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Hassan, Raffit, and Mitchell Ho. "Mesothelin targeted cancer immunotherapy." European Journal of Cancer 44, no. 1 (January 2008): 46–53. http://dx.doi.org/10.1016/j.ejca.2007.08.028.
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Yeo, Dannel, Laura Castelletti, Nico van Zandwijk, and John E. J. Rasko. "Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma." Cancers 13, no. 16 (August 4, 2021): 3932. http://dx.doi.org/10.3390/cancers13163932.
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Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.
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Hassan, R., E. Alley, H. Kindler, S. Antonia, T. Jahan, J. Grous, S. Honarmand, et al. "87 Mesothelin-targeted immunotherapy CRS-207 plus chemotherapy as treatment for malignant pleural mesothelioma (MPM)." Lung Cancer 91 (January 2016): S31—S32. http://dx.doi.org/10.1016/s0169-5002(16)30104-0.
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Borgeaud, Maxime, Floryane Kim, Alex Friedlaender, Filippo Lococo, Alfredo Addeo, and Fabrizio Minervini. "The Evolving Role of Immune-Checkpoint Inhibitors in Malignant Pleural Mesothelioma." Journal of Clinical Medicine 12, no. 5 (February 22, 2023): 1757. http://dx.doi.org/10.3390/jcm12051757.
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Malignant pleural mesothelioma (MPM) is a rare cancer usually caused by asbestos exposure and associated with a very poor prognosis. After more than a decade without new therapeutic options, immune checkpoint inhibitors (ICIs) demonstrated superiority over standard chemotherapy, with improved overall survival in the first and later-line settings. However, a significant proportion of patients still do not derive benefit from ICIs, highlighting the need for new treatment strategies and predictive biomarkers of response. Combinations with chemo-immunotherapy or ICIs and anti-VEGF are currently being evaluated in clinical trials and might change the standard of care in the near future. Alternatively, some non-ICI immunotherapeutic approaches, such as mesothelin targeted CAR-T cells or denditric-cells vaccines, have shown promising results in early phases of trials and are still in development. Finally, immunotherapy with ICIs is also being evaluated in the peri-operative setting, in the minority of patients presenting with resectable disease. The goal of this review is to discuss the current role of immunotherapy in the management of malignant pleural mesothelioma, as well as promising future therapeutic directions.
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Luke, Jason J., Fabrice Barlesi, Ki Chung, Anthony W. Tolcher, Karen Kelly, Antoine Hollebecque, Christophe Le Tourneau, et al. "Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors." Journal for ImmunoTherapy of Cancer 9, no. 2 (February 2021): e002015. http://dx.doi.org/10.1136/jitc-2020-002015.
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BackgroundCD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity.MethodsABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression.ResultsFifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population.ConclusionsABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer.Trial registration numberNCT02955251.
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Hassan, R., S. J. Antonia, E. W. Alley, H. L. Kindler, T. Jahan, J. J. Grous, S. Honarmand, et al. "515 CRS-207, a mesothelin-targeted immunotherapy, in combination with standard of care chemotherapy as treatment for malignant pleural mesothelioma (MPM)." European Journal of Cancer 51 (September 2015): S108. http://dx.doi.org/10.1016/s0959-8049(16)30316-1.
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Xiao, Zebin, Leslie A. Hopper, Meghan C. Kopp, Emily McMillan, Yue Li, Richard L. Barrett, and Ellen Puré. "Abstract C009: Disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells enhances anti-tumor immunity and immunotherapy." Cancer Research 82, no. 22_Supplement (November 15, 2022): C009. http://dx.doi.org/10.1158/1538-7445.panca22-c009.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to the poor response to current therapeutic treatments. A major barrier to effective treatment of PDAC is the extensive remodeling of tumor stroma characterized by accumulation of cancer associated fibroblasts (CAFs) and extracellular matrix which forms a physical barrier that limits access of the drugs to the cancer cells, suppresses the immune system, and attenuates efficacy of immunotherapies. Fibroblast activation protein (FAP) is highly expressed in a pro-tumorigenic subset of CAFs in PDAC. We hypothesized that depletion of FAP+-CAFs would deplete extracellular matrix (ECM) and reduce the immune suppressive function of the stroma and thereby enhance the efficacy of tumor antigen targeted CAR T cell therapy in PDAC. Using real-time tumor fragment-based 2-photon microscopy, multiparametric flow cytometry and multiplexed immunofluorescence staining, we showed that FAP targeted CAR T cells (FAP-CAR T) efficiently traffic into tumors compared with tumor-antigen (mesothelin) targeted CAR (Meso-CAR) T cells which were trapped in the stroma-rich or matrix-dense areas and led to depletion of immunosuppressive FAP+ cells and reprogrammed the fibrillar collagen network surrounding tumor nests, advancing the infiltration of FAP-CAR T cells into tumor nests. Strikingly, FAP-CAR T cell-mediated depletion for FAP+ cells also rendered the tumor microenvironment permissive to the infiltration and anti-tumor activity of tumor antigen meso-CAR T cells. Moreover, ablation of FAP+ cells markedly enhanced endogenous T cell infiltration which further enhanced anti-tumor immunity and immunotherapy in PDAC models. Thus, our findings established that FAP-CAR T cell-mediated ablation of immunosuppressive FAP+-CAFs and disruption of the desmoplastic stroma they generate, can enhance accumulation and functionality of endogenous anti-tumor immunity and CAR-T cell therapy in the context of highly desmoplastic solid tumors. Citation Format: Zebin Xiao, Leslie A. Hopper, Meghan C. Kopp, Emily McMillan, Yue Li, Richard L Barrett, Ellen Puré. Disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells enhances anti-tumor immunity and immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C009.
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Adusumilli, Prasad S., Marjorie Glass Zauderer, Valerie W. Rusch, Roisin O'Cearbhaill, Amy Zhu, Daniel Ngai, Erin McGee, et al. "Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2511. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2511.
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2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.
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Hermanson, David L., Zhenya Ni, David A. Knorr, Laura Bendzick, Lee J. Pribyl, Melissa Geller, and Dan S. Kaufman. "Functional Chimeric Antigen Receptor-Expressing Natural Killer Cells Derived From Human Pluripotent Stem Cells." Blood 122, no. 21 (November 15, 2013): 896. http://dx.doi.org/10.1182/blood.v122.21.896.896.
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Abstract Natural killer (NK) cells are a key part in the innate immune system and have the ability to recognize diverse types of tumors and virally-infected targets. NK cells represent an attractive cell population for adoptive immunotherapy due to their ability to kill target cells in a human leukocyte antigen (HLA) non-restricted manner and without prior sensitization. Clinical studies using IL-2 activated NK cells demonstrate significant anti-tumor effects when adoptively transferred into patients with refractory leukemia (mainly AML). However, there has been a more limited response observed in clinical trials for the treatment of ovarian cancer and other solid malignancies. Chimeric antigen receptors (CARs) consist of an antigen-specific single chain antibody variable fragment fused to intracellular signaling domains derived from receptors involved in lymphocyte activation. CARs targeting various tumor-associated antigens have been developed and tested via expression in primary T cells with promising clinical results. However, engineering these T cells must be done on a patient-specific basis, thus limiting the number of patients who can be treated. In order to produce a potential targeted, “off-the-shelf” product suitable to treat patients with diverse tumors or chronic infections, we have generated human pluripotent stem cells with stable CAR expression. Previous studies by our group demonstrate that human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide an accessible, genetically tractable, and homogenous starting cell population to develop NK cells. We use a combined approach using “Spin-EB”- mediated differentiation of hESCs/iPSCs, followed by co-culture with artificial antigen presenting cells (aAPCs) that express mbIL-21. Using this strategy, we can generate 109 NK cells from a population of approximately 106 undifferentiated hESCs or iPSCs. This GMP compatible method is fully defined, without xenogeneic stromal cells or serum. Here, we have expressed both an anti-CD19 (targeting B cell malignancies) and an anti-mesothelin CAR (targeting ovarian cancer cells and other adenocarcinomas) in both hESCs and iPSCs. Using the Sleeping Beauty transposon system, both hESCs and iPSCs have been genetically engineered to express 3rd generation CARs, which express a single chain antibody fragment recognizing either CD19 or mesothelin, a CD8α hinge region, the transmembrane protein CD28, a co-stimulatory protein 4-1BB, and the activating domain CD3ζ. NK cells derived from hESCs/iPSCs with or without CAR expression are phenotypically similar to NK cells isolated from peripheral blood. These NK cells are CD56+, CD94+/CD117-, Nkp44+, Nkp46+, NKG2A+, NKG2D+, and KIR+. In 51Cr release assays against tumor targets expressing either CD19 or mesothelin, NK cells expressing the corresponding CAR show an enhanced killing ability. In cell lines lacking CD19 or mesothelin expression, the engineered cell lines exhibit equal activity compared to their non-engineered counterparts. Specifically, at a 10:1 effector:target ratio, anti-CD19 CAR+ iPSC-NK cells kill 58% of Lax7R cells (a CD19+ ALL cell line) compared to just 5% cell killing by CAR- iPSC-NK cells. Anti-CD19 CAR+ iPSC-NK cells also killed 2 other CD19+ ALL cell lines (018Z and Raji) better than CAR- iPSC-NK cells killing 63% vs 18% and 61% vs 8%, respectively. Similar results are seen against the mesothelin+ ovarian tumor line A1847. Here, anti-mesothelin CAR+ iPSC-NK cells kill 39% vs 14% for CAR- iPSC-NK cells. Currently, CAR-expressing NK cells derived from hESCs and iPSCs are being tested in vivo against both mesothelin+ ovarian tumor lines and CD19+ leukemia cells. Together, these studies demonstrate engineering hESCs and iPSCs with tumor-specific receptors provides a novel strategy to produce targeted NK cells suitable for immune therapies against refractory malignancies. Disclosures: No relevant conflicts of interest to declare.
