAR-T cell therapy. (f) Day 7 TRT + Day 32 CAR-T cell therapy. Response to therapy is evaluated using progression-free survival (PFS), overall survival (OS) and time to minimum tumor burden (tmin), all of which are calculated using the predicted in silico tumor burden dynamics and the tumor burden at the start of first therapy. We evaluate these response metrics for various dosing and scheduling regimens. Results: Therapy intervals that were too short or too long are shown to be detrimental for therapeutic efficacy. TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing, while the interval being too long results in tumor regrowth, negatively impacting tumor control and survival. If a single dose is split into multiple doses, the splitting is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Based on the model parameters we estimate the minimum required TRT activity and CAR-T cell dose to demonstrate an improvement in PFS. Conclusions: The proposed model demonstrates the impact of different dosing and scheduling regimens of TRT and CAR-T therapy on survival metrics. It is a potent tool for translating preclinical results to the clinic and eventually tailor therapy regimens for patients. Citation Format: Vikram Adhikarla, Dennis Awuah, Enrico Caserta, Megan Minnix, Maxim Kuznetsov, Amrita Krishnan, Jeffrey Y. Wong, John E. Shively, Xiuli Wang, Flavia Pichiorri, Russell C. Rockne. Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7374.
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Ruder, Samuel, Michael Sun, Andres Ricaurte Fajardo, Jones Nauseef, Zachary Davidson, Joseph Thomas, Sandra Huicochea Castellanos, et al. "Abstract 7582: Descriptive analysis of patients with mCRPC and liver metastases receiving alpha and beta PSMA targeted radionuclide therapy (PSMA-TRT)." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7582. http://dx.doi.org/10.1158/1538-7445.am2024-7582.
Анотація:
Abstract Introduction: Predictors of outcomes after PSMA-TRT are still being established. Liver metastases (mets) have been associated with poor response. Mutations in genes encoding DNA damage repair (DDR) and TP53 affect radiosensitivity. Here we describe a cohort of patients with mCRPC and liver metastases treated on clinical trials of PSMA-TRT. Methods: 39 patients with liver mets were enrolled on phase I/II PSMA-TRT studies between Jan 2006 to Apr 2022. Patients received alpha therapy (225Ac-J591), beta therapy (fractionated 177Lu-PSMA-617, single-dose and fractionated 177Lu-J591) or a combination of both (225Ac-591 and 177Lu-PSMA-I&T). All patients included in this analysis had CT imaging; patients enrolled after 2017 had PSMA-PET imaging. 15 patients also had genomic analysis completed. Results: Median age was 69 (range 55-93), PSA 85.7 (2.45-9614). 39 (100%) bone mets, 33 (84.6%) LN, 9 (23.1%) lung. 22 (56.4%) greater than 1 ARPI, 23 (59.0%) greater thanc 1 chemo, 13 (33.3%) sip-T, 7 (17.9%) Ra-223, 4 (10.2%) prior TRT (with concurrent liver mets). Of the 19 with both CT and PSMA PET, 18 (94.7%) were identified on PSMA PET (including 8 PET only), 10 (55.6%) on CT (1 CT only, i.e. non-PSMA PET avid). Median whole body PSMA-imaging score (PSMA-IS) was 4 (range 1-4), with 7 (17.9%) 1-2 and 32 (82.1%) 3-4. 9 (23.0%) received alpha-TRT, 26 (66.7%) beta-TRT, and 4 (10.3%) combo-TRT. Somatic or germline analysis was completed in 15 (38.5%) of 39 patients. 8 (53.3%) had mutations in DNA repair pathways (3 in BRCA2, 3 in CHEK 2, 1 in FANC, 1 in MSH2). 7 (46.7%) had mutations in TP53. 31 patients (79.5%) had PSA decline, with 15 (38.5%) achieving PSA 50. 26 (66.7%) had baseline CTC measured; 19 (73.0%) had detectable CTC at baseline. Of these 19, 3 (15.8%) converted to undetectable after therapy and 2 (10.5%) converted to favorable CTC. PSA50 rate in alpha-TRT was 4 (44.4%), beta-TRT 8 (30.7%), combo-TRT 3 (75%). PSA50 in patients with PSMA-IS 1-2 was 1 (14.2%) compared to 14 (43.9%) in PSMA-IS 3-4. 3 (37.5%) of 8 patients with mutDDR achieved PSA50, compared to 3 (42.9%) with mutTP53. Conclusions: This dataset adds to the collective literature of two subgroups of patients with mCRPC receiving TRT: those with liver disease and those with mutations in DNA repair pathways. The results of this study suggest higher rates of response in patients receiving alpha therapy, either alone or in combination with beta therapy, and in patients with high radiotracer uptake on PSMA-PET, based on PSMA-imaging score of 3 or 4. Genomic alterations in DRR proteins did not have clear implications. Citation Format: Samuel Ruder, Michael Sun, Andres Ricaurte Fajardo, Jones Nauseef, Zachary Davidson, Joseph Thomas, Sandra Huicochea Castellanos, Ana Molina, Cora Sternberg, Amie Patel, Escarleth Fernandez, Sarah Yuan, Edward Fung, Vasilios Avlonitis, Elisabeth O'Dwyer, David Nanus, Joseph Osborne, Neil Bander, Scott Tagawa. Descriptive analysis of patients with mCRPC and liver metastases receiving alpha and beta PSMA targeted radionuclide therapy (PSMA-TRT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7582.
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Sheehan-Klenk, Julia, Caroline P. Kerr, Thanh P. Nguyen, Joseph J. Grudzinski, David Adam, Maria Powers, Raghava N. Sriramaneni, et al. "Abstract 6117: Dose, dose rate, and linear energy transfer influence tumor immunologic and DNA damage response following alpha- and beta-emitting radionuclides." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6117. http://dx.doi.org/10.1158/1538-7445.am2023-6117.
Анотація:
Abstract Background: The low response rate to immunotherapies in poorly immunogenic cancers highlights the potential for combination therapies that propagate an anti-tumor response in metastatic settings. Targeted radionuclide therapy (TRT) can deliver radiation to metastatic tumor sites. In preclinical studies, combining low dose TRT with immune checkpoint blockade augments the anti-tumor immune response, promoting the immune susceptibility of metastatic disease sites. Radionuclides differ in their physical properties such as emission type, linear energy transfer (LET), half-life, and tissue range. In this study, clinically relevant α- and β-emitting radionuclides (225Ac, 90Y, 177Lu) were compared in vitro in MOC2 head and neck squamous cell carcinoma and B78 melanoma. We hypothesized that the unique physical properties of radionuclides would differentially impact the quantity and accumulation over time of double stranded DNA breaks, mirroring the timing of effects on tumor cell immune susceptibility markers. Methods: MOC2 or B78 cells were grown in culture and treated with external beam radiation (EBRT), or culture media containing 90Y, 177Lu, or 225Ac delivering continuous radiation at activity levels using GEANT4 Monte Carlo to deliver 12 Gy (MOC2) and 4 Gy (B78) to the cell monolayer. Cells were harvested, and cDNA was isolated for RT-qPCR one, three, and seven days after the start of irradiation. Additional cells treated in this manner were fixed and stained with DAPI/γ-H2AX antibody for confocal microscopy at the same timepoints. γ-H2AX foci/cell were quantified manually using ImageJ. Results: γ-H2AX foci counts/cell increased significantly and accumulated over time following treatment with 225Ac, but not with 90Y or 177Lu. EBRT, 90Y, and 225Ac, but not 177Lu, upregulated expression of immune response associated genes (Fas, Pdl1, Mhc1) compared to non-irradiated controls. In cells treated with EBRT every 24h at doses mimicking the interval dose delivered by continuous exponential decay of 90Y and 225Ac, but not 177Lu, the time course and magnitude of Fas and Pdl1 expression phenocopied that of these radionuclides. Conclusions: DNA damage accumulation and the timing of immunomodulation are modified by the dose, dose-rate, and LET of radiation emitted from a given radionuclide. Understanding the effects of radionuclide therapies on cancer cell immunogenicity could enable rational design of clinical trials that investigate the integration of TRT and immunotherapies into the clinical care of patients with metastatic cancers. Citation Format: Julia Sheehan-Klenk, Caroline P. Kerr, Thanh P. Nguyen, Joseph J. Grudzinski, David Adam, Maria Powers, Raghava N. Sriramaneni, Paul A. Clark, Reinier Hernandez, Bryan Bednarz, Jamey P. Weichert, Zachary S. Morris. Dose, dose rate, and linear energy transfer influence tumor immunologic and DNA damage response following alpha- and beta-emitting radionuclides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6117.
