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1
Zhang, Yuhan, Changming Fang, Rongsheng E. Wang, Ying Wang, Hui Guo, Chao Guo, Lijun Zhao, et al. "A tumor-targeted immune checkpoint blocker." Proceedings of the National Academy of Sciences 116, no. 32 (July 22, 2019): 15889–94. http://dx.doi.org/10.1073/pnas.1905646116.
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To direct checkpoint inhibition to the tumor microenvironment, while avoiding systemic immune activation, we have synthesized a bispecific antibody [norleucine4, d-Phe7]-melanocyte stimulating hormone (NDP-MSH)-antiprogrammed cell death-ligand 1 antibody (αPD-L1) by conjugating a melanocyte stimulating hormone (α-MSH) analog to the antiprogrammed cell death-ligand 1 to (αPD-L1) antibody avelumab. This bispecific antibody can bind to both the melanocortin-1 receptor (MC1R) and to PD-L1 expressed on melanoma cells and shows enhanced specific antitumor efficacy in a syngeneic B16-SIY melanoma mouse model compared with the parental antibody at a 5 mg/kg dose. Moreover, the bispecific antibody showed increased infiltrated T cells in the tumor microenvironment. These results suggest that a tumor-targeted PD-L1-blocking bispecific antibody could have a therapeutic advantage in vivo, especially when used in combination with other checkpoint inhibitors.
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Galluzzi, Lorenzo, and Guido Kroemer. "Novel immune checkpoint blocker to treat Merkel cell carcinoma." OncoImmunology 6, no. 6 (April 20, 2017): e1315496. http://dx.doi.org/10.1080/2162402x.2017.1315496.
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Wang, Feihu, Dongqing Xu, Hao Su, Weijie Zhang, Xuanrong Sun, Maya K. Monroe, Rami W. Chakroun, et al. "Supramolecular prodrug hydrogelator as an immune booster for checkpoint blocker–based immunotherapy." Science Advances 6, no. 18 (April 29, 2020): eaaz8985. http://dx.doi.org/10.1126/sciadv.aaz8985.
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Immune checkpoint blockers (ICBs) have shown great promise at harnessing immune system to combat cancer. However, only a fraction of patients can directly benefit from the anti–programmed cell death protein 1 (aPD1) therapy, and the treatment often leads to immune-related adverse effects. In this context, we developed a prodrug hydrogelator for local delivery of ICBs to boost the host’s immune system against tumor. We found that this carrier-free therapeutic system can serve as a reservoir for extended tumoral release of camptothecin and aPD1 antibody, resulting in an immune-stimulating tumor microenvironment for boosted PD-1 blockade immune response. Our in vivo results revealed that this combination chemoimmunotherapy elicits robust and durable systemic anticancer immunity, inducing tumor regression and inhibiting tumor recurrence and metastasis. This work sheds important light into the use of small-molecule prodrugs as both chemotherapeutic and carrier to awaken and enhance antitumor immune system for improved ICBs therapy.
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Hassel, Jessica Cecile, Michael Flossdorf, Sonja Hänzelmann, Julia Winkler, Jasmin Roth, Claudia Lauenstein, Lena Appel, et al. "Investigation of the immune infiltrate of melanoma metastases under immune checkpoint inhibition." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 9570. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9570.
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9570 Background: Tumor infiltrating lymphocytes (TIL) play a crucial role in the therapeutic impact of immune checkpoint blockers. Methods: We investigated metastases from 56 melanoma patients before and during treatment with immune checkpoint blockers (i) immunohistochemically, (ii) with TCR repertoire profiling and (iii) analysis of the transcriptome. The patients were treated with ipilimumab (n = 25) or pembrolizumab (n = 23) or ipilimumab/nivolumab (n = 7); half of them had a disease control, the other half progressed as best response to treatment. Results: In contrast to previous reports immunohistochemical analysis of the immune infiltrate revealed no significant difference in the number of CD8+ TILs in pretreatment samples of responders and non-responders. Instead, the number of CD4 + TILs including regulatory T cells (Treg) and the number of PD-1 + cells was higher in responders especially when receiving pembrolizumab. Samples taken at least 6 weeks after start of the immune checkpoint blocker showed a significant higher number of immune cells in responders through all T cell subsets (CD3,4,8,FoxP3, PD-1), B cells (CD20) as well as macrophages (CD68, CD163). TCR repertoire profiling by deep TCR sequencing demonstrated that responders develop a more diverse repertoire under treatment (p = 0.05). Pretreatment samples as well as the size of the top 10 TCR clones posttreatment did not differ significantly in responders and non-responders. By RNA sequencing no differential expression profiles between responders and non-responders was found pretreatment. Posttreatment samples expressed different genes compared to pretreatment samples in responders including MHC molecules, CDK2/4, Myc, TNF family members and different apoptosis-inducing genes. There was no differential gene expression in non-responders pre- and posttreatment. Conclusions: Pretreatment metastases from responders and non-responders do not differ much. With treatment responding patients have significant higher numbers of immune cells including T- and B- cells as well as macrophages and develop a more diverse TCR repertoire. RNA sequencing revealed a differential expression pre- versus posttreatment only in responding patients.