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Glez-Vaz, Javier, Arantza Azpilikueta, Irene Olivera, Assunta Cirella, Alvaro Teijeira, Maria C. Ochoa, Maite Alvarez, et al. "Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies." Journal for ImmunoTherapy of Cancer 10, no. 3 (March 2022): e003532. http://dx.doi.org/10.1136/jitc-2021-003532.
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BackgroundOn the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic.MethodsWe used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression.ResultsCD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137.ConclusionsCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.
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Banerji, Shantanu, Daniel E. Meyers, Craig Harlos, and David E. Dawe. "The Role of Immunotherapy in the Treatment of Malignant Pleural Mesothelioma." Current Oncology 28, no. 6 (November 8, 2021): 4542–52. http://dx.doi.org/10.3390/curroncol28060385.
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Malignant pleural mesothelioma is a rare and aggressive malignancy arising from mesothelial cells that line the serous membranes of the body. Cytotoxic chemotherapy has been a mainstay of therapy, resulting in a modest improvement in overall survival, but toxicity limits the eligible patient population. Few targeted agents beyond bevacizumab have demonstrated superior efficacy compared to placebos. With an improved understanding of the relationship between the immune system and cancer progression, immunotherapies are playing a greater role in the treatment of many cancers. Several early- and late-phase trials in malignant pleural mesothelioma, including assessments of the first-line efficacy of combination ipilimumab/nivolumab treatment, have now demonstrated promising results for both immune checkpoint inhibition and cell-based therapies. These immune therapies are likely to play a central role in the treatment of this disease going forward.
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Xu, Chunxiao, Brain Rabinovich, Amit Deshpande, Xueyuan Zhou, Frederic Christian Pipp, Rene Schweickhardt, Lindsay Webb, et al. "757 M9657, a novel tumor-targeted conditional anti-CD137 agonist displays MSLN-dependent anti-tumor immunity." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A792. http://dx.doi.org/10.1136/jitc-2021-sitc2021.757.
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BackgroundThe costimulatory receptor CD137 (also known as 4-1BB and TNFRSF9) plays an important role in sustaining effective cytotoxic T cell immune responses and its agonism has been investigated as a cancer immunotherapy. In clinical trials, the systemic administration of the 1st generation CD137 agonist monotherapies, utomilumab and urelumab, were suspended due to either low anti-tumor efficacy or hepatotoxicity mediated by recognized epitope on CD137 and FcγR ligand-dependent clustering.MethodsM9657, a bispecific antibody was engineered a tetravalent bispecific antibody (mAb2) format with the Fab portion binding to the tumor antigen Mesothelin (MSLN) and a modified CH2-CH3 domain as Fc antigen binding (Fcab) portion binding to CD137. M9657 has a human IgG1 backbone with LALA mutations to abrogate the binding to Fcγ receptor. The biological characteristics and activities of M9657 were investigated in a series of in vitro assays and the in vivo efficacy was investigated in syngeneic tumor models with FS122m, a murine-reactive surrogate with the same protein structure of M9657.ResultsM9657 binds efficiently to both human and Cynomolgus CD137 as well as MSLN. In the cellular functional assay, M9657 displayed MSLN- and TCR/CD3 interaction (signal 1)-dependent cytokine release and tumor cell cytotoxicity associated with Bcl-XL activation and immune memory formation. FS122m demonstrated potent MSLN- and dose- dependent in vivo anti-tumor efficacy (figure 1). Comparing with 3H3, a Urelumab surrogate Ab, FS122m displayed an improved therapeutic window with significantly lower for on-target /off-tumor toxicity.ConclusionsTaken together, M9657 exhibits a promising developability profile as a tumor-targeted immune agonist with potent anti-cancer activity, but without systemic immune activation.Ethics ApprovalAll animal experiments were performed in accordance with EMD Serono Research & Development Institute (protocol 17-008, 20-005) and Wuxi AppTec Animal Care and Use Committee (IACUC) guidelines.Abstract 757 Figure 1FS122m displayed dose-dependent anti-tumor efficacy
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Liu, Jiangyue, Xianhui Chen, Jason Karlen, Alfonso Brito, Tiffany Jheng, Philippe Foubert, Janani Krishnamurthy, Yannick Bulliard, and Blake Aftab. "98 ATA3271: an armored, next-generation off-the-shelf, allogeneic, mesothelin-CAR T cell therapy for solid tumors." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A109. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0098.
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BackgroundMesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with high expression levels in an array of malignancies including mesothelioma, ovaria, non-small cell lung cancer, and pancreatic cancers and is an attractive target antigen for immune-based therapies. Early clinical evaluation of autologous MSLN-targeted chimeric antigen receptor (CAR)-T cell therapies for malignant pleural mesothelioma has shown promising acceptable safety1 and have recently evolved with incorporation of next-generation CAR co-stimulatory domains and armoring with intrinsic checkpoint inhibition via expression of a PD-1 dominant negative receptor (PD1DNR).2 Despite the promise that MSLN CAR-T therapies hold, manufacturing and commercial challenges using an autologous approach may prove difficult for widespread application. EBV T cells represent a unique, non-gene edited approach toward an off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently being evaluated in phase 3 trials [NCT03394365] and, to-date, have demonstrated a favorable safety profile including limited risks for GvHD and cytokine release syndrome.3 4 Clinical proof-of-principle studies for CAR transduced allogeneic EBV T cell therapies have also been associated with acceptable safety and durable response in association with CD19 targeting.5 Here we describe the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy targeting MSLN and incorporating PD1DNR, designed for the treatment of solid tumor indications.MethodsWe generated allogeneic MSLN CAR+ EBV T cells (ATA3271) using retroviral transduction of EBV T cells. ATA3271 includes a novel 1XX CAR signaling domain, previously associated with improved signaling and decreased CAR-mediated exhaustion. It is also armored with PD1DNR to provide intrinsic checkpoint blockade and is designed to retain functional persistence.ResultsIn this study, we characterized ATA3271 both in vitro and in vivo. ATA3271 show stable and proportional CAR and PD1DNR expression. Functional studies show potent antitumor activity of ATA3271 against MSLN-expressing cell lines, including PD-L1-high expressors. In an orthotopic mouse model of pleural mesothelioma, ATA3271 demonstrates potent antitumor activity and significant survival benefit (100% survival exceeding 50 days vs. 25 day median for control), without evident toxicities. ATA3271 maintains persistence and retains central memory phenotype in vivo through end-of-study. Additionally, ATA3271 retains endogenous EBV TCR function and reduced allotoxicity in the context of HLA mismatched targets. ConclusionsOverall, ATA3271 shows potent anti-tumor activity without evidence of allotoxicity, both in vitro and in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers and warrant further clinical investigation.ReferencesAdusumilli PS, Zauderer MG, Rusch VW, et al. Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Cancer Research 2019;79:CT036-CT036.Kiesgen S, Linot C, Quach HT, et al. Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial. Cancer Research 2020;80:LB-378-LB-378.Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 2020;130:733–747.Prockop S, Hiremath M, Ye W, et al. A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy. Blood 2019; 134: 5326–5326.Curran KJ, Sauter CS, Kernan NA, et al. Durable remission following ‘Off-the-Shelf’ chimeric antigen receptor (CAR) T-Cells in patients with relapse/refractory (R/R) B-Cell malignancies. Biology of Blood and Marrow Transplantation 2020;26:S89.
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Kawalekar, Omkar Uday, Avery D. Posey, Joseph Fraietta, Jihyun Lee, John Scholler, Yangbing Zhao, and Carl H. June. "Distinct Signaling By Chimeric Antigen Receptors (CARs) Containing CD28 Signaling Domain Versus 4-1BB In Primary Human T Cells." Blood 122, no. 21 (November 15, 2013): 2902. http://dx.doi.org/10.1182/blood.v122.21.2902.2902.
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Abstract Background Chimeric Antigen Receptors (CARs) have shown great promise in the field of targeted adoptive immunotherapy against cancer. These receptors are specific for tumor antigens and have the binding properties of monoclonal antibodies with signaling molecules of T cells. When expressed on T cells, these receptors help the cells home to tumor targets and perform their cytotoxic functions. CARs containing the 4-1BB signaling domain have been used against B-cell chronic lymphocytic leukemia and have shown the most clinical success in terms of tumor targeting and persistence in patients upon engraftment. In contrast, their CD28-containing CAR counterpart failed to show comparable persistence in patients. Despite extensive clinical use, the detailed molecular mechanisms involved in the activation of CAR-grafted T cells remain elusive. To address this, we hypothesize that CARs take advantage of the endogenous T cell receptor (TCR) signaling pathways in a manner unique to their analogous intracellular domains. Methods By electroporation of CAR encoding in vitro transcribed RNA into primary human T cells, we achieved >90% CAR-positive T cell population. We expressed different CARs constructs, all specific for a widely expressed tumor antigen - mesothelin. Keeping the scFv region constant to SS1 that is specific for mesothelin, we varied the intracellular signaling domains (ICDs) ranging from first generation CARs (containing only the CD3z ICD) to the second generation CARs (CD28-CD3z or 41BB-CD3z ICDs) Upon verifying CAR expression by flow cytometry, these T cells were stimulated with mesothelin antigen to analyze differences in signaling between the different CAR groups. Results Here we report that CARs with CD28 show stronger activation of T cells when compared to CARs with 4-1BB or CD3z alone. Stimulation of different CAR constructs revealed that the antigen-specific activation threshold for CAR-T cells is greatly reduced when the CD28 endodomain is included in the CAR architecture. This activation state, measured by the activation of proximal signaling proteins, as well as the MAPK and Akt signaling pathways continues to increase and persist for longer time durations in T cells with the CD28-containing CAR construct. Co-immunoprecipitation studies reveal direct interaction of CARs with pZAP70 and TRAF proteins, but not other known signaling molecules of the TCR complex. T cells with CARs containing CD28 intracellular domain showed a high and sustained level of calcium flux in comparison to T cells with the 4-1BB containing CARs. Experiments to determine the molecular signatures of CAR-grafted T cells stimulated with cognate antigen for longer time durations are currently underway. Taken together, these studies have significant impact on the future design of CARs and adoptive immunotherapy. Disclosures: Kawalekar: Novartis: Research Funding. Posey:Novartis: Research Funding. Fraietta:Novartis: Research Funding. Lee:Novartis: Research Funding. Zhao:Novartis: Research Funding. June:Novartis: Research Funding.