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Vorontsova, M., T. Karmakova, A. Pankratov, and A. Kaprin. "Current Trends in Targeted Radionuclide Therapy Development." Medical Radiology and radiation safety 66, no. 6 (December 17, 2021): 63–70. http://dx.doi.org/10.12737/1024-6177-2021-66-6-63-70.
Анотація:
Introduction
1. Features of Targeted Delivery of Therapeutic Radionuclides
2. Design of Pharmaceuticals for Targeted Radionuclide Therapy (TRT)
2.1. Radionuclides
2.2. Synthesis of Radioconjugates
2.3. Targeting Carriers
4. Subcellular Targeting of Radionuclides
5. TRT Dosimetry
Conclusion
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van der Wal, Bart C. H., and Ekaterina Dadachova. "Targeted Radionuclide Therapy of Cancer and Infections." International Journal of Molecular Sciences 24, no. 10 (May 22, 2023): 9081. http://dx.doi.org/10.3390/ijms24109081.
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Metcalf, Julie, Alexander Nielsen, Suma Prabhu, Nicole Robinson, Sarah Marinacci, Natalie Grinshtein, Brigitte L. Theriault, et al. "Abstract LB313: EGFRvIII-targeted alpha therapy shows significant therapeutic efficacy as both a single-agent and in combination with standard of care against preclinical GBM models." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB313. http://dx.doi.org/10.1158/1538-7445.am2023-lb313.
Анотація:
Abstract Targeted alpha therapy (TAT) is a rapidly advancing class of radiotherapeutics that can effectively deliver potent and local radiation to cancer cells while sparing the surrounding normal cells. TATs hold great promise for treatment-resistant tumors such as glioblastoma multiforme (GBM) due to the extensive DNA damage and cell death induced by alpha particles. GBM is an aggressive and lethal primary adult brain tumor that is highly resistant to external beam radiation and chemotherapy. Herein, we present the preclinical evaluation of a novel TAT for treatment of GBM targeting the most common tumour-specific mutant, epidermal growth factor receptor variant 3 (EGFRvIII). Our EGFRvIII TAT consists of a humanized EGFRvIII monoclonal antibody, a proprietary bifunctional chelate, and the alpha-emitting radionuclide, actinium-225 (225Ac). In vivo biodistribution and efficacy of our EGFRvIII TAT was evaluated in two aggressive orthotopic EGFRvIII-expressing GBM patient-derived xenograft models (PDXs; G06 and G39) with varying degrees of blood-brain-tumor barrier (BBTB) permeability. Imaging biodistribution studies were performed using an [111In]-anti-EGFRvIII agent analogous to our [225Ac] therapeutic candidate. SPECT/BLT imaging 96 h after intravenous administration of the imaging agent revealed high tumor-specific uptake of 50.2 %ID/cc in G39 tumors with a disrupted BBTB, and 10.4% ID/cc in G06 tumors with a relatively intact BBTB. Normal brain showed very low uptake (1.6-2.1% ID/cc), and all other normal organs were <10 % ID/cc except for highly perfused organs such as heart and liver, indicating no significant off-target uptake. [225Ac]-anti-EGFRvIII single-dose and fractionated multi-dose efficacy studies were conducted in G06 and G39 orthotopic PDX models, respectively. Survival analysis showed a dose-dependent increase in survival in response to treatment with [225Ac]-anti-EGFRvIII therapy, with a greater than 3-fold increase in survival compared to vehicle controls at doses of 200-400 nCi. Furthermore, the survival benefit of the 400 nCi single-dose or fractionated equivalent dose groups were comparable, demonstrating that efficacy was dependent upon the total administered radioactivity dose. Finally, we show that combined treatment of [225Ac]-anti-EGFRvIII with the standard of care (SoC), external beam radiation plus temozolomide, resulted in a significant survival advantage (>1.7-fold) compared to TAT or SoC therapy alone. Collectively, these results demonstrate that [225Ac]-anti-EGFRvIII is a highly selective and potent therapeutic for GBM which holds great potential as both a single-agent and in combination with SoC. Citation Format: Julie Metcalf, Alexander Nielsen, Suma Prabhu, Nicole Robinson, Sarah Marinacci, Natalie Grinshtein, Brigitte L. Theriault, Anne Marcil, Maria L. Jaramillo, Traian Sulea, Ivan A. Lessard, Maria Moreno, Christopher P. Leamon, Eric Burak, John Valliant. EGFRvIII-targeted alpha therapy shows significant therapeutic efficacy as both a single-agent and in combination with standard of care against preclinical GBM models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB313.
12
Kerr, Caroline P., Joseph J. Grudzinski, Thanh Phuong Nguyen, Reinier Hernandez, Jamey P. Weichert, and Zachary S. Morris. "Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment." Pharmaceutics 15, no. 1 (December 30, 2022): 128. http://dx.doi.org/10.3390/pharmaceutics15010128.
Анотація:
Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention—a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies.
13
Obata, Honoka, Mikako Ogawa, and Michael R. Zalutsky. "DNA Repair Inhibitors: Potential Targets and Partners for Targeted Radionuclide Therapy." Pharmaceutics 15, no. 7 (July 11, 2023): 1926. http://dx.doi.org/10.3390/pharmaceutics15071926.
Анотація:
The present review aims to explore the potential targets/partners for future targeted radionuclide therapy (TRT) strategies, wherein cancer cells often are not killed effectively, despite receiving a high average tumor radiation dose. Here, we shall discuss the key factors in the cancer genome, especially those related to DNA damage response/repair and maintenance systems for escaping cell death in cancer cells. To overcome the current limitations of TRT effectiveness due to radiation/drug-tolerant cells and tumor heterogeneity, and to make TRT more effective, we propose that a promising strategy would be to target the DNA maintenance factors that are crucial for cancer survival. Considering their cancer-specific DNA damage response/repair ability and dysregulated transcription/epigenetic system, key factors such as PARP, ATM/ATR, amplified/overexpressed transcription factors, and DNA methyltransferases have the potential to be molecular targets for Auger electron therapy; moreover, their inhibition by non-radioactive molecules could be a partnering component for enhancing the therapeutic response of TRT.
14
Li, Mengshi, Edwin A. Sagastume, Dongyoul Lee, Daniel McAlister, Anthony J. DeGraffenreid, Keith R. Olewine, Stephen Graves, et al. "203/212Pb Theranostic Radiopharmaceuticals for Image-guided Radionuclide Therapy for Cancer." Current Medicinal Chemistry 27, no. 41 (December 8, 2020): 7003–31. http://dx.doi.org/10.2174/0929867327999200727190423.
Анотація:
Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.
15
Adhikarla, Vikram, Dennis Awuah, Alexander B. Brummer, Enrico Caserta, Amrita Krishnan, Flavia Pichiorri, Megan Minnix, et al. "A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy." Cancers 13, no. 20 (October 15, 2021): 5171. http://dx.doi.org/10.3390/cancers13205171.
Анотація:
Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies.
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Malcolm, Javian, Nadia Falzone, Boon Lee, and Katherine Vallis. "Targeted Radionuclide Therapy: New Advances for Improvement of Patient Management and Response." Cancers 11, no. 2 (February 25, 2019): 268. http://dx.doi.org/10.3390/cancers11020268.
Анотація:
Compared to external beam radiotherapy, targeted radionuclide therapy (TRT) allows for systemic radiation treatment of metastatic lesions. Published work on recent strategies to improve patient management and response to TRT through individualising patient treatment, modifying treatment pharmacokinetics and increasing anticancer potency are discussed in this review, with a special focus on the application of clinically evaluated radiolabelled ligands and peptides in the treatment of neuroendocrine and prostate cancers.
17
Ruigrok, Eline A. M., Wytske M. van Weerden, Julie Nonnekens, and Marion de Jong. "The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research." Pharmaceutics 11, no. 11 (October 29, 2019): 560. http://dx.doi.org/10.3390/pharmaceutics11110560.