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Yuan, Bo, Linlin Miao, Disen Mei, Lingzhi Li, Qiongyan Zhou, Dong Dong, Songting Wang, Xiaoxia Zhu, and Suling Xu. "Value of a Signature of Immune-Related Genes in Predicting the Prognosis of Melanoma and Its Responses to Immune Checkpoint Blocker Therapies." Computational and Mathematical Methods in Medicine 2022 (June 20, 2022): 1–13. http://dx.doi.org/10.1155/2022/9633416.
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Melanoma is becoming increasingly common worldwide, with high rates of transformation into malignancy compared to other skin lesions. The prognosis of patients with melanoma at an advanced stage is highly unsatisfying despite the development of immunotherapy, target therapy, or combinative therapy. The major barrier to exploiting immune checkpoint therapies and achieving the best benefits clinically is resistance that can easily develop if regimens are not selected appropriately. In this study, we investigated the possibility of using immune-related genes to predict patient survival and their responses to immune checkpoint blocker therapies with the expression profiles available at The Cancer Genome Atlas (TCGA) Program plus expression data from the Gene Expression Omnibus (GEO) for validation. A five gene signature that is highly correlated with the local infiltration of cytotoxic lymphocytes in the tumor microenvironment was identified, and a scoring model was developed with stepwise regression after multivariate Cox analyses. The score calculated strongly correlates with Breslow depth, and this model effectively predicts the prognosis of patients with melanoma, whether primary or metastasized. It also depicts the heterogenous immune-related nature of melanoma by revealing different predicted responses to immune checkpoint blocker therapies through its correlation to tumor immune dysfunction and exclusion (TIDE) score.
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Galluzzi, Lorenzo, Guido Kroemer, and Alexander Eggermont. "Novel immune checkpoint blocker approved for the treatment of advanced melanoma." OncoImmunology 3, no. 11 (November 2, 2014): e967147. http://dx.doi.org/10.4161/21624011.2014.967147.
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Shi, Connie R., Tracey S. Otto, Leah L. Thompson, Michael S. Chang, Kerry L. Reynolds, and Steven T. Chen. "Methotrexate in the treatment of immune checkpoint blocker-induced bullous pemphigoid." European Journal of Cancer 159 (December 2021): 34–37. http://dx.doi.org/10.1016/j.ejca.2021.09.032.
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Makam, Raghavendra, Youssef Rahban, David Gerson, and Glenn Stokken. "A CASE OF ACUTE CARDIOMYOPATHY DUE TO IMMUNE CHECKPOINT BLOCKER PEMBROLIZUMAB." Journal of the American College of Cardiology 75, no. 11 (March 2020): 3100. http://dx.doi.org/10.1016/s0735-1097(20)33727-x.
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Sharma, Munish, Giselle A. Suero-Abreu, and Bernard Kim. "A Case of Acute Heart Failure due to Immune Checkpoint Blocker Nivolumab." Cardiology Research 10, no. 2 (2019): 120–23. http://dx.doi.org/10.14740/cr838.
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Hassel, Jessica C. "Checkpoint blocker induced autoimmunity as an indicator for tumour efficacy in melanoma." British Journal of Cancer 126, no. 2 (October 25, 2021): 163–64. http://dx.doi.org/10.1038/s41416-021-01390-1.
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SummaryImmune checkpoint inhibitors (ICI) have improved survival of patients with metastatic melanoma but can induce autoimmunologic side effects. Ye et al. report a retrospective analysis that further supports the finding that these are biomarkers for patients’ clinical benefit. Thereby, patients with immune-related adverse events show a differential gene expression in chemokine-mediated signalling.
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Xie, Pingxing, Philippe Lefraçnois, and Ivan V. Litvinov. "Cytotoxic T Cells Are Replaced by Novel Clones After Immune Checkpoint Blocker Therapy." Journal of Cutaneous Medicine and Surgery 24, no. 3 (May 2020): 314–15. http://dx.doi.org/10.1177/1203475419890843.
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Mei, Jie, Jiahui Chu, Kai Yang, Zhiwen Luo, Jiayue Yang, Junying Xu, Qing Li, et al. "Angiotensin receptor blocker attacks armored and cold tumors and boosts immune checkpoint blockade." Journal for ImmunoTherapy of Cancer 12, no. 9 (September 2024): e009327. http://dx.doi.org/10.1136/jitc-2024-009327.