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Glez-Vaz, Javier, Arantza Azpilikueta, Irene Olivera, Assunta Cirella, Álvaro Teijeira, Carmen Ochoa, Maite Álvarez, et al. "Abstract 628: Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 628. http://dx.doi.org/10.1158/1538-7445.am2022-628.
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Abstract Background: On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved Chimeric Antigen Receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and co-stimulation of T cells will facilitate clinical development of CD137 agonists in the clinic. Methods: We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both of the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored upon treatment with agonist anti-CD137 mAbs. Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-Mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISAs and Luminex and flow cytometry was used to monitor CD137 surface expression. Results: CD137 co-stimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 co-stimulation inside subcutaneous implanted Matrigel® plugs. CD137 signaling domain-containing CAR T cells readily released sCD137 upon antigen recognition in a manner favored by the CD137 signaling domain. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137. Conclusion: sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic co-stimulatory activity elicited by agonist CD137-targeted agents. Citation Format: Javier Glez-Vaz, Arantza Azpilikueta, Irene Olivera, Assunta Cirella, Álvaro Teijeira, Carmen Ochoa, Maite Álvarez, Iñaki Eguren, Carlos Luri-Rey, Miguel F. Sanmamed, Ignacio Melero. Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies [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 628.
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Thyparambil, Sheeno P., Wei-Li Liao, Robert Heaton, Amanda Strasbaugh, Marya Abebe Melkie, and Xuefeng Ling. "Proteomic profiling of antibody-drug conjugate (ADC) biomarkers in pancreatic cancer." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 671. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.671.
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671 Background: Pancreatic cancer (PaC) is a highly fatal disease with a 5-year survival rate of 5-10%. Effective screening is not available, and most patients (50-55%) present with metastatic (50%-55%) disease at diagnosis. For patients with advanced PaC, the standard chemotherapy combinations include FOLFIRINOX and/or gemcitabine/nab-paclitaxel which has results in a overall survival of 7-11 months. The lack of effective therapies underscores the importance of exploring other agents. We propose that quantitating therapy-associated protein biomarkers including markers of antibody-drug conjugates (ADC) can improve treatment personalization for PaC. Methods: FFPE tumor tissues from 185 clinical PaC patients were microdissected and solubilized for mass spectrometry-based targeted proteomic analysis. We quantified biomarkers for ADCs simultaneously from 2-3 section of FFPE. These biomarkers include antibody targets such as EGFR, HER2, HER3, FRalpha, and Trop2 and payload biomarkers of sensitivity (TOPO1) and resistance (TUBB3). The multiplexed assay also quantified additional 65 clinically relevant protein biomarkers for chemotherapy, immunotherapy and targeted therapy. Results: Expression of EGFR was observed in majority of samples (88%) while only overexpressed ( > 1000 amol/µg) in 3% of samples. HER2 was expressed in half of patients (52%) and overexpressed ( > 750 amol/µg) in 5% of cases while the rest of HER2 protein expression ranged from 300 -750 amol/µg which corresponds to low Her2 expression. Trop2 was expressed in majority of patients (91%) with a 25x distribution between lowest and highest expressor. Other ADC biomarkers include HER3(55%, 5x), Axl (24%, 12x), Mesothelin (65%, 58x), Folate receptor alpha (10%, 17x). Expression of TUBB3 (77%, 8x) and TOPO1 (92%, 8x) in antibody target-positive subset may suggest resistance or response for several known payloads, such as taxanes and irinotecan/deruxtecan/govitecan, respectively. Conclusions: There is currently no approved ADC for pancreatic cancer, but several ADC clinical trials are underway. Quantitative proteomics identified antibody targets as well as markers of resistance or response to payloads for a variety of approved and investigational ADC therapies, which could aid in patient stratification in ADC clinical trials.
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Oda, Shannon, Leah Schmidt, Ashley Thelen, Cody Jenkins, Edison Chiu, Aitong Ruan, and Philip Greenberg. "Abstract PR008: Overcoming PDAC T cell therapy barriers with CD47-targeted costimulatory fusion proteins." Cancer Research 82, no. 22_Supplement (November 15, 2022): PR008. http://dx.doi.org/10.1158/1538-7445.panca22-pr008.
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Abstract T cell therapy is a promising immunotherapy treatment option that uses genetically modified immune cells (T cells) to eliminate tumors. This approach uses the patients’ own immune cells to generate a “living drug” and can avoid the toxic side effects of other common therapies, such as radiation or chemotherapies. However, the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) can establish several obstacles to protect the tumor from T cells, including delivery of inhibitory and death signals that shut down T cells, usurping metabolic nutrients, and recruiting and/or converting immune cells to inhibitory phenotypes that block the T cell response. CD47 is upregulated in PDAC tumors, and patients with CD47hi tumors exhibit worse survival. CD47 serves as a “don’t eat me” signal by binding to the SIRPα receptor on macrophages to block phagocytosis. CD47 expression also inhibits T cell-mediated tumor rejection by blocking cross-presentation of tumor antigens by SIRPα+ dendritic cells. Reagents that interfere with SIRPα-CD47 signaling, such as monoclonal antibodies, are currently in clinical trials and have been shown to synergize with chemotherapy in PDA models, but native CD47 expression can produce erythrocyte and platelet depletion. Costimulatory signals delivered by surface-bound receptors can initiate gene expression programs that address multiple issues in the PDAC TME by mechanisms such as lowering the threshold of activation, altering metabolic programming, and reducing exhaustion. We develop engineering strategies to deliver costimulatory signals to engineered T cells. Immunomodulatory fusion proteins (IFPs) combine the ectodomain of an inhibitory T cell receptor with an intracellular costimulatory signaling domain and we have shown in proof-of-concept studies that this effectively “replaces a brake with an accelerator” in CD8 T cells. We have found that generating IFPs is not as simple as indiscriminately fusing any two proteins together and we have developed critical design concepts that inform the selection of the fusion site, ectodomain and costimulatory signaling domain pairing, and immunological synapse localization to enhance signaling. To develop a CD47-targeted IFP, we combined the SIRPa ectodomain with the CD28 signaling endodomain and tested this technology with our mesothelin-targeted TCR-T cell platform. In in vitrostudies, SIRPa-CD28 T cells exhibited enhanced proliferation, accumulation, and tumor cytotoxicity. SIRPa IFP-T cells exhibited increased intratumoral accumulation and therapeutic efficacy in the KrasLSL-G12D/+; Trp53LSL-R172H/+;p48Cre/+ (KPC) model, without toxicity or erythrocyte depletion. Here we describe how a thoughtfully engineered fusion protein can “armor” T cells against multiple obstacles and significantly improve therapeutic efficacy against PDAC. Citation Format: Shannon Oda, Leah Schmidt, Ashley Thelen, Cody Jenkins, Edison Chiu, Aitong Ruan, Philip Greenberg. Overcoming PDAC T cell therapy barriers with CD47-targeted costimulatory fusion proteins [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR008.
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Wang, Guanmeng, Xin Zhou, Giovanni Fucà, Elena Dukhovlinova, Peishun Shou, Hongxia Li, Colette Johnston, Brian Mcguinness, Gianpietro Dotti, and Hongwei Du. "Fully human antibody VH domains to generate mono and bispecific CAR to target solid tumors." Journal for ImmunoTherapy of Cancer 9, no. 4 (April 2021): e002173. http://dx.doi.org/10.1136/jitc-2020-002173.
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BackgroundChimeric antigen receptor (CAR) T cells are effective in B-cell malignancies. However, heterogeneous antigen expression and antigen loss remain important limitations of targeted immunotherapy in solid tumors. Therefore, targeting multiple tumor-associated antigens simultaneously is expected to improve the outcome of CAR-T cell therapies. Due to the instability of single-chain variable fragments, it remains challenging to develop the simultaneous targeting of multiple antigens using traditional single-chain fragment variable (scFv)-based CARs.MethodsWe used Humabody VH domains derived from a transgenic mouse to obtain fully human prostate-specific membrane antigen (PSMA) VH and mesothelin (MSLN) VH sequences and redirect T cell with VH based-CAR. The antitumor activity and mode of action of PSMA VH and MSLN VH were evaluated in vitro and in vivo compared with the traditional scFv-based CARs.ResultsHuman VH domain-based CAR targeting PSMA and MSLN are stable and functional both in vitro and in vivo. VH modules in the bispecific format are capable of binding their specific target with similar affinity as their monovalent counterparts. Bispecific CARs generated by joining two human antibody VH domains can prevent tumor escape in tumor with heterogeneous antigen expression.ConclusionsFully human antibody VH domains can be used to generate functional CAR molecules, and redirected T cells elicit antitumoral responses in solid tumors at least as well as conventional scFv-based CARs. In addition, VH domains can be used to generate bispecific CAR-T cells to simultaneously target two different antigens expressed by tumor cells, and therefore, achieve better tumor control in solid tumors.