Анотація:
Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA has shown to be an excellent target for PCa theranostics because of its high expression on the membrane of PCa cells and the increase in expression during disease progression. Therefore, numerous PSMA-targeting tracers have been developed and (pre)clinically studied with promising results. However, many of these PSMA-targeting tracers show uptake in healthy organs such as the salivary glands, causing radiotoxicity. Furthermore, not all patients respond to PSMA-targeted radionuclide therapy (TRT). This created the necessity of additional preclinical research studies in which existing tracers are reevaluated and new tracers are developed in order to improve PSMA-TRT by protecting the (PSMA-expressing) healthy organs and improving tumor uptake. In this review we will give an overview of the recent preclinical research projects regarding PCa-TRT using PSMA-specific radiotracers, which will give an indication of where the PSMA-TRT research movement is going and what we can expect in future clinical trials.
18
Müller, Cristina, Martin Béhé, Susanne Geistlich, Nicholas P. van der Meulen, and Roger Schibli. "Targeted Radiotherapeutics from 'Bench-to-Bedside'." CHIMIA International Journal for Chemistry 74, no. 12 (December 23, 2020): 939–45. http://dx.doi.org/10.2533/chimia.2020.939.
Анотація:
The concept of targeted radionuclide therapy (TRT) is the accurate and efficient delivery of radiation to disseminated cancer lesions while minimizing damage to healthy tissue and organs. Critical aspects for successful development of novel radiopharmaceuticals for TRT are: i) the identification and characterization of suitable targets expressed on cancer cells; ii) the selection of chemical or biological molecules which exhibit high affinity and selectivity for the cancer cell-associated target; iii) the selection of a radionuclide with decay properties that suit the properties of the targeting molecule and the clinical purpose. The Center for Radiopharmaceutical Sciences (CRS) at the Paul Scherrer Institute in Switzerland is privileged to be situated close to unique infrastructure for radionuclide production (high energy accelerators and a neutron source) and access to C/B-type laboratories including preclinical, nuclear imaging equipment and Swissmedic-certified laboratories for the preparation of drug samples for human use. These favorable circumstances allow production of non-standard radionuclides, exploring their biochemical and pharmacological features and effects for tumor therapy and diagnosis, while investigating and characterizing new targeting structures and optimizing these aspects for translational research on radiopharmaceuticals. In close collaboration with various clinical partners in Switzerland, the most promising candidates are translated to clinics for 'first-in-human' studies. This article gives an overview of the research activities at CRS in the field of TRT by the presentation of a few selected projects.
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Patel, Ravi B., Reinier Hernandez, Peter Carlson, Joseph Grudzinski, Amber M. Bates, Justin C. Jagodinsky, Amy Erbe, et al. "Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade." Science Translational Medicine 13, no. 602 (July 14, 2021): eabb3631. http://dx.doi.org/10.1126/scitranslmed.abb3631.
Анотація:
Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radiotherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.
20
Sun, M., C. Thomas, J. Stangl-Kremser, A. Fajardo, J. Palmer, J. Thomas, S. Huicochea Castellanos, et al. "1822P PSMA-alpha targeted radionuclide therapy (TRT) with or without prior PSMA-beta TRT." Annals of Oncology 34 (October 2023): S987. http://dx.doi.org/10.1016/j.annonc.2023.09.2770.
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Spoormans, Kaat, Melissa Crabbé, Lara Struelens, Marijke De Saint-Hubert, and Michel Koole. "A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT)." Pharmaceutics 14, no. 10 (September 22, 2022): 2007. http://dx.doi.org/10.3390/pharmaceutics14102007.
Анотація:
Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.
22
Aprile, Carlo, Onelio Geatti, Letizia Canziani, and Lorenzo Lodola. "Editorial for the Special Issue “Molecular Biology in Targeted Radionuclide Therapy Radiopharmaceutical Design”." Current Issues in Molecular Biology 46, no. 3 (March 13, 2024): 2398–401. http://dx.doi.org/10.3390/cimb46030152.
Анотація:
Targeted radionuclide therapy (TRT) is gaining wide and rapid acceptance in clinical practice as it can deliver alpha or beta irradiation to a tumor-associated target which may be present in the tumor cell itself or in the microenvironment [...]
23
Funeh, Cyprine Neba, Jessica Bridoux, Thomas Ertveldt, Timo W. M. De Groof, Dora Mugoli Chigoho, Parinaz Asiabi, Peter Covens, Matthias D’Huyvetter, and Nick Devoogdt. "Optimizing the Safety and Efficacy of Bio-Radiopharmaceuticals for Cancer Therapy." Pharmaceutics 15, no. 5 (April 30, 2023): 1378. http://dx.doi.org/10.3390/pharmaceutics15051378.
Анотація:
The precise delivery of cytotoxic radiation to cancer cells through the combination of a specific targeting vector with a radionuclide for targeted radionuclide therapy (TRT) has proven valuable for cancer care. TRT is increasingly being considered a relevant treatment method in fighting micro-metastases in the case of relapsed and disseminated disease. While antibodies were the first vectors applied in TRT, increasing research data has cited antibody fragments and peptides with superior properties and thus a growing interest in application. As further studies are completed and the need for novel radiopharmaceuticals nurtures, rigorous considerations in the design, laboratory analysis, pre-clinical evaluation, and clinical translation must be considered to ensure improved safety and effectiveness. Here, we assess the status and recent development of biological-based radiopharmaceuticals, with a focus on peptides and antibody fragments. Challenges in radiopharmaceutical design range from target selection, vector design, choice of radionuclides and associated radiochemistry. Dosimetry estimation, and the assessment of mechanisms to increase tumor uptake while reducing off-target exposure are discussed.
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Potluri, Hemanth, Carolina Ferreira, Joseph Grudzinski, Christopher Massey, Reinier Hernandez, Jamey Weichert, and Douglas McNeel. "594 Combination of antigen-specific vaccination and targeted radionuclide therapy improves anti-tumor efficacy in a murine prostate model." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A624. http://dx.doi.org/10.1136/jitc-2021-sitc2021.594.
Анотація:
BackgroundWhile checkpoint blockade has been unsuccessful in prostate cancer trials, the approval of Sipuleucel-T demonstrates the value of antigen-specific vaccination approaches for this disease. We have studied a DNA vaccine specific for the ligand-binding domain of the androgen receptor (pTVG-AR) as a more scalable vaccination approach, though its efficacy is likely limited by the immunosuppressive prostate microenvironment. External beam radiotherapy has been shown to sensitize poorly responsive tumors to immunotherapy, but is infeasible for patients with widely metastatic disease. Our group has developed a compound called NM600 that can deliver radiation to all cancer sites simultaneously, similar to other targeted radionuclide therapy (TRT) approaches. In this study, we used TRT in combination with pTVG-AR to improve anti-tumor efficacy in a murine prostate cancer model.Methods6-week old male C57BL/6 mice were implanted subcutaneously with TRAMP-C1 cells. pTVG-AR or the empty vector were administered weekly from the day after tumor implantation. An intravenous injection was administered of 50 (”low-dose”) or 250 μCi (”high dose”) of 90Y-NM600, estimated to deliver a dose of 3.1 Gy or 15.5 Gy to 300 mm3 tumors, respectively. In one study, this TRT treatment was repeated once after three weeks. Groups of mice (n=5) were euthanized at several time points for flow cytometry analysis of the tumors. Separate cohorts (n=7) were followed for survival.ResultsLow-dose TRT administered once in combination with pTVG-AR (median survival 91 days) significantly improved survival more than low-dose TRT alone (median survival 59 days; p=.049) or pTVG-AR alone (median survival 59 days; p=0.01). Low-dose TRT plus pTVG-AR was also superior to high-dose TRT plus pTVG-AR (median survival 67 days; p=0.05). We next examined the effect of giving high-dose TRT twice in combination pTVG-AR. We found that the combination of fractionated TRT and pTVG-AR greatly slowed tumor growth unlike fractionated TRT alone (p=0.03). High-dose TRT + pTVG-AR caused a two-fold increase in CD86 expression on dendritic cells (p=0.0009) on Day 3 and a 10% increase in effector memory CD8+ T cells (p=0.002) on Day 1 compared to TRT alone. This combination also resulted in T cells with 3-fold lower PD-1 expression (p=4e-7) and 2-fold lower TIGIT expression (p=0.01).ConclusionsThese data suggest that the combination of antigen-specific vaccination and TRT can be an effective treatment for cancers that are refractory to immunotherapy. This combination may act through increasing co-stimulation by dendritic cells, leading to a more active cytolytic CD8+ T cell population.