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BackgroundImmune checkpoint blockade (ICB) has made remarkable achievements, but newly identified armored and cold tumors cannot respond to ICB therapy. The high prevalence of concomitant medications has huge impact on immunotherapeutic responses, but the clinical effects on the therapeutic outcome of armored and cold tumors are still unclear.MethodsIn this research, using large-scale transcriptomics datasets, the expression and potential biological functions of angiotensin II receptor 1 (AGTR1), the target of angiotensin receptor blocker (ARB), were investigated. Next, the roles of ARB in tumor cells and tumor microenvironment cells were defined by a series of in vitro and in vivo assays. In addition, the clinical impacts of ARB on ICB therapy were assessed by multicenter cohorts and meta-analysis.ResultsAGTR1 was overexpressed in armored and cold tumors and associated with poor response to ICB therapy. ARB, the inhibitor for AGTR1, only suppressed the aggressiveness of tumor cells with high AGTR1 expression, which accounted for a very small proportion. Further analysis revealed that AGTR1 was always highly expressed in cancer-associated fibroblasts (CAFs) and ARB inhibited type I collagen expression in CAFs by suppressing the RhoA-YAP axis. Moreover, ARB could also drastically reverse the phenotype of armored and cold to soft and hot in vivo, leading to a higher response to ICB therapy. In addition, both our in-house cohorts and meta-analysis further supported the idea that ARB can significantly enhance ICB efficacy.ConclusionOverall, we identify AGTR1 as a novel target in armored and cold tumors and demonstrate the improved therapeutic efficacy of ICB in combination with ARB. These findings could provide novel clinical insight into how to treat patients with refractory armored and cold tumors.
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Qiao, Guanxi, Minhui Chen, Hemn Mohammadpour, Mark Bucsek, Cameron MacDonald, Bonnie Hylander, and Elizabeth Repasky. "Adrenergic stress regulates the exhausted phenotype of T cells in the tumor microenvironment." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 165.36. http://dx.doi.org/10.4049/jimmunol.204.supp.165.36.
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Abstract We have shown previously that host adrenergic stress (model of standard ambient temperature-induced chronic stress) slows tumor progression by enhancing CD8+ T-cell activation and limiting the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment (TME). We also found that reducing/blocking β-adrenergic receptor (β-AR) signaling significantly improves anti-tumor immune responses and efficacy of immune checkpoint immunotherapy. It has been reported that expression of immune checkpoint receptors (e.g. PD-1, TIM3, LAG3) is characteristic of exhausted T-cells and has been linked to failure of immune checkpoint inhibitors. Now we report that host adrenergic stress plays a previously unrecognized role in regulating T-cell exhaustion in the TME. In murine melanoma and colon cancer models, we found that propranolol (a pan β-AR blocker) significantly reduces the number of exhausted T-cells expressing immune checkpoint receptors in the TME and increases numbers of T-cells expressing effector cytokines. The overexpression of immune checkpoint receptors has also been associated with mitochondrial dysfunction. Our previous work shows that β-AR signaling during CD8+ T-cell activation in vitro impairs metabolic reprogramming. In new in vivo data, we observed that propranolol treatment increases both glycolysis and oxidative phosphorylation in tumor infiltrating CD8+ T-cells. Together these data suggest that β-AR signaling is a significant factor regulating the functional status of CD8+ T-cells in the TME. Blockade and/or reduction of adrenergic stress has the potential to improve anti-tumor immunity as well as the efficacy of immune checkpoint inhibitors.
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Lorrey, Selena, Lucas Wachsmuth, Jessica Waibl Polania, Alexandra Hoyt-Miggelbrink, Corey Neff, Mackenzie Price, John Finlay, et al. "IMMU-49. BETA-ADRENERGIC BLOCKADE LICENSES THE USE OF IMMUNOTHERAPY IN PRIMARY AND METASTATIC BRAIN TUMORS." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v153. http://dx.doi.org/10.1093/neuonc/noad179.0581.
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Abstract Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success.Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment with an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Further, using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely-prescribed FDA-approved beta-blocker, extended survival. Moving forward, we suggest that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.
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Zeng, Zhimin, Yuxia Liang, Jia Shi, Lisha Xiao, Lu Tang, Yubiao Guo, Fengjia Chen, and Gengpeng Lin. "Identification and Application of a Novel Immune-Related lncRNA Signature on the Prognosis and Immunotherapy for Lung Adenocarcinoma." Diagnostics 12, no. 11 (November 21, 2022): 2891. http://dx.doi.org/10.3390/diagnostics12112891.