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Gopalakrishnapillai, Anilkumar, Colin Correnti, Anne Kisielewski, Allison Kaeding, Soheil Meshinchi, E. Anders Kolb, and Sonali Barwe. "Mesothelin Targeting Bites for Pediatric AML: In Vivo Efficacy and Specificity." Blood 134, Supplement_1 (November 13, 2019): 3925. http://dx.doi.org/10.1182/blood-2019-130941.
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Acute myeloid leukemia (AML) remains the type of pediatric leukemia with poorest outcome. Despite maximally intensive therapy, approximately 20% of patients experience recurrent disease. Novel targeted therapies are needed to improve survival. We recently identified that mesothelin, a well-validated target in some cancers, is also highly expressed in a subset of pediatric AML samples (Tarlock et al., Blood, 128:2873, 2016). Considering that it is not expressed in normal tissues in children (Fan et al., Blood, 130:3792, 2017), MSLN is a viable target for immunotherapies such as Bispecific T-cell Engaging antibodies (BiTEs) that combine antibody single chain variable (scFv) regions targeting a cancer antigen and the T-cell co-receptor CD3. We designed and tested the efficacy and specificity of BiTEs targeting MSLN in disseminated xenograft models of pediatric AML. Using scFv sequences derived from Amatuximab, which recognizes the N-terminal domain of the GPI-linked ectodomain of MSLN, targeting region 1 of MSLN, and from Blinatumomab/AMG-330 targeting CD3, we engineered and expressed two kinds of BiTE molecules - a canonical BiTE and an IgG BiTE, a larger molecule with improved serum half life in vivo. To evaluate the specificity and efficacy of canonical BiTEs, MV4;11-MSLN cell line was generated by lentiviral transduction of parental MV4;11 cells which do not constitutively express MSLN (Fig. 1A, B). These two cell lines were injected i.v. into NSG-SGM3 mice. Once engraftment was confirmed, purified human T cells (3 x 106) were injected to act as effector cells. Mice were then treated with the canonical αMSLN-αCD3 BiTE at a dose of 3 mg/kg/day daily for 6 days. A cohort of mice that were untreated or received BiTE or T-cell infusion only served as controls. Mice from both treated and untreated groups had to be euthanized when they presented with distended abdomens due to myeloid sarcomas and no significant differences in survival were observed. Post euthanasia, bone marrows were flushed and evaluated for the percentage of AML cells (human CD45+CD33+) and T cells (human CD45+CD3+). We observed that the αMSLN-αCD3 BiTE was effective in promoting T-cell activation (based on high T-cell counts compared to mice injected with T-cells alone) and greatly reducing leukemic burden in mice injected with MV4;11 cells engineered to express MSLN (Fig. 1C, D). Similar results were obtained using BiTEs targeting a different MSLN epitope. No T-cell expansion and anti-leukemic effect was observed in mice engrafted with parental MV4;11 cells. Although, there were no significant differences between the median survival of untreated and treated miceThese data highlight the specificity and efficacy of the aMSLN-CD3 BiTEs. Among a panel of 8 AML patient-derived xenograft (PDX) lines generated in the laboratory, NTPL-146 bearing MLL-ENL fusion was found to have endogenous MSLN expression (Fig. 1E). We evaluated the efficacy of αMSLN-αCD3 canonical BiTE (3 mg/Kg Qdx6) against NTPL-146 PDX line in NSG-B2m mice by transfusing human CD3+ T-cells to act as effector cells. A Kaplan-Meier survival plot based on the time when each mouse reached experimental end-point (reduced body weight greater than 20%, impaired mobility, hind limb paralysis) showed that the survival benefit for mice receiving BiTE in the presence of human T-cells (4/6 mice survived at the end of experiment) greatly exceeded the efficacy of T-cells alone (22-day improvement in median survival with no surviving mice), or BiTE treatment alone (no improvement in survival) compared to untreated mice (Fig. 1F, P<0.001). These data validate the efficacy of MSLN targeting BiTEs in a PDX model with endogenous MSLN expression. The efficacy of canonical vs IgG BiTEs was evaluated in MV4;11-MSLN xenografted mice. Mice were dosed Qd5x3 for canonical BiTE and Q7dx3 for IgG BiTE as shown (Fig. 1G). IgG BiTE treatment along with T-cell infusion significantly prolonged survival in mice transplanted with MV4;11-MSLN (Fig. 1H), suggesting that IgG BiTE was far more efficacious than canonical BiTEs (P<0.01). Taken together, these data indicate that MSLN-targeting BiTEs could be used as novel immunotherapy for pediatric AML with MSLN expression. Figure 1 Disclosures Kaeding: Celgene: Employment.
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Hua, Timothy, Ziwei Zeng, Junji Chen, Yu Xue, Yan Li, and Qing-Xiang Sang. "Human Malignant Rhabdoid Tumor Antigens as Biomarkers and Potential Therapeutic Targets." Cancers 14, no. 15 (July 28, 2022): 3685. http://dx.doi.org/10.3390/cancers14153685.
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Introduction: Atypical teratoid rhabdoid tumor (ATRT) is a lethal type of malignant rhabdoid tumor in the brain, seen mostly in children under two years old. ATRT is mainly linked to the biallelic inactivation of the SMARCB1 gene. To understand the deadly characteristics of ATRT and develop novel diagnostic and immunotherapy strategies for the treatment of ATRT, this study investigated tumor antigens, such as alpha-fetoprotein (AFP), mucin-16 (MUC16/CA125), and osteopontin (OPN), and extracellular matrix modulators, such as matrix metalloproteinases (MMPs), in different human malignant rhabdoid tumor cell lines. In addition, the roles of MMPs were also examined. Materials and methods: Five human cell lines were chosen for this study, including two ATRT cell lines, CHLA-02-ATRT and CHLA-05-ATRT; a kidney malignant rhabdoid tumor cell line, G401; and two control cell lines, human embryonic kidney HEK293 and HEK293T. Both ATRT cell lines were treated with a broad-spectrum MMP inhibitor, GM6001, to investigate the effect of MMPs on cell proliferation, viability, and expression of tumor antigens and biomarkers. Gene expression was examined using a reverse transcription polymerase chain reaction (RT-PCR), and protein expression was characterized by immunocytochemistry and flow cytometry. Results: All the rhabdoid tumor cell lines tested had high gene expression levels of MUC16, OPN, AFP, and MSLN. Low expression levels of neuron-specific enolase (ENO2) by the two ATRT cell lines demonstrated their lack of neuronal genotype. Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) and tissue inhibitor of metalloproteinases-2 (TIMP-2) were highly expressed in these malignant rhabdoid tumor cells, indicating their invasive phenotypes. GM6001 significantly decreased ATRT cell proliferation and the gene expression of MSLN, OPN, and several mesenchymal markers, suggesting that inhibition of MMPs may reduce the aggressiveness of rhabdoid cancer cells. Conclusion: The results obtained from this study may advance our knowledge of the molecular landscapes of human malignant rhabdoid tumors and their biomarkers for effective diagnosis and treatment. This work analyzed the expression of human malignant rhabdoid tumor antigens that may serve as biomarkers for the development of novel therapeutic strategies, such as cancer vaccines and targeted and immunotherapies targeting osteopontin and mesothelin, for the treatment of patients with ATRT and other malignant rhabdoid tumors.
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Hatterer, E., X. Chauchet, F. Richard, L. Barba, V. Moine, L. Chatel, N. Fischer, et al. "P01.07 Targeting a membrane proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on tumor cells." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A11.1—A11. http://dx.doi.org/10.1136/jitc-2020-itoc7.20.