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Delpassand, Ebrahim S., Mohammad Jawed Hashmi, Julia Kazakin, Omer Nawaz, Gabriella Garufi, Joanne Schindler, and Luke Nordquist. "Abstract CT224: Preliminary efficacy and safety results from the (TATCIST) trial: A PSMA-directed targeted alpha therapy with FPI-2265 (225Ac-PSMA-I&T) for the treatment of metastatic castration-resistant prostate cancer (mCRPC)." Cancer Research 84, no. 7_Supplement (April 5, 2024): CT224. http://dx.doi.org/10.1158/1538-7445.am2024-ct224.
Анотація:
Abstract INTRODUCTION: Targeted α therapy (TAT) in mCRPC is a rapidly advancing class of radiotherapeutics that can effectively deliver potent and local radiation selectively to cancer cells while sparing the surrounding normal cells. Retrospective studies of 225Ac PSMA-RLT (radioligand therapy), have shown promise in pts with mCRPC, where activity correlates with disease characteristics and prior therapies. FPI-2265 (225Ac-PSMA-I&T) consists of a small-molecule PSMA-targeting ligand coupled with a 225Ac radionuclide. Here we present the initial results from TATCIST, an ongoing, open-label, single-arm study (NCT05219500) to evaluate the efficacy and safety of FPI-2265 in pts with mCRPC that was initiated as an investigator-sponsored study then converted into an industry-sponsored trial with more stringent eligibility criteria. METHODS: Eligible pts are required to have progressive mCRPC with PSMA-positive PET. Prior radioligand therapy is permitted. Pts with skeletal metastases presenting as a superscan were excluded upon protocol amendment and excluded from this analysis. Four doses of FPI-2265 at 100 kBq/kg (±10%) are administered at 8-week intervals; de-escalation in cycle 2 and beyond is allowed. Proportion of pts with PSA ≤50%, maximum %PSA decrease, and safety and tolerability of FPI-2265 were assessed. RESULTS: At the time of the data cut (30Jan2024) 30 pts have received ≥1 dose FPI-2265, with 25 pts having ≥12 weeks follow up. For this analysis, 21 pts were evaluable for safety and 20 pts were evaluable for PSA response: 4 pts with superscan were excluded and 1 pt was excluded due to uninterpretable PSA data. In general, pts were heavily pretreated in terms of prior lines of therapy. Most pts (17/21 [81%]) had received a prior taxane, including 8 pts who received ≥2 lines of taxanes. Eight pts received prior 177Lu PSMA-RLT (Lu). PSA50 was achieved in 10/20 pts (50%); In a subset of pts with the baseline PSMA SUVmean >6 (n=13 overall; post-Lu, n=6), PSA50 was achieved in 9 pts (69%). Treatment-related adverse events (TRAEs) included dry mouth (18/21 [86%]), fatigue (10/21 [48%]) dry eye (6/21 [28%]), and anemia (6/21 [28%]). All were Grade 1-2 in severity, expect anemia Grade 3 which was observed in (5/21 [24%]). Other Grade 3 TRAEs included decreased platelet count (3/21 [14%]). No Grade 4 or 5 TRAEs were reported. Dry mouth was primarily Grade 1 (13/21 [62%]) with only 5 patients (24%) experiencing Grade 2 dry mouth; there were no related discontinuations. CONCLUSION: Preliminary efficacy and safety data as of 30Jan24 suggest that FPI-2265 is active in heavily pretreated pts with progressive mCRPC, including pts who received prior Lu therapy. Higher PSMA SUVmean was associated with improved PSA responses, Safety and tolerability were consistent with other published studies of 225Ac-PSMA-RLTs. These initial results support further investigation of FPI-2265 and a new phase 2/3 trial will begin enrolling soon. Citation Format: Ebrahim S. Delpassand, Mohammad Jawed Hashmi, Julia Kazakin, Omer Nawaz, Gabriella Garufi, Joanne Schindler, Luke Nordquist. Preliminary efficacy and safety results from the (TATCIST) trial: A PSMA-directed targeted alpha therapy with FPI-2265 (225Ac-PSMA-I&T) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT224.
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Ruigrok, Eline A. M., Nicole S. Verkaik, Erik de Blois, Corrina de Ridder, Debra Stuurman, Stefan J. Roobol, Dik C. Van Gent, Marion de Jong, Wytske M. Van Weerden, and Julie Nonnekens. "Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment." International Journal of Molecular Sciences 23, no. 14 (July 21, 2022): 8037. http://dx.doi.org/10.3390/ijms23148037.
Анотація:
Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.
27
Williams, L. "WE-E-214-03: Biology and Physiology of Targeted Radionuclide Therapy (TRT)." Medical Physics 38, no. 6Part33 (June 2011): 3822. http://dx.doi.org/10.1118/1.3613392.
28
Speer, T. W., P. Bernhardt, B. Bednarz, P. Harari, J. Saker, and B. Thomadsen. "Feasibility of the Systemic Cure of Cancer With Targeted Radionuclide Therapy (TRT)." International Journal of Radiation Oncology*Biology*Physics 84, no. 3 (November 2012): S709. http://dx.doi.org/10.1016/j.ijrobp.2012.07.1898.
29
Potluri, Hemanth K., Carolina A. Ferreira, Joseph Grudzinski, Christopher Massey, Eduardo Aluicio-Sarduy, Jonathan W. Engle, Ohyun Kwon, et al. "Antitumor efficacy of 90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors." Journal for ImmunoTherapy of Cancer 10, no. 8 (August 2022): e005060. http://dx.doi.org/10.1136/jitc-2022-005060.
Анотація:
BackgroundSystemic radiation treatments that preferentially irradiate cancer cells over normal tissue, known as targeted radionuclide therapy (TRT), have shown significant potential for treating metastatic prostate cancer. Preclinical studies have demonstrated the ability of external beam radiation therapy (EBRT) to sensitize tumors to T cell checkpoint blockade. Combining TRT approaches with immunotherapy may be more feasible than combining with EBRT to treat widely metastatic disease, however the effects of TRT on the prostate tumor microenvironment alone and in combinfation with checkpoint blockade have not yet been studied.MethodsC57BL/6 mice-bearing TRAMP-C1 tumors and FVB/NJ mice-bearing Myc-CaP tumors were treated with a single intravenous administration of either low-dose or high-dose 90Y-NM600 TRT, and with or without anti-PD-1 therapy. Groups of mice were followed for tumor growth while others were used for tissue collection and immunophenotyping of the tumors via flow cytometry.Results90Y-NM600 TRT was safe at doses that elicited a moderate antitumor response. TRT had multiple effects on the tumor microenvironment including increasing CD8 +T cell infiltration, increasing checkpoint molecule expression on CD8 +T cells, and increasing PD-L1 expression on myeloid cells. However, PD-1 blockade with TRT treatment did not improve antitumor efficacy. Tregs remained functional up to 1 week following TRT, but CD8 +T cells were not, and the suppressive function of Tregs increased when anti-PD-1 was present in in vitro studies. The combination of anti-PD-1 and TRT was only effective in vivo when Tregs were depleted.ConclusionsOur data suggest that the combination of 90Y-NM600 TRT and PD-1 blockade therapy is ineffective in these prostate cancer models due to the activating effect of anti-PD-1 on Tregs. This finding underscores the importance of thorough understanding of the effects of TRT and immunotherapy combinations on the tumor immune microenvironment prior to clinical investigation.
30
Akil, Hussein, Mercedes Quintana, Jérémy H. Raymond, Tommy Billoux, Valentin Benboubker, Sophie Besse, Philippe Auzeloux, et al. "Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma." Cancers 13, no. 6 (March 20, 2021): 1421. http://dx.doi.org/10.3390/cancers13061421.
Анотація:
Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.
31
Müller, Cristina, Maria De Prado Leal, Marco D. Dominietto, Christoph A. Umbricht, Sairos Safai, Rosalind L. Perrin, Martina Egloff, et al. "Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute." Pharmaceutics 11, no. 9 (September 2, 2019): 450. http://dx.doi.org/10.3390/pharmaceutics11090450.
Анотація:
Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy.
32
Mdanda, Sipho, Lindokuhle M. Ngema, Amanda Mdlophane, Mike M. Sathekge, and Jan Rijn Zeevaart. "Recent Innovations and Nano-Delivery of Actinium-225: A Narrative Review." Pharmaceutics 15, no. 6 (June 13, 2023): 1719. http://dx.doi.org/10.3390/pharmaceutics15061719.