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BackgroundMesothelin (MSLN) is recognized as a relevant tumor-associated antigen for cancer immunotherapy, because of its overexpression on various solid tumors, including mesothelioma, pancreatic, lung, gastric and ovarian carcinoma. However, an anti-MSLN monoclonal antibody (mAb), amatuximab, has demonstrated only limited efficacy in clinical trials. It has been already demonstrated that the targeting of a membrane-distal domain of an antigen with a mAb is suboptimal at inducing Fc-related effector functions. As amatuximab targets a membrane-distal domain of MSLN, we investigated whether mAbs targeting different epitopes would bestow a better efficacy. Furthermore, in order to incorporate novel modalities to enhance tumor-killing, we have paired these MSLN targeting arms with an anti-CD47 arm to generate bispecific antibodies (bsAb). Indeed, the ‘don’t eat me signal’ CD47 is a promising target in cancer and therapeutic blockade has recently showed clinical evidence of efficacy. Therefore, we investigated the contribution of a CD47 arm and the impact of the different anti-MSLN targeting arms on the tumoricidal activities of CD47xMSLN bsAbs.Materials and MethodsA panel of anti-MSLN mAbs and CD47xMSLN biAbs carrying the same anti-CD47 arm and different anti-MSLN arms were generated and characterized for their epitope specificity. Their tumor cell killing efficacy in vitro and in vivo was analyzed using cell-based assays, xenograft models and various MSLN+ human malignant cell lines originated from different tissues (e.g., lung, gastric and hepatic origin).ResultsOur data revealed that all CD47xMSLN bsAbs, regardless of the recognized MSLN epitope, showed higher activity than the corresponding anti-MSLN mAbs in tumor-cell killing assays and demonstrated superior anti-tumor activity in a xenograft model. Targeting a membrane-proximal epitope rendered an anti-MSLN mAb more effective in mediating antibody-dependent cell-mediated cytotoxicity (ADCC) but did not optimize antibody dependent cellular phagocytosis (ADCP) activity. However, targeting the membrane-proximal epitope of MSLN afforded the CD47xMSLN bsAb enhanced ADCC and ADCP activity, resulting in superior activity in vivo. Mechanistically, engaging a MSLN membrane proximal region with a CD47-bsAb format not only enhanced FcγR-IIIA signaling but also interestingly disrupted more efficiently the CD47/SIRPα axis, resulting in optimized phagocytosis of tumor cells. Finally, we showed that treatment with CD47xMSLN bsAb targeting membrane proximal MSLN epitope induced an accumulation of myeloid cells and NK cells in the tumor microenvironment.ConclusionsThis study demonstrated that when designing antibody-based molecules, the targeted region on a tumor-associated antigen needs to be carefully considered to ensure maximal effector function. In the context of MSLN-positive solid tumors, we showed that an approach targeting a membrane-proximal epitope coupled to a CD47-blocking arm afforded an improved ADCC and ADCP profile, translating into increased in vivo efficacy.Disclosure InformationE. Hatterer: None. X. Chauchet: None. F. Richard: None. L. Barba: None. V. Moine: None. L. Chatel: None. N. Fischer: None. W. Ferlin: None. V. Buatois: None. K. Masternak: None. L. Shang: None.
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Einama, Takahiro, Futoshi Kawamata, Hirofumi Kamachi, Hiroshi Nishihara, Shigenori Homma, Fumihiko Matsuzawa, Tatsuzo Mizukami, et al. "Mesothelin-Specific Immune Responses and Targeted Immunotherapy for Mesothelin-Expressing Tumors." EBioMedicine 24 (October 2017): 16–17. http://dx.doi.org/10.1016/j.ebiom.2017.09.033.
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Church, Sarah Elizabeth, Carmen Ballesteros-Merino, Amy H. Sullivan, Andrew M. White, Michael D. Bailey, Shawn M. Jensen, John R. Handy, et al. "Immune gene signatures and integrative spatially-resolved digital profiling of prognostic biomarkers for mesothelioma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e20071-e20071. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e20071.
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e20071 Background: Malignant mesothelioma has been an incurable disease with few effective therapies. While PD-1 targeted therapies have elicited some patient responses, the overall response rate for mesothelioma is low. Since mesothelioma is derived from the mesothelium of the lung, we hypothesize that immune cells in the tumor microenvironment (TME) may behave differently than other solid tumors that are responsive to immunotherapy. Here we characterize prognostic immune gene signatures and spatial protein expression in the mesothelioma TME. Methods: 50 FFPE mesothelioma samples were analyzed using the NanoString PanCancer IO360 assay which measures expression of 770 genes, including the abundance of 14 immune cell types and of 32 IO signatures. All genes and signatures were correlated with overall survival (OS). GeoMx digital spatial profiling (DSP) was performed on 40 samples assessing the protein expression along 12 geometric circular regions-of-interest (ROI). Tissue slides were stained with a combination of fluorescent-labeled antibodies (pan-cytokeratin, CD3, CD68) and a panel of 38-antibodies each conjugated to a unique UV-photocleavable DNA barcode. UV light was applied to the defined ROI, which releases the DNA barcodes for quantitation on the nCounter platform. Results: Unsupervised clustering of samples based on gene signatures showed two distinct groups; one, with low expression of lymphocyte activation/exhaustion signatures and the second, with moderate expression of immune signatures. Two samples had high expression of all immune gene signatures, also confirmed by DSP had increased expression of T cell markers. Tumor proliferation (p < 0.001), hypoxia (p = 0.04), glycolysis (p < 0.001), B7-H3 (p = 0.007) and TGF-β (p = 0.001) signatures were significantly associated with shorter OS. Additional DSP profiling of these mesothelioma samples showed both T cell excluded and desert TMEs. Conclusions: We show that the mesothelioma TME has distinct immune biology associated with OS. Tumors from patients with poor survival had expression profiles previously described to be associated with immune excluded and desert phenotypes. We show that gene expression and DSP identifies unique targets for immunotherapy and we hypothesize that these findings may guide the development of combination trials that will be effective against mesothelioma.
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Oda, Shannon, Kristin Anderson, Philip Greenberg, Nicolas Garcia, Pranali Ravikumar, Patrick Bonson, Cody Jenkins, Summer Zhuang, and Andrew Daman. "175 A Fas-4–1BB immunomodulatory fusion protein converts a pro-death to a pro-survival signal, enhancing T cell function and efficacy of adoptive cell therapy in murine models of AML and pancreatic cancer." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A189. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0175.
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BackgroundAdoptive cell therapy (ACT) with genetically-modified T cells has shown impressive results against some hematologic cancers, but limited efficacy against tumors with restrictive tumor microenvironments (TMEs). FasL is a particular obstacle for ACT;1 it is expressed in many tumors and TMEs,1 including AML,2 ovarian3 and pancreatic cancers,4 and upregulated on activated T cells, where it can mediate activation-induced cell death (AICD).5MethodsWe engineered T cells to boost function with novel immunomodulatory fusion proteins (IFPs) that combine an inhibitory ectodomain with a costimulatory endodomain. Like current checkpoint-blocking therapies, IFPs can abrogate an inhibitory signal, but also provide an often absent costimulatory signal. Additionally, IFP-driven signals are delivered only to the T cells concurrently engineered to be tumor-specific, thereby avoiding systemic T cell activation. For FasL-expressing TMEs, we developed an IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. We tested the the Fas-4-1BB IFP in primary human T cells and in immunocompetent murine models of leukemia and pancreatic cancer.ResultsFas-4-1BB IFP expression enhanced primary human T cell function and enhanced lysis of Panc1 pancreatic tumor cells in vitro. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function and altered metabolism in vitro. Notably, the Fas ectodomain is trimeric5 and the 4-1BB intracellular domain requires trimerization to signal.6 In contrast, the CD28 domain is dimeric and did not enhance function when paired with 4-1BB.In vivo, Fas-4-1BB increased T cell persistence and function, and Fas-4-1BB T cell ACT significantly improved survival in a murine AML model. When delivered with a mesothelin-specific TCR, Fas-4-1BB T cells prolonged survival in the autochthonous KPC pancreatic cancer model, increasing median survival to 65 from 37 days (with TCR-only, **P=0.0042). Single-cell RNA sequencing revealed differences in the endogenous tumor-infiltrating immune cells, included changes in cell frequency and programming.ConclusionsWe developed an engineering approach to enhance the in vivo persistence and antitumor efficacy of transferred T cells. Our targeted, two-hit strategy uses a single fusion protein to overcome a death signal prevalent in the TME of many cancers and on activated T cells, and to provide a pro-survival costimulatory signal to T cells. Our results suggest that this fusion protein can increase T cell function when combined with murine or human TCRs, and can significantly improve therapeutic efficacy in liquid and solid tumors, supporting clinical translation.ReferencesYamamoto, T.N., et al., T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy. J Clin Invest 2019.Contini P, et al., In vivo apoptosis of CD8(+) lymphocytes in acute myeloid leukemia patients: involvement of soluble HLA-I and Fas ligand. Leukemia 2007;21(2):p. 253–60.Motz GT, et al., Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014;20(6):p. 607–15.Kornmann M, et al., Fas and Fas-ligand expression in human pancreatic cancer. Ann Surg 2000. 231(3): p. 368–79.Villa-Morales M and J Fernandez-Piqueras, Targeting the Fas/FasL signaling pathway in cancer therapy. Expert Opin Ther Targets 2012;16(1):p. 85–101.Wyzgol, A., et al., Trimer stabilization, oligomerization, and antibody-mediated cell surface immobilization improve the activity of soluble trimers of CD27L, CD40L, 41BBL, and glucocorticoid-induced TNF receptor ligand. J Immunol 2009;183(3):p. 1851–61.
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Hassan, Raffit, Anish Thomas, Christine Alewine, Dung T. Le, Elizabeth M. Jaffee, and Ira Pastan. "Mesothelin Immunotherapy for Cancer: Ready for Prime Time?" Journal of Clinical Oncology 34, no. 34 (December 1, 2016): 4171–79. http://dx.doi.org/10.1200/jco.2016.68.3672.
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Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes–expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer.
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Moreno Cortes, Eider F., Caleb K. Stein, Paula A. Lengerke Diaz, Cesar A. Ramirez-Segura, and Januario E. Castro. "Chimeric Antigen Receptor T Cell Therapy Pipeline at a Glance: A Retrospective and Systematic Analysis from Clinicaltrials.Gov." Blood 134, Supplement_1 (November 13, 2019): 5629. http://dx.doi.org/10.1182/blood-2019-132273.
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Background: Chimeric Antigen Receptor (CAR) T cell therapy is a promising cancer immunotherapy that is growing exponentially. The doubling time of medical knowledge in 2010 was 3.5 years, and the projection for 2020 is just 73 days. In the last five years, the number of PubMed publications on cancer applications of CAR T cells has tripled. Therefore, to remain updated in the field represents a challenge for patients, care providers and researchers. In this review we provide a focused summary of the currently ongoing clinical trials, with a comprehensive overview of advances in CAR T cell therapy, beyond CD19, emphasizing on antigenic targets, development phases, and leading sponsor pharmaceutical companies. Methods: We retrieved the available data from the national registry of clinical trials (clinicaltrials.gov) using the following keywords: "CAR T cell", "CAR T cell and cancer", "chimeric antigen receptor", "CAR T AND tumor antigen", 'CAR T cell antigens", "Tumor antigens targeted by CAR T cells", "engineered T cells", "modified T cell", "CAR T cells in Cancer", "CAR T cell therapy", "CAR T cell therapy AND Cancer" until December 31, 2018 and manually excluded the trials unrelated to CAR T-cell therapies on cancer, by reviewing the detailed information provided on the website as well as preliminary data published. Results: The analysis included 271 clinical trials posted on the clinicaltrials.gov website from the United States by the cut-off date. For efficacy analysis, we retrieved information from 52 trials, by NCT number on a PubMed search. The majority of CAR T clinical research is focused on hematological cancer (57%), followed by CNS 8%, GI 6%, Skin 5%, Genitourinary 4%, Breast 4%, Gynecologic 4%, Respiratory 3%, Sarcoma 2%, Mesothelioma 2% and others 5%. The most used target in CAR T cell therapy and the leaders in phase 3 trials are CD19 (42%) and BCMA (12%), followed by CD20, NY-ESO-1, Mesothelin, HER2, GD2, MAGE-A3 and CD30. An essential step in CAR T cell therapy development is the selection of the right antigen/target. Here, we provide an overview of the clinically relevant targets that are actively being using by clinical trials in the United States. For example, CD19 appears to be a leading target regarding CAR T cell therapy on cancer with 116 trials (42% of total CAR T cells trials) on going just in the United States with a significant increment in the previous years. Similarly, with BCMA is one of the targets with more phase 3 trials (Figure 1) with promising results on patients with Multiple Myeloma with and the objective response of 85%, CR 45%, and PFS of 11.8 months. Second-generation CARs with either CD28 or 4-1BB as costimulatory signaling domain are preferred, with 4-1BB being the most commonly chosen. Conclusions: Our findings show growing trends in the development of CAR T cell-based therapies, combination and possible retargeting therapies in the future for solid tumor and hematologic malignances; taking into account the amount of important information and the complexity of the database, we have developed this analysis to understand how to generate in the future a friendly platform for researchers and patients to have an detailed overview of the clinical trials in cellular therapies Disclosures No relevant conflicts of interest to declare.
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Bhoj, Vijay, Lucy Li, Benjamin J. Samelson-Jones, Bhavya S. Doshi, Christoph Ellebrecht, Aimee Payne, Valder R. Arruda, and Michael C. Milone. "Optimized FVIII-Domain-Based Chimeric Antigen Receptors to Specifically Target FVIII Inhibitor-Producing B Cells in Hemophilia a." Blood 132, Supplement 1 (November 29, 2018): 2196. http://dx.doi.org/10.1182/blood-2018-99-120031.
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Abstract Hemophilia A (HA) is a X-linked bleeding disorder caused by deficiency of coagulation factor VIII (FVIII). Optimal clinical management centers on FVIII protein concentrate replacement. However, up to 30% of patients with severe HA develop neutralizing antibodies to FVIII (inhibitors) upon exposure to therapeutic FVIII. Inhibitors neutralize the infused FVIII and, thus, pose a significant challenge in the management of these patients. Immune tolerance induction (ITI) using high-dose FVIII infusions can eliminate inhibitors but is not effective at generating long-term eradication in all patients. Thus, we developed an immunotherapy to more effectively eliminate FVIII-specific B cells to induce lasting eradication of inhibitors. Adoptive T cell immunotherapies using chimeric antigen receptor (CAR)-modified T cells (CARTs) are showing encouraging results in the treatment of cancer. We previously reported a proof-of-concept CART approach to eliminate autoantibodies to desmoglein-3, implicated in pemphigus vulgaris, by targeting non-malignant B cells. Here, using a similar strategy, we constructed two FVIII-based CARs using isolated FVIII A2 and C2 domains, which are commonly targeted by inhibitors Both FVIII fragments were used as the CAR extracellular domain followed by CD8a-derived hinge and transmembrane domains and intracellular signaling domains derived from 4-1BB and CD3z (BBz), as has been used in a recently FDA-approved CD19-targeted CAR (CART19) that have shown efficacy in patients. A2- and C2-CARs were introduced into primary human T cells using lentivirus vectors and were found to express on the cell surface. Primary expansion following anti-CD3/CD28 activation and lentivirus transduction yielded comparable population doublings of CART19 and A2-CARTs over 9-11 days (mean, 4.3 vs. 3.7; p=0.16). However, C2-CARTs consistently achieved fewer doublings compared to CART19 (mean 4.3 vs. 2.6; p=0.01). Additionally, C2-CARTs maintained larger cell volumes following initial activation compared to A2 and CART19, reminiscent of other CARs that demonstrate a high-level of ligand-independent basal activation. Consistent with hyper-activation and activation-induced cell death, flow cytometric analysis of C2-CART cultures showed prolonged expression of CD69, increased levels of cell death, and gradual loss of CAR+ cells compared to A2 and CART19 cultures. The FVIII C2 domain contains hydrophobic surfaces involved in binding to phospholipid membranes and von Willebrand Factor. We hypothesized that these hydrophobic regions may cause unfavorable interactions that result in CAR clustering and, in-turn, ligand-independent signaling. However, since these regions are also targeted by FVIII inhibitors, mutation of hydrophobic residues to improve CAR function would likely result in loss of binding to intended targets. Thus, we tested two independent strategies to improve function of C2-CARTs, both of which maintain native FVIII domain sequences. First, to block unfavorable interactions with C2 hydrophobic surfaces, we tested whether addition of C2 domain specific antibodies to the CART culture would improve expansion. Indeed, addition of anti-C2 antibodies improved C2-CART expansion by approximately one population doubling and reduced both cell volume and CD69 expression in C2-CARTs. As an alternate and perhaps more easily translatable approach, we replaced the BBz CAR signaling domain with a killer immunoglobulin receptor (KIR)-based multi-chain signaling system, which we previously utilized to improve function of a mesothelin-targeted CAR. KIR-based signaling effectively "rescued" the C2 CAR, and showed an expansion and activation profile comparable to CART19. Lastly, KIR-based FVIII CARs, demonstrated specific lysis of and cytokine response to target cells engineered to express surface anti-FVIII, even in the presence of soluble inhibitors. These data indicate that unfavorable interactions may be ameliorated directly by blocking agents or, indirectly, by altering intracellular signal transduction domains. These strategies have allowed us to construct optimized FVIII-based CARTs to target FVIII-specific B cells that are responsible for producing FVIII inhibitors in patients with HA. Disclosures Doshi: Bayer Hemophilia Awards Program: Research Funding. Milone:Novartis: Patents & Royalties.
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Parinyanitikul, Napa, George R. Blumenschein, Yun Wu, Xiudong Lei, Mariana Chavez-Mac Gregor, Melody L. Smart, and Ana M. Gonzalez-Angulo. "Mesothelin expression and survival outcomes in triple-receptor negative breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e12002-e12002. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e12002.
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e12002 Background: Mesothelin is an ideal tumor-associated marker for the development of targeted therapy due to its limited expression in normal tissues. Identify the frequency of mesothelin expression in triple negative breast cancer may lead the path to customize the drug development in this lack of effective targeted subgroup. The aim of this study was to evaluate mesothelin expression in triple-negative breast cancer (TNBC) and its correlation with survival outcomes. Methods: Mesothelin expression was completed using immunohistochemistry on formalin fixed paraffin tumor sections, and quantified by H-score. An H-score >10 was considered positive. Patient’s characteristics were compared by mesothelin expression. Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics. Results: Median age was 52 years. Of the 109 TNBC, 37 (34%) were positive for mesothelin expression. There were no differences on patient/tumor characteristics by mesothelin expression with the exception of high frequency of lymphovascular space invasion in mesothelin-negative tumors (P=0.03). At a median follow up of 75.8 months 20 (18.3%) had experienced a recurrence and 22 (20.2%) had died. Five-year progression-free survival was 87% and 92% in patients with mesothelin-positive and mesothelin-negative tumors (P=0.43), and 5-year overall survival was 85% and 91% patients with mesothelin-positive and mesothelin-negative tumors (P=0.57), respectively. Mesothelin expression was not independently associated with PFS or OS in TNBC after adjustment for other patient and disease characteristics including grade, pathologic stage, lymphovascular invasion, and adjuvant chemotherapy survival outcomes. Conclusions: There was mesothelin expression in 34% of TNBC. No significant differences in the clinical characteristics by mesothelin expression with the exception of high lymphovascular invasion in mesothelin-negative tumors. Mesothelin expression did not correlate with survival outcomes in TNBC.
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Faust, Joshua R., Darcy Hamill, Edward Anders Kolb, Anilkumar Gopalakrishnapillai, and Sonali P. Barwe. "Mesothelin: An Immunotherapeutic Target beyond Solid Tumors." Cancers 14, no. 6 (March 18, 2022): 1550. http://dx.doi.org/10.3390/cancers14061550.