Анотація:
The actinium-225 (225Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the 225Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities for treating several cancers. Accordingly, the importance of nanomaterials in retaining the 225Ac daughters from recoiling into unintended organs has been established. This review expounds on the advancements of targeted radionuclide therapy (TRT) as an alternative anticancer treatment. It discusses the recent developments in the preclinical and clinical investigations on 225Ac as a prospective anticancer agent. Moreover, the rationale for using nanomaterials in improving the therapeutic efficacy of α-particles in targeted alpha therapy (TAT) with an emphasis on 225Ac is discussed. Quality control measures in the preparation of 225Ac-conjugates are also highlighted.
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Sun, M., C. Thomas, F. Orlando, M. Sigouros, J. Osborne, J. Nauseef, A. M. Molina, et al. "1390P Circulating tumor DNA (ctDNA) and prognosis with PSMA-targeted radionuclide therapy (TRT)." Annals of Oncology 33 (September 2022): S1179. http://dx.doi.org/10.1016/j.annonc.2022.07.1522.
34
de Roode, Kim E., Lieke Joosten, and Martin Behe. "Towards the Magic Radioactive Bullet: Improving Targeted Radionuclide Therapy by Reducing the Renal Retention of Radioligands." Pharmaceuticals 17, no. 2 (February 16, 2024): 256. http://dx.doi.org/10.3390/ph17020256.
Анотація:
Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this application. But, a major issue for many radiolabeled low-to-moderate-molecular-weight molecules is their clearance via the kidneys and their subsequent reuptake. High renal accumulation of radioactive compounds may lead to nephrotoxicity, and therefore, the kidneys are often the dose-limiting organs in TRT with these radioligands. Over the years, different strategies have been developed aiming for reduced kidney retention and enhanced therapeutic efficacy of radioligands. In this review, we will give an overview of the efforts and achievements of the used strategies, with focus on the therapeutic potential of low-to-moderate-molecular-weight molecules. Among the strategies discussed here is coadministration of compounds that compete for binding to the endocytic receptors in the proximal tubuli. In addition, the influence of altering the molecular design of radiolabeled ligands on pharmacokinetics is discussed, which includes changes in their physicochemical properties and implementation of cleavable linkers or albumin-binding moieties. Furthermore, we discuss the influence of chelator and radionuclide choice on reabsorption of radioligands by the kidneys.
35
Cortiana, Viviana, Jade Gambill, Harshal Chorya, Diksha Mahendru, Fabiha Amin, Chandler H. Park, and Yan Leyfman. "PSMA-Targeted Therapy: Advancements in Detection and Treatment Modalities with Dr. Scott T. Tagawa." Cancers 16, no. 10 (May 11, 2024): 1833. http://dx.doi.org/10.3390/cancers16101833.
Анотація:
Prostate cancer is one of the most challenging malignancies due to its high incidence and prevalence, as it is the most frequently diagnosed non-skin cancer in men. The timely identification of prostate cancer and its metastasis is paramount for ensuring favorable outcomes for patients. Prostate-specific membrane antigen (PSMA) emerges as a promising biomarker for its detection, due to its specificity. This makes it an ideal target for the early identification of a metastatic phenotype. Situated on the membrane of tumor cells, PSMA facilitates the attachment of PSMA-targeting particles, enabling their detection through positron emission tomography (PET) scans with relative ease. Utilizing these imaging agents in conjunction with PET scans enhances the accuracy of prostate cancer tumor detection compared to PET scans alone. The advancement in prostate cancer imaging has paved the way for innovative treatment modalities. Prostate-specific membrane antigen-targeted radionuclide therapies (PSMA-TRT) exploit PSMA imaging agents to target identified prostate cancer malignancies with precise radiation, thereby reducing or eliminating the tumor mass. PSMA-TRT exhibits significant promise in prostate cancer therapy, evident from the notable declines in prostate-specific antigen (PSA) levels post treatment. However, PSMA-TRT carries both beneficial and adverse effects. While it represents a substantial leap forward in tumor cell imaging, PSMA-based antigens, being larger particles than ligands, offer prolonged imaging capabilities. Yet, the long-term effects of PSMA-TRT remain unknown, with the short-term adverse ones including fatigue, nausea, pain flares, and potential radiation exposure to others.
36
Sun, Michael, Charlene Thomas, Benedict Ho, Muhammad Junaid Niaz, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil Harrison Bander, and Scott T. Tagawa. "Long-term adverse events (AE) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 5055. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5055.
Анотація:
5055 Background: PSMA-TRT is a promising investigational treatment for patients with mCRPC. Expected short-term toxicities associated with PSMA-TRT include dose-dependent myelosuppression and xerostomia. However, there is a lack of information regarding long-term effects of PSMA-TRT on marrow, renal, and liver function. Additionally, potential organ dose limits for radiation are derived from studies of external beam radiation, which may not be applicable to TRT. Methods: Men treated on prospective clinical trials of PSMA-TRT, from 2003 through 2020 with at least six months of follow-up were included. Variables included treatment, co-morbidities, baseline and most recent renal, liver, and marrow function, along with respective short-term ( < 6 months) and long-term toxicities. AEs were graded using CTCAE version 5 and attribution was assessed with most recent clinical follow up. Multivariable logistic regression was used to control for type of TRT, comorbidities, and subsequent therapies. Results: 71 (59.7%) patients who received 177Lu-J591, 30 (25.2%) 177Lu-PSMA-617, 11 (9.2%) 225Ac-J591, and 7 (5.9%) 90Y-J591 were included, with median follow up 18 months (range 6-133). Long-term (most recent) laboratory values and AEs are summarized in the table. A majority of AEs were attributed to alternate etiologies. 5 of 14 cases of grade (Gr) ≥2 creatinine increase, 3 of 36 cases of Gr ≥2 platelets, 2 of 14 cases of Gr ≥2 bilirubin, 1 of 15 cases of Gr ≥2 AST increase, and 1 of 5 cases of Gr ≥2 ALT increase were deemed possibly related to PSMA-TRT. Only two Gr ≥3 AEs were attributed to possibly being related to PSMA-TRT: one case of Gr 4 creatinine elevation and one case of Gr 3 ALT elevation. On multivariable analysis, alpha-TRT was associated with hepatic AEs (OR 4.38, p = 0.047), and there was a trend towards higher Charlson Comorbidity scores associating with hematologic AEs (OR 1.27, p = 0.095). Conclusions: This is the largest analysis to-date of long-term AEs in patients who have received PSMA-TRT. Long-term effects on renal, liver, and marrow function are infrequent.[Table: see text]
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Thomas, Joseph Earl, Jones T. Nauseef, Michael Philip Sun, Amie Patel, Angela Tan, Mahelia Bissassar, Jyothi Manohar, et al. "Increased utilization of prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (PSMA-TRT) in African American (AA) patients at an academic medical center." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 36. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.36.
Анотація:
36 Background: At Weill Cornell Medicine (WCM), we have had a research program utilizing anti-PSMA mAb J591 since the year 2000. With the addition of PSMA ligand-based therapies in 2017, we have enrolled around 300 patients on investigational PSMA-TRT clinical trials. Since the approval of 177Lu-PSMA-617 (Pluvicto; Lu-177 vipivotide tetraxetan), we began standard-of-care (SOC) treatment, co-enrolling willing patients into a research registry. Recognizing the low numbers of AA patients enrolled on therapeutic clinical trials in the U.S., we made a concerted effort to increase the number of AA patients with prostate cancer (PC) enrolled on clinical trials at WCM. We retrospectively assessed the demographic data of patients enrolled on PSMA-TRT clinical trials to determine changing patterns of enrollment, and to determine if our efforts have improved access to these novel treatments for this under-represented, but high-risk population of patients. Methods: We collected demographic data (namely race and ethnicity) on patients with PC from WCM who were included on our PSMA-TRT investigational clinical trial databases or enrolled on our SOC 177Lu-PSMA-617 research registry. We used self-reported race and, when not available (due to patient death or loss of follow-up), demographic information documented in the medical record. Patients were grouped into 5-year cohorts based on either the date of consent for trial enrollment, or the start date of PSMA-TRT treatment (based on available information). Institutional tumor registry data was used as a comparator to assess the total percentage of AA patients with PC seen at WCM. Results: The percentages of patients included on PSMA-TRT clinical trials at WCM who were identified as AA were as follows: 2000-2004: 3.1% (2/65), 2005-2009: 5.1% (3/59), 2010-2014: 6.1% (2/33), and 2015-2019: 5.9% (5/85). The percentage of AA patients on PSMA-TRT studies from 2020 through July 2022 was 18.2% (16/88, inclusive of 8/72 investigational TRT subjects and 8/16 SOC registry participants). The total percentages of AA patients seen at Cornell based upon analysis of our tumor registry data were as follows: 2000-2004: 10.5% (182/1728), 2005-2009: 6.9% (250/3607), 2010-2014: 10% (326/3255), 2015-2019: 11.5% (278/2413), and 2020: 14.1%. Tumor registry data for 2021-present were not yet available. Conclusions: The percentage of AA patients on investigational PSMA-TRT trials at our institution notably increased from 2000-2019 (3.1%-6.1%) to 2020-2022 (11.1%). Moreover, 50% of those treated with 177Lu-PSMA-617 since its FDA approval and co-enrolled on our research registry identified as AA. These data suggest that outreach and increasing access to AA patients for novel PC treatment such as PSMA-TRT can result in increased numbers of underrepresented patients enrolling on clinical trials and receiving the most modern standards of care (i.e., PSMA-TRT).