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Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, and most recently in hematological malignancies, including acute myeloid leukemia (AML). Although the function of mesothelin is widely unknown, interactions with MUC16/CA125 indicate that mesothelin plays a role in the regulation of proliferation, growth, and adhesion signaling. Most research on mesothelin currently focuses on utilizing mesothelin to design targeted cancer therapies such as monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK cells, bispecific T cell engaging molecules, and targeted alpha therapies, amongst others. Both in vitro and in vivo studies using different immunotherapeutic modalities in mesothelin-positive AML models highlight the potential impact of this approach as a unique opportunity to treat hard-to-cure AML.
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Park, Min-Sung, and Byungheon Lee. "Abstract 1743: Identification of mesothelin binding peptide for targeted therapy against pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1743. http://dx.doi.org/10.1158/1538-7445.am2022-1743.
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Abstract Pancreatic cancer is the main cause of cancer-related deaths worldwide and is difficult to diagnose before the extensive local invasion and distant organ metastasis. Mesothelin is abnormally overexpressed in tumors such as ovary cancer and pancreatic cancer. Studies show a significant link between mesothelin overexpression and short survival in patients with pancreatic cancer. In this study, we screened a phage displayed-peptide library for peptides that selectively bind to mesothelin using mesothelin-overexpressing cells. After five rounds of screening, we selected a 9-mer peptide (named MSLN-Pep) that preferentially bound to mesothelin-high pancreatic cancer cells such as ASPC-1 and Panc-1 cells over mesothelin-low cells such as HEK 293 cells. MSLN-Pep was efficiently internalized into ASPC-1 cells and inhibited the cell migration and invasion while little affected the phosphorylation of Akt. Moreover, a MSLN-Pep-guided proapoptotic peptide (MSLN-Pep-KLA) exerted selective cytotoxicity against pancreatic cancer cells over mesothelin-low cells. MSLN-Pep-KLA when combined with gemcitabine, a chemotherapeutic agent against pancreatic cancer, sensitized ASPC-1 cells to the gemcitabine treatment. These results suggest that MSLN-Pep is a promising tool for a targeted therapy against pancreatic cancer expressing mesothelin at high levels. Citation Format: Min-Sung Park, Byungheon Lee. Identification of mesothelin binding peptide for targeted therapy against pancreatic cancer [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 1743.
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Montemagno, Cassim, Trichanh, Savary, Pouyssegur, Pagès, Fagret, Broisat, and Ghezzi. "99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma." Cancers 11, no. 10 (October 10, 2019): 1531. http://dx.doi.org/10.3390/cancers11101531.
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: Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (99mTc-A1). Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. 99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of 99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (P < 0.05). In vivo, the 99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (99mTc-Ctl) (P < 0.01). Conclusions: 99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies.
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Müller, Dafne. "Targeted cancer immunotherapy." OncoImmunology 1, no. 7 (October 2012): 1213–14. http://dx.doi.org/10.4161/onci.20824.
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Zigler, Maya, Alexei Shir, and Alexander Levitzki. "Targeted cancer immunotherapy." Current Opinion in Pharmacology 13, no. 4 (August 2013): 504–10. http://dx.doi.org/10.1016/j.coph.2013.04.003.
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Kelly, Ronan Joseph, Ira Pastan, Morgan L. Cowan, Elizabeth Montgomery, Raffit Hassan, Christine Campo Alewine, Laiman Xiang, and Peter B. Illei. "Mesothelin expression in patients as a novel target in gastric cancer." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 61. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.61.
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61 Background: Novel targets and therapeutics are of profound importance if we are to improve outcomes in gastric cancer. This study assessed the incidence of mesothelin expression in tumors of Western patients with gastric cancer. In addition, gastric cancer cell lines were then tested for their sensitivity to SS1(dsFv)PE38 (SS1P), a mesothelin-targeted immunotoxin. Methods: Tissue specimens from 127 patients with gastric or gastro-esophageal junction (GEJ) tumors were examined by immuno-histochemistry (IHC) for intensity of staining for mesothelin. Expression of HER2-neu, e-cadherin and c-Met were also assessed. Tumors were considered positive for mesothelin if moderate cytoplasmic/membranous or luminal staining was present in at least 10% of the cells. Gastric cancer cell lines were assessed for surface mesothelin expression by flow cytometry and the viability of cells treated with SS1P was measured. Results: Gastric and GEJ cancers were mesothelin positive in 64/127 tumors (50%) while only 9 tumors (7%) were Her2-neu IHC +3 positive and 8 tumors (6%) were c-Met positive (c-Met low 5% and c-Met high 1%). Mesothelin expression rates changed from stage I tumors to stage IV tumors (39% to 56% respectively). We found that both the AGS and MKN28 gastric cancer cell lines express mesothelin and are sensitive to the immunotoxin with EC50 values in the low picomolar range (0.4 and 0.3 ng/mL, respectively). Conclusions: Mesothelin is a cell surface glycoprotein that is expressed in 50% of resected gastric cancers. Gastric cancer cell lines were exquisitely sensitive to SS1P. The high expression of mesothelin and its sensitivity to the immunotoxin SS1P makes it an attractive tumor associated antigen for therapeutic targeting. Based on these observations clinical trials involving novel mesothelin targeted drugs in gastric cancer are currently in development.
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Wang, Xudong, Wenzong Ma, Weihao Liu, Huan Ma, Yuanyou Yang, Yugang Wang, Ning Liu, and Gen Yang. "Construction and Preclinical Evaluation of 211At Labeled Anti-mesothelin Antibodies as Potential Targeted Alpha Therapy Drugs." Journal of Radiation Research 61, no. 5 (July 10, 2020): 684–90. http://dx.doi.org/10.1093/jrr/rraa049.
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ABSTRACT Targeted alpha therapy (TAT) is a promising tumor therapy that can specifically transport α particle to the vicinity of tumor cells while the normal cells are only slightly irradiated. Mesothelin is a highly promising molecular signature for many types of solid tumors including malignant mesothelioma, pancreatic cancer, ovarian cancer and lung adenocarcinoma etc., while the expression in normal human tissues are limited, thus making mesothelin a promising antigen for TAT. Previously we developed a theoretical model that could predict and optimize in vitro screening of potential TAT drugs. The aim of the study is construction and preclinical evaluation of 211At labeled anti-mesothelin antibodies as potential TAT drugs. Mesothelin expression of two tumor cell lines were confirmed by flow cytometry, and their radiosensitivities were also evaluated. We used two kinds of anti-mesothelin antibodies, ET210–6 and ET210–28, to construct TAT drugs. Then, radiochemical purity, stability in vitro, affinity of the conjugates and mesothelin expression level were assessed. The specific killing of mesothelin-positive cancer cells treated by 211At-ET210–28 and 211At-ET210–6 were studied via Cell Counting Kit-8 assay and colony formation assay. 211At-ET210–28 and 211At-ET210–6 revealed excellent affinity and stability in both phosphate buffer saline and fetal bovine serum environment. Radiolabeled antibody conjugates bound specifically to mesothelin-positive cells in vitro. Both 211At-ET210–28 and 211At-ET210–6 could specifically kill mesothelin-positive cells with negligible damages to mesothelin-negative cells. Our findings provide initial proof-of-concept for the potential use of 211At labeled ET210–28/ET210–6 anti-mesothelin antibody in specific killings of mesothelin-positive tumor cells.
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Mizukoshi, Eishiro, and Shuichi Kaneko. "Telomerase-Targeted Cancer Immunotherapy." International Journal of Molecular Sciences 20, no. 8 (April 12, 2019): 1823. http://dx.doi.org/10.3390/ijms20081823.
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Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to metastasize to distant organs. Studies to date have examined the mechanisms involved in the survival of cancer cells as targets for cancer therapeutics. These efforts led to the development of telomerase inhibitors as anticancer drugs, drugs targeting telomere DNA, viral vectors carrying a promoter for human telomerase reverse transcriptase (hTERT) genome, and immunotherapy targeting hTERT. Among these novel therapeutics, this review focuses on immunotherapy targeting hTERT and discusses the current evidence and future perspectives.
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Tchou, Julia, Liang-Chuan Wang, Ben Selven, Hongtao Zhang, Jose Conejo-Garcia, Hossein Borghaei, Michael Kalos, et al. "Mesothelin, a novel immunotherapy target for triple negative breast cancer." Breast Cancer Research and Treatment 133, no. 2 (March 15, 2012): 799–804. http://dx.doi.org/10.1007/s10549-012-2018-4.
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Hagemann, Urs B., Christine Ellingsen, Joachim Schuhmacher, Alexander Kristian, Anne Mobergslien, Véronique Cruciani, Katrine Wickstroem, et al. "Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers." Clinical Cancer Research 25, no. 15 (May 7, 2019): 4723–34. http://dx.doi.org/10.1158/1078-0432.ccr-18-3476.
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Jain, Akhil, and Sajjan Rajpurohit. "Cancer immunotherapy." International Journal of Molecular and Immuno Oncology 3, no. 2 (July 25, 2018): 45. http://dx.doi.org/10.18203/issn.2456-3994.intjmolimmunooncol20183227.
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<p class="s4">The era has begun where oncology meets immunology. The recent advancement in the field of molecular biology has led to the discovery of various pathways through which cancer establishes, proliferates, grows, and disseminates. These pathways provided major insight for targeting specific molecules with the targeted therapies that show predicted responses. This targeted therapy is usually referred to as immunotherapy. These immunotherapies possess and display a unique set of toxicities mainly immunologic in nature and different from chemotherapies. This article focuses on mechanisms of immune activity of the body and various therapies available to boost these mechanisms.</p>
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Kunk, Paul Raymond, Joseph Mounir Obeid, Kevin Winters, Patcharin Pramoonjago, Dirk G. Brockstedt, Chan C. Whiting, Amanda Enstrom, et al. "Correlation of mesothelin expression and CD8 tumor infiltrating lymphocytes with prognosis in cholangiocarcinoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15650-e15650. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15650.