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Sodji, Quaovi H., Matthew H. Forsberg, Dan Cappabianca, Caroline P. Kerr, Lauren Sarko, Amanda Shea, David P. Adam, et al. "Comparative Study of the Effect of Radiation Delivered by Lutetium-177 or Actinium-225 on Anti-GD2 Chimeric Antigen Receptor T Cell Viability and Functions." Cancers 16, no. 1 (December 30, 2023): 191. http://dx.doi.org/10.3390/cancers16010191.
Анотація:
Background and purpose. Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting. This study investigated the effects of radiation delivered by Lutetium-177 (177Lu) and Actinium-225 (225Ac) on the viability and effector function of CAR T cells in vitro to evaluate the feasibility of such therapeutic combinations. After the irradiation of anti-GD2 CAR T cells with various doses of radiation delivered by 177Lu or 225Ac, their viability and cytotoxic activity against GD2-expressing human CHLA-20 neuroblastoma and melanoma M21 cells were determined by flow cytometry. The expression of the exhaustion marker PD-1, activation marker CD69 and the activating receptor NKG2D was measured on the irradiated anti-GD2 CAR T cells. Both 177Lu and 225Ac displayed a dose-dependent toxicity on anti-GD2 CAR T cells. However, radiation enhanced the cytotoxic activity of these CAR T cells against CHLA-20 and M21 irrespective of the dose tested and the type of radionuclide. No significant changes in the expression of PD-1, CD69 and NKG2D was noted on the CAR T cells following irradiation. Given a lower CAR T cell viability at equal doses and an enhancement of cytotoxic activity irrespective of the radionuclide type, 177Lu-based TRT may be preferred over 225Ac-based TRT when evaluating a potential synergism between these therapies in vivo against solid tumors.
39
Li, Mengshi, Dijie Liu, Dongyoul Lee, Yinwen Cheng, Nicholas J. Baumhover, Brenna M. Marks, Edwin A. Sagastume, et al. "Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma." Cancers 13, no. 15 (July 22, 2021): 3676. http://dx.doi.org/10.3390/cancers13153676.
Анотація:
Radiotherapy can facilitate the immune recognition of immunologically “cold” tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically “cold” tumors throughout the body responsive to ICIs and immunologically “hot”. Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.
40
Everix, Liesbeth, Shankari Nair, Cathryn H. S. Driver, Ingeborg Goethals, Mike M. Sathekge, Thomas Ebenhan, Charlot Vandevoorde, and Julie Bolcaen. "Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma." Cancers 14, no. 7 (April 3, 2022): 1821. http://dx.doi.org/10.3390/cancers14071821.
Анотація:
Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.
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Magee, Kara, Ian R. Marsh, Michelle M. Turek, Joseph Grudzinski, Eduardo Aluicio-Sarduy, Jonathan W. Engle, Ilene D. Kurzman, et al. "Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting." PLOS ONE 16, no. 8 (August 12, 2021): e0255798. http://dx.doi.org/10.1371/journal.pone.0255798.
Анотація:
Rationale Murine syngeneic tumor models have revealed efficacious systemic antitumor responses following primary tumor in situ vaccination combined with targeted radionuclide therapy to secondary or metastatic tumors. Here we present studies on the safety and feasibility of this approach in a relevant translational companion dog model (n = 17 dogs) with advanced cancer. Methods The three component of the combination immuno-radiotherapy approach were employed either separately or in combination in companion dogs with advanced stage cancer. In situ vaccination was achieved through the administration of hypofractionated external beam radiotherapy and intratumoral hu14.18-IL2 fusion immunocytokine injections to the index tumor. In situ vaccination was subsequently combined with targeted radionuclide therapy using a theranostic pairing of IV 86Y-NM600 (for PET imaging and subject-specific dosimetry) and IV 90Y-NM600 (therapeutic radionuclide) prescribed to deliver an immunomodulatory 2 Gy dose to all metastatic sites in companion dogs with metastatic melanoma or osteosarcoma. In a subset of dogs, immunologic parameters preliminarily assessed. Results The components of the immuno-radiotherapy combination were well tolerated either alone or in combination, resulting in only transient low grade (1 or 2) adverse events with no dose-limiting events observed. In subject-specific dosimetry analyses, we observed 86Y-NM600 tumor:bone marrow absorbed-dose differential uptakes ≥2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy 90Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by 90Y-NM600 TRT. Conclusions The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.
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Muralidhar, Anusha, Reinier Hernandez, Zachary S. Morris, Hansel Comas Rojas, Malick Bio Idrissou, Jamey P. Weichert, and Douglas G. McNeel. "Myeloid-derived suppressor cells attenuate the antitumor efficacy of radiopharmaceutical therapy using90Y-NM600 in combination with androgen deprivation therapy in murine prostate tumors." Journal for ImmunoTherapy of Cancer 12, no. 4 (April 2024): e008760. http://dx.doi.org/10.1136/jitc-2023-008760.
Анотація:
RationaleAndrogen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized disease. However, for metastatic castration-resistant prostate cancer, EBRT is typically only used in the palliative setting, because of the inability to radiate all sites of disease. Systemic radiation treatments that preferentially irradiate cancer cells, known as radiopharmaceutical therapy or targeted radionuclide therapy (TRT), have demonstrable benefits for treating metastatic prostate cancer. Here, we explored the use of a novel TRT,90Y-NM600, specifically in combination with ADT, in murine prostate tumor models.Methods6-week-old male FVB mice were implanted subcutaneously with Myc-CaP tumor cells and given a single intravenous injection of90Y-NM600, in combination with ADT (degarelix). The combination and sequence of administration were evaluated for effect on tumor growth and infiltrating immune populations were analyzed by flow cytometry. Sera were assessed to determine treatment effects on cytokine profiles.ResultsADT delivered prior to TRT (ADT→TRT) resulted in significantly greater antitumor response and overall survival than if delivered after TRT (TRT→ADT). Studies conducted in immunodeficient NRG mice failed to show a difference in treatment sequence, suggesting an immunological mechanism. Myeloid-derived suppressor cells (MDSCs) significantly accumulated in tumors following TRT→ADT treatment and retained immune suppressive function. However, CD4+ and CD8+ T cells with an activated and memory phenotype were more prevalent in the ADT→TRT group. Depletion of Gr1+MDSCs led to greater antitumor response following either treatment sequence. Chemotaxis assays suggested that tumor cells secreted chemokines that recruited MDSCs, notably CXCL1 and CXCL2. The use of a selective CXCR2 antagonist, reparixin, further improved antitumor responses and overall survival when used in tumor-bearing mice treated with TRT→ADT.ConclusionThe combination of ADT and TRT improved antitumor responses in murine models of prostate cancer, however, this was dependent on the order of administration. This was found to be associated with one treatment sequence leading to an increase in infiltrating MDSCs. Combining treatment with a CXCR2 antagonist improved the antitumor effect of this combination, suggesting a possible approach for treating advanced human prostate cancer.