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e15650 Background: Cholangiocarcinoma (CC) is a rapidly progressing malignancy with an unmet treatment need. Little is known about the CC tumor immune microenvironment or about relevant antigenic targets. We hypothesized that lack of T cell infiltration or PD-L1 expression may identify patients at high risk of death, and that mesothelin may be a relevant antigenic target. Methods: A retrospective analysis was conducted of CC tumors at the University of Virginia from 2000-2014. TMAs were constructed of 3-4 cores from each tumor and were stained by IHC for CD4 and CD8 tumor infiltrating lymphocytes (TILs), mesothelin and PD-L1. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. TILs and protein expression were analyzed for association with overall survival, grouped as high or low expression based either on the median or the 33rdpercentile. Correlation with overall survival was assessed using a log rank test and a classification and regression tree with p-values < 0.05 being considered statistically significant. Results: Ninety-nine tumors were available for analysis: 26 intrahepatic, 37 hilar, and 36 distal. PD-L1 and mesothelin expression > 1% of tumor cells were found in 16% and 92% of tumors, respectively. CD4 and CD8 TILs were found in nearly all tumors (98% and 96%), with the majority showing intraepithelial CD4 and CD8 infiltration (73% and 68%). There were no significant associations between survival and PD-L1, mesothelin, or CD4 and CD8 infiltration. However when considered together, the group with low mesothelin/low CD8 (each below 33rdpercentile) had worse survival (9.1 months) compared to high mesothelin/high CD8 (25 months), high mesothelin/low CD8 (30.1 months) and low mesothelin/high CD8 (26.1 months), p = 0.015. Conclusions: CC tumors that lack CD8 infiltration and mesothelin expression have a poor prognosis. Mesothelin represents an attractive target in cholangiocarcinoma, opening the door for future immunotherapy for CC.
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Lode, Holger N., and Ralph A. Reisfeld. "Targeted Cytokines for Cancer Immunotherapy." Immunologic Research 21, no. 2-3 (2000): 279–88. http://dx.doi.org/10.1385/ir:21:2-3:279.
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Sato Dahlman, Mizuho, Yoshiaki Miura, Kari Jacobsen, Julia Davydova, and Masato Yamamoto. "Systemic treatment of mesothelin-targeted oncolytic adenovirus eliminates pancreatic cancer." Pancreatology 16, no. 4 (August 2016): S171. http://dx.doi.org/10.1016/j.pan.2016.06.615.
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Pastan, Ira, and Raffit Hassan. "Discovery of Mesothelin and Exploiting It as a Target for Immunotherapy." Cancer Research 74, no. 11 (May 13, 2014): 2907–12. http://dx.doi.org/10.1158/0008-5472.can-14-0337.
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Scholler, Nathalie, Paul Stein, Claire Repellin, Kalika Kamat, M. Travis Harrison, Robert Shoemaker, and Lidia Sambucetti. "Mesothelin Vaccination for the Prevention of Ovarian Cancer." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 214.8. http://dx.doi.org/10.4049/jimmunol.196.supp.214.8.
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Abstract Survival of ovarian cancer patients with high-grade serous carcinoma (HGSC) remains low. We hypothesized that a tumor antigen-targeted vaccine capable of eliciting a robust cell-mediated immune response may substantially improve women’s health. Mesothelin is a glycosylphosphatidylinisotol (GPI)-anchored, conserved protein that is overexpressed by ovarian, lung and pancreatic cancers. We designed mesothelin vaccines containing cyclic dinucleotide (CDN)-based adjuvants or alum-based adjuvants to trigger CD8 T cell activation. Anti-mesothelin antibody titers were stable or slightly increased after 2 vaccine boosts, and the highest and most stable titers were obtained with CDN-based adjuvants (meso/CDN). In addition, splenocytes from all mice receiving CDN-containing vaccines secreted mesothelin-specific IFNγ. Next, immunized mice were injected orthotopically with luciferase-transduced mouse ovarian cancer cells (ID8). In vivo imaging performed 3 weeks after tumor injections revealed that most of the mice from the groups immunized with Alum-based vaccines (92%) presented a positive signal of bioluminescence, which corresponds to the routine take rate of the ID8 tumors. In contrast, only 1/3 of the mice in the meso/CDN group showed a positive signal compared with 2/3 of the mice immunized with the control CDN-only vaccine. These results suggest that the meso/CDN vaccine regimen delayed tumor establishment. Longer observation of the mice is ongoing to determine whether the vaccination regimen can prevent tumor development. We tentatively conclude that ovarian cancer prevention may be possible through vaccination against mesothelin tumor antigen in combination with adjuvants that trigger cellular immunity.
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Illei, Peter B., Christine Alewine, Marianna Zahurak, Morgan L. Cowan, Elizabeth Montgomery, Raffit Hassan, Laiman Xiang, Ira Pastan, and Ronan J. Kelly. "Mesothelin Expression in Advanced Gastroesophageal Cancer Represents a Novel Target for Immunotherapy." Applied Immunohistochemistry & Molecular Morphology 24, no. 4 (April 2016): 246–52. http://dx.doi.org/10.1097/pai.0000000000000292.
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Bonati, Lucia, and Li Tang. "Cytokine engineering for targeted cancer immunotherapy." Current Opinion in Chemical Biology 62 (June 2021): 43–52. http://dx.doi.org/10.1016/j.cbpa.2021.01.007.
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Søgaard, Morten, Johan Hansson, Mark J. Litton, Lennart Ohlsson, Alexander Rosendahl, Peter A. Lando, Per Antonsson, Terje Kalland, and Mikael Dohlsten. "Antibody-targeted superantigens in cancer immunotherapy." Immunotechnology 2, no. 3 (September 1996): 151–62. http://dx.doi.org/10.1016/s1380-2933(96)00047-4.
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Ribas, Antoni, and Jedd D. Wolchok. "Combining cancer immunotherapy and targeted therapy." Current Opinion in Immunology 25, no. 2 (April 2013): 291–96. http://dx.doi.org/10.1016/j.coi.2013.02.011.
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Chokshi, Saurin, and Howard S. Hochster. "An open-label, phase II study of intravenous anetumab ravtansine, an anti-mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): TPS540. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.tps540.
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TPS540 Background: Advanced pancreatic cancer remains one of the deadliest malignancies with median OS of 11 months with the most aggressive therapy regimen. Hence, a need exists for more effective, durable, and targeted therapies. Mesothelin is a membrane associated antigen overexpressed in most pancreatic adenocarcinomas. The biological function of mesothelin remains unknown but it is an internalizing antigen. Given its limited expression in normal tissue and high expression in malignant cells, mesothelin is an excellent target for antibody directed cytotoxic drug delivery. Anetumab ravtansine (AR) is an ADC consisting of a fully human IgG1 antibody directed at mesothelin and conjugated to tubulin-binding toxophore, DM4 (maytansine derivative). Preclinical efforts have shown antiproliferative activity in mesothelin positive cancer cell lines and 75% tumor regression in pancreatic xenograft models (Golfier S, et al. Mol Cancer Ther 13(6):1537-48, 2014). Methods: This is a multicenter, non-randomized, Phase II study evaluating the efficacy of AR in pretreated mesothelin-expressing advanced pancreatic cancer. The study utilizes minimax, Simon 2-stage design testing 5% null hypothesis versus 21% alternative. If no response among the first 20, trial will terminate early. If at least one response among the first 20, trial will accrue additional 10 patients for maximum of 30. Four or more responses out of 30 will reject the null hypothesis. Significance level (alpha) is 0.1 and power is 90%. Probability of stopping early is 36% if the response rate is 5% or lower. Patients will receive AR infusion at 6.5 mg/kg on Day 1 of 21-day cycle. Primary objective: response rate per RECIST 1.1. Secondary objectives: time to progression; toxicity. Eligibility: measurable disease per RECIST 1.1; no more than two prior chemotherapy regimens; 30% of cells with 2+/3+ mesothelin staining per IHC; no history of keratitis or corneal disease. Correlative studies: serum soluble mesothelin levels and apoptotic factors (CK18, caspase-cleaved fragments) at baseline and throughout the study to predict treatment response/outcome. Enrollment is on-going. Clinical trial information: NCT03023722.
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Liu, Xiu Fen, Laiman Xiang, Qi Zhou, Jean-Philippe Carralot, Marco Prunotto, Gerhard Niederfellner, and Ira Pastan. "Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis." Proceedings of the National Academy of Sciences 113, no. 38 (September 6, 2016): 10666–71. http://dx.doi.org/10.1073/pnas.1611481113.
Full textAbstract:
RG7787 is a mesothelin-targeted immunotoxin designed to have low-immunogenicity, high-cytotoxic activity and fewer side effects. RG7787 kills many types of mesothelin-expressing cancer cells lines and causes tumor regressions in mice. Safety and immunogenicity of RG7787 is now being assessed in a phase I trial. To enhance the antitumor activity of RG7787, we screened for clinically used drugs that can synergize with RG7787. Actinomycin D is a potent transcription inhibitor that is used for treating several cancers. We report here that actinomycin D and RG7787 act synergistically to kill many mesothelin-positive cancer cell lines and produce major regressions of pancreatic and stomach cancer xenografts. Analyses of RNA expression show that RG7787 or actinomycin D alone and together increase levels of TNF/TNFR family members and NF-κB–regulated genes. Western blots revealed the combination changed apoptotic protein levels and enhanced cleavage of Caspases and PARP.