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Métivier, Cassandra, Patricia Le Saëc, Joëlle Gaschet, Catherine Chauvet, Séverine Marionneau-Lambot, Peter O. Hofgaard, Bjarne Bogen, et al. "Preclinical Evaluation of a 64Cu-Based Theranostic Approach in a Murine Model of Multiple Myeloma." Pharmaceutics 15, no. 7 (June 25, 2023): 1817. http://dx.doi.org/10.3390/pharmaceutics15071817.
Анотація:
Although the concept of theranostics is neither new nor exclusive to nuclear medicine, it is a particularly promising approach for the future of nuclear oncology. This approach is based on the use of molecules targeting specific biomarkers in the tumour or its microenvironment, associated with optimal radionuclides which, depending on their emission properties, allow the combination of diagnosis by molecular imaging and targeted radionuclide therapy (TRT). Copper-64 has suitable decay properties (both β+ and β- decays) for PET imaging and potentially for TRT, making it both an imaging and therapy agent. We developed and evaluated a theranostic approach using a copper-64 radiolabelled anti-CD138 antibody, [64Cu]Cu-TE1PA-9E7.4 in a MOPC315.BM mouse model of multiple myeloma. PET imaging using [64Cu]Cu-TE1PA-9E7.4 allows for high-resolution PET images. Dosimetric estimation from ex vivo biodistribution data revealed acceptable delivered doses to healthy organs and tissues, and a very encouraging tumour absorbed dose for TRT applications. Therapeutic efficacy resulting in delayed tumour growth and increased survival without inducing major or irreversible toxicity has been observed with 2 doses of 35 MBq administered at a 2-week interval. Repeated injections of [64Cu]Cu-TE1PA-9E7.4 are safe and can be effective for TRT application in this syngeneic preclinical model of MM.
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Vlachostergios, Panagiotis J., Muhammad Junaid Niaz, Seyed Ali Mosallaie, Paul J. Christos, Amy Hackett, Joseph R. Osborne, Yuliya Jhanwar, et al. "Association of noninvasive, radiographic measurement of prostate-specific membrane antigen (PSMA) expression with response to PSMA-targeted radionuclide therapy (TRT)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5013. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5013.
Анотація:
5013 Background: Prostate surface membrane antigen (PSMA) is usually overexpressed in PC and is enriched in castration-resistant tumors. PSMA-TRT is of increasing interest to the field. Many in the field of theranostics have assumed that PSMA uptake on imaging is a pre-requisite for response. We have conducted a number of trials which have incorporated PSMA imaging, but have not selected patients for treatment based upon imaging results and performed an analysis examining the relationship between imaging and response. Methods: Men with mCRPC had either planar radiolabeled J591 imaging (111In-J591 and/or 177Lu-J591) or 68Ga-PSMA11 PET/CT. Visual scores were assigned based upon PSMA uptake in tumors compared to liver uptake and scored on a 0-4 scale. Imaging scores were associated with PSA decline (≥30%, ≥50%) using Cox regression analysis. As several studies were dose-escalation in nature with prior demonstration of dose-response, we controlled for dose administered. Results: 216 men with metastatic CRPC, median PSA 72.45ng/dl, were treated with PSMA-TRT as follows: 177Lu-J591 (n=136), 177Lu-PSMA-617 (n=38), Lu-J591 + Lu-PSMA-617 combination (n=6), 225Ac-J591 (n=7), 90Y-J591 (n=29). 116 (53.7%) pts received low dose and 100 (46.3%) high dose as previously defined in the individual studies. 55 (25.5%) pts had low PSMA expression by imaging (VS 0-1) whereas 161 (74.5%) had high PSMA (VS 2-4). High PSMA expression was associated with more frequent PSA decline (≥30%: 39.2 vs 17.9% p=0.003; ≥50%: 27.5 vs 8.9% p=0.004). When controlling for dose level, this association remained significant for low (≥30%: 25 vs 8.6% p=0.04) and high doses of radionuclide therapy (≥50%: 34.9 vs 9.5% p=0.02). 13 (6%) pts with no PSMA uptake (VS=0) had PSA declines. Conclusions: This is the first study to formally analyze response to PSMA-TRT by PSMA imaging expression in an unselected patient population. The level of PSMA expression measured by imaging is associated with the chance of response. However, a subset of patients without any significant PSMA uptake on imaging did demonstrate response to PSMA-TRT, indicating that imaging cannot exclude all patients that might benefit. Clinical trial information: NCT03545165, NCT03276572, NCT03042468, NCT02552394.
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Reiner, Dora, Matthias Blaickner, and Frank Rattay. "Discrete beta dose kernel matrices for nuclides applied in targeted radionuclide therapy (TRT) calculated withMCNP5." Medical Physics 36, no. 11 (October 2, 2009): 4890–96. http://dx.doi.org/10.1118/1.3231995.
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Sun, Michael, Justin M. Lebenthal, Jones T. Nauseef, Muhammad Junaid Niaz, Sabrina Guervil, Escarleth Fernandez, Amie Patel, et al. "Baseline and post-treatment circulating tumor cell (CTC) counts with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) in men with metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 158. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.158.
Анотація:
158 Background: CTC counts are an independent prognostic factor in men with mCRPC; certain changes following treatment (conversion from detectable to undetectable or unfavorable to favorable) are associated with improved overall survival. Most PSMA-TRT efficacy data have focused on PSA or imaging changes. Here, we describe baseline and post-treatment CTC counts from subjects receiving PSMA-TRT. Methods: Men with mCRPC treated on prospective clinical trials of PSMA-TRT and with available CTC counts (CellSearch) were included in our analysis. Depending upon the era of the trial, post-treatment counts were performed at 4-6 (initial era) or 12 weeks (recent era) after a single cycle of PSMA-TRT (individual trial data reported elsewhere). We describe CTC counts at baseline and compare pre-treatment counts to those after PSMA-TRT. Results: 116 men treated with PSMA-TRT had baseline CTC count (90 with both pre- and post-treatment CTC). Forty-four patients (37.9%) received 177Lu-J951, 46 (39.7%) received 177Lu-PSMA-617, and 26 (22.4%) received 225Ac-J591. Median age was 71.5. Fifty-eight patients (50%) had previously received taxane chemotherapy, median PSA was 82.98 ng/mL, and 66 (56.9%) were in the high-risk Halabi (CALGB) prognostic group. Eighty-nine out of one hundred sixteen (76.7%) had detectable baseline CTC and 58/116 (50%) had unfavorable baseline CTC count. Forty-nine out of seventy (70%) had post-treatment CTC count decline, 23/70 (32.9%) converted from detectable to undetectable, and 17/47 (36.2%) converted from unfavorable to favorable. CTC changes stratified by type of PSMA-TRT are reported in the table. Conclusions: This is the largest analysis of CTC changes in patients who have received PSMA-TRT. In addition to PSA changes and other previously reported outcomes, even when low doses of radionuclide therapy as part of dose-escalation studies are included, the majority with detectable CTC counts have post-treatment CTC count decline. A significant portion of patients experience favorable CTC changes. [Table: see text]
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Fernandes, Célia, Elisa Palma, Francisco Silva, Ana Belchior, Catarina I. G. Pinto, Joana F. Guerreiro, Hugo M. Botelho, Filipa Mendes, Paula Raposinho, and António Paulo. "Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and/or the Cell Nucleus." International Journal of Molecular Sciences 23, no. 13 (June 29, 2022): 7238. http://dx.doi.org/10.3390/ijms23137238.
Анотація:
Although 99mTc is not an ideal Auger electron (AE) emitter for Targeted Radionuclide Therapy (TRT) due to its relatively low Auger electron yield, it can be considered a readily available “model” radionuclide useful to validate the design of new classes of AE-emitting radioconjugates. With this in mind, we performed a detailed study of the radiobiological effects and mechanisms of cell death induced by the dual-targeted radioconjugates 99mTc-TPP-BBN and 99mTc-AO-BBN (TPP = triphenylphosphonium; AO = acridine orange; BBN = bombesin derivative) in human prostate cancer PC3 cells. 99mTc-TPP-BBN and 99mTc-AO-BBN caused a remarkably high reduction of the survival of PC3 cells when compared with the single-targeted congener 99mTc-BBN, leading to an augmented formation of γH2AX foci and micronuclei. 99mTc-TPP-BBN also caused a reduction of the mtDNA copy number, although it enhanced the ATP production by PC3 cells. These differences can be attributed to the augmented uptake of 99mTc-TPP-BBN in the mitochondria and enhanced uptake of 99mTc-AO-BBN in the nucleus, allowing the irradiation of these radiosensitive organelles with the short path-length AEs emitted by 99mTc. In particular, the results obtained for 99mTc-TPP-BBN reinforce the relevance of targeting the mitochondria to promote stronger radiobiological effects by AE-emitting radioconjugates.
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Rao, Yi, Tara Viray, Kurt Gehlsen, Matt Harris, Lachlan McInnes, Olufolake Majekodunmi, and Jason Lewis. "Abstract 6038: Copper-67 based targeted radiotherapy primes immunologically cold PDAC for immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6038. http://dx.doi.org/10.1158/1538-7445.am2024-6038.
Анотація:
Abstract Background and Purpose: Immune checkpoint therapy (ICT) has revolutionized cancer treatment however efficacy remains dismal for some cancers, including pancreatic cancers. Strategies to enhance immune responses include combining ICT with other existing cancer therapies. Targeted radiotherapy (TRT) uses a radiolabeled cancer-targeting vector, allowing for systematic delivery of specific radiation to all tumor sites while minimizing radiation exposure to healthy tissues. We propose Targeted Copper Theranostics (TCTs) as a TRT, utilizing copper-67 to irradiate and prime immunologically “cold” pancreatic adenocarcinoma (PDAC) and evaluate the efficacy of copper-67-based TRT-ICT combination therapy. Methods: We evaluated two tumor-targeting vectors conjugated to a sarcophagine macrobicyclic chelator (SAR), an antibody—5B1, targeting the PDAC-specific biomarker carbohydrate antigen-19-9 (CA19-9), and a peptide RGD, targeting the αvβ3 integrin receptor, which is highly expressed in some PDAC tumors. We administrated ~1.1 MBq of [64Cu]Cu-SAR-bisRGD (~0.1 μg) or [64Cu]Cu-SAR-5B1 (~10 μg) to FC1245 Ft2Ab PDAC (a murine PDAC cell line expressing CA19-9) tumor-bearing C57BL/6 mice and performed biodistribution studies at 1 and 4 h for [64Cu]Cu-SAR-bisRGD-injected mice and at 24 and 48 h for [64Cu]Cu-5B1-injected mice. [67Cu]Cu-SAR-bisRGD- and [67Cu]Cu-SAR-5B1-based dose escalation studies and the combination of a copper-67-based TRT and ICT were performed to evaluate therapeutic efficacy of copper-67-based TRT and potential synergistic effects of combination therapy. Results: Tumor uptake of [64Cu]Cu-SAR-bisRGD is ~5 %ID/g at 4h-post injection, and tumor uptake of [64Cu]Cu-SAR-5B1 is ~55 %ID/g 24h-post injection. In dose escalation studies, administration of ~11, 22, and 37 MBq of [67Cu]Cu-SAR-bisRGD (~1 μg) or administration of ~4, 11, 18 MBq of [67Cu]Cu-5B1(~150 μg) improved overall survival to 25 or 32 days respectively, compared to the control cohort (14 days). Based on weekly whole-blood analyses, no significant radiotoxicity was observed in mice receiving various doses of TRTs. The combination of 11 MBq of either [67Cu]Cu-SAR-bisRGD or [67Cu]Cu-SAR-5B1 in combination with either antiPD-L1/PD1 or antiCTLA4, improved overall survival by ~7 days compared to ICT-treated control groups. Conclusion: Biodistribution studies demonstrated relatively high tumor specific uptake for [64Cu]Cu-SAR-bisRGD and [64Cu]Cu-SAR-5B1. Dose escalation study results suggest copper-67-based TRT could effectively inhibit tumor growth with minimal radiotoxicity. The combination of TRT with ICTs improved overall survival compared to single-ICT-treated control groups. Collectively, our results strongly support the hypothesis that TRT with [67Cu]Cu-SAR-bisRGD or [67Cu]Cu-SAR-5B1 could prime immunologically “cold” pancreatic adenocarcinoma (PDAC) to be responsive to ICTs. Citation Format: Yi Rao, Tara Viray, Kurt Gehlsen, Matt Harris, Lachlan McInnes, Olufolake Majekodunmi, Jason Lewis. Copper-67 based targeted radiotherapy primes immunologically cold PDAC for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6038.
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Ruder, Samuel Francis, Michael Philip Sun, Charlene Thomas, Ana M. Molina, Jones T. Nauseef, Joseph Osborne, Cora N. Sternberg, David M. Nanus, Neil Harrison Bander, and Scott T. Tagawa. "Comparison of adverse event rate of prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) with antibody or small molecule ligand targeting vector." Journal of Clinical Oncology 42, no. 4_suppl (February 1, 2024): 161. http://dx.doi.org/10.1200/jco.2024.42.4_suppl.161.
Анотація:
161 Background: PSMA-targeted radionuclide therapy (PSMA-TRT) has been established with use of either monoclonal antibodies (mAb) or small molecule ligands (SML) as the targeting vectors for delivery of 177Lu to PSMA-expressing prostate cancer. mAb and SML differ in their molecular weight, pharmacokinetics, and biodistribution which is predicted to result in different adverse effect profiles. Methods: In this study with written informed consent, we compare the adverse effects from individual patients receiving PSMA-TRT for mCRPC using mAb (J591) vs SML (PSMA-617 or PSMA I&T) for delivering 177Lu in prospective clinical trials or registry. All-grade treatment-emergent adverse events (TEAEs) were extracted from trial databases. Adverse effects were graded 0-5. Pearson’s Chi-squared test was used to assess TEAEs and association with treatment type. Multivariable logistic regression was used to compare TEAEs after adjusting for administered radioactivity dose and CALGB (Halabi) prognostic score. Results: 248 patients with mCRPC were treated from March 2001 to February 2023. 166 (67.7%) received mAb (177Lu-J591), 81 received SML [76 (30.6%) 177Lu-PSMA-617, 5 (2%) 177Lu-PSMA-I&T)]. The median age was 70.9 years (44.5 yrs to 93.8 yrs). At the time of trial enrollment, 137 (55.2% [68% SML and 49% mAb]) patients had exposure to chemotherapy, 112 (45.1%) had exposure to androgen-receptor pathway therapy, 193 (77.8%) had bone metastases, 120 (48.3%) LN mets, 42 (16.9%) lung mets, and 20 (8.0%) liver mets. 142 (57.2%) had Halabi score high disease. All-grade hematologic TEAEs were more common with mAb: neutropenia in 122 (74%) patients vs 16 (20%) (p<0.001), anemia in 122 (73%) vs 26 (33%) (P<0.001), and thrombocytopenia in 145 (87%) vs 25 (32%) (p<0.001). Gr >3 neutropenia occurred in 79 (47%) and Gr >3 thrombocytopenia in 98 (59%) receiving mAb. All-grade non-hematologic TEAEs were generally more common with SML: fatigue in 31 (53%) vs 79 (48%) (p=0.5), pain in 32 (54%) vs 73 (44%) (p=0.2), nausea in 21 (36%) vs 34 (20%) (p=0.02) and xerostomia in 36 (61%) vs 1 (0.6%) (p<0.001). After adjusting for administered dose and Halabi score, treatment with 177Lu via SML vector was associated with less neutropenia (OR 0.04, 95% CI 0.02-0.09, p<0.001), anemia (OR 0.11, 95% CI 0.06-0.22, p<0.001), and thrombocytopenia (OR 0.04, 95% CI 0.02-0.09, p<0.001) but more nausea (OR 3.2, 95% CI 1.54-6.72, p=0.002) and xerostomia (NA due to low event rate in mAb). Conclusions: As predicted, PSMA-TRT with mAb vs SML is associated with different toxicity profiles. PSMA-TRT with the mAb 177Lu-J591 is more commonly associated with hematologic toxicities compared to the SML 177Lu-PSMA-617 and 177Lu-PSMA-I&T, which are more commonly associated with non-hematologic toxicities.
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Sanchez-Garcia, Manuel, Isabelle Gardin, Rachida Lebtahi, and Arnaud Dieudonné. "A new approach for dose calculation in targeted radionuclide therapy (TRT) based on collapsed cone superposition: validation with90Y." Physics in Medicine and Biology 59, no. 17 (August 6, 2014): 4769–84. http://dx.doi.org/10.1088/0031-9155/59/17/4769.