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Background: Long non-coding RNA (lncRNA) participates in the immune regulation of lung cancer. However, limited studies showed the potential roles of immune-related lncRNAs (IRLs) in predicting survival and immunotherapy response of lung adenocarcinoma (LUAD). Methods: Based on The Cancer Genome Atlas (TCGA) and ImmLnc databases, IRLs were identified through weighted gene coexpression network analysis (WGCNA), Cox regression, and Lasso regression analyses. The predictive ability was validated by Kaplan–Meier (KM) and receiver operating characteristic (ROC) curves in the internal dataset, external dataset, and clinical study. The immunophenoscore (IPS)-PD1/PD-L1 blocker and IPS-CTLA4 blocker data of LUAD were obtained in TCIA to predict the response to immune checkpoint inhibitors (ICIs). The expression levels of immune checkpoint molecules and markers for hyperprogressive disease were analyzed. Results: A six-IRL signature was identified, and patients were stratified into high- and low-risk groups. The low-risk had improved survival outcome (p = 0.006 in the training dataset, p = 0.010 in the testing dataset, p < 0.001 in the entire dataset), a stronger response to ICI (p < 0.001 in response to anti-PD-1/PD-L1, p < 0.001 in response to anti-CTLA4), and higher expression levels of immune checkpoint molecules (p < 0.001 in PD-1, p < 0.001 in PD-L1, p < 0.001 in CTLA4) but expressed more biomarkers of hyperprogression in immunotherapy (p = 0.002 in MDM2, p < 0.001 in MDM4). Conclusion: The six-IRL signature exhibits a promising prediction value of clinical prognosis and ICI efficacy in LUAD. Patients with low risk might gain benefits from ICI, although some have a risk of hyperprogressive disease.
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Koks, Marije S., Gurbey Ocak, Britt B. M. Suelmann, Cornelia A. R. Hulsbergen-Veelken, Saskia Haitjema, Marieke E. Vianen, Marianne C. Verhaar, Karin A. H. Kaasjager, and Meriem Khairoun. "Immune checkpoint inhibitor-associated acute kidney injury and mortality: An observational study." PLOS ONE 16, no. 6 (June 8, 2021): e0252978. http://dx.doi.org/10.1371/journal.pone.0252978.
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Background Immune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors. Methods Patients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value. Results Among 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality. Conclusions In this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.
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Nelson, Michelle, Keisuke Shirai, Ridhi Gupta, Gary Gilkeson, and Chrystal M. Paulos. "Understanding how immune checkpoint modulators alter pre-existing rheumatologic disorders in cancer patients." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 120.7. http://dx.doi.org/10.4049/jimmunol.198.supp.120.7.
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Abstract The aim of cancer immunotherapy is to reinvigorate an exhausted immune system. Checkpoint modulators PD1/PDL1 and CTLA4 antagonists “release the breaks” on ineffective T cells and subsequently bolster tumor-targeted T cells. These checkpoint modulators are increasingly available for numerous cancers and therefore the number of patients on immunotherapy are ever increasing. In contrast, patients with autoimmune diseases are prescribed immune therapies that dampen the immune system. Of note, immune suppressive therapies increase the incidence of various cancers. The interesting question that has not been fully addressed- what is happening immunologically in patients who have pre-existing autoimmune diseases and are treated with checkpoint modulators for cancer? We have been evaluating the immune correlates in patients with pre-existing rheumatoid arthritis (RA; often being treated with TNF-α blocker) who later receive checkpoint therapy when diagnosed with cancer. Following checkpoint therapy, we saw an increase in central memory T cells, a decrease in PD1 and CTLA4 expression, and a decrease in Th1 and Th17 cells in the peripheral blood. Additionally, we have been working on a dual disease animal model- collagen-induced arthritis (CIA) and lung cancer models. This will has allowed us to study the direct immunological consequences of giving treatments that either dampen or boost the immune system on both cancer and CIA disease states. Outcomes from this work will continue to expand our understanding of the immune system in patients with dual diseases and thus be better equipped to evaluate immunological correlates for exacerbated autoimmune disease and to productively treat patients with both autoimmune and cancer diagnoses.
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Kim, Aeyung, Eun-Ji Lee, Jung Ho Han, and Hwan-Suck Chung. "Caryophylli Cortex Suppress PD-L1 Expression in Cancer Cells and Potentiates Anti-Tumor Immunity in a Humanized PD-1/PD-L1 Knock-In MC-38 Colon Cancer Mouse Model." Nutrients 16, no. 24 (December 23, 2024): 4415. https://doi.org/10.3390/nu16244415.
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Background/Objectives: Immune checkpoints are essential for regulating excessive autoimmune responses and maintaining immune homeostasis. However, in the tumor microenvironment, these checkpoints can lead to cytotoxic T cell exhaustion, allowing cancer cells to evade immune surveillance and promote tumor progression. The expression of programmed death-ligand 1 (PD-L1) in cancer cells is associated with poor prognoses, reduced survival rates, and lower responses to therapies. Consequently, downregulating PD-L1 expression has become a key strategy in developing immune checkpoint inhibitors (ICIs). Caryophylli cortex (CC), derived from the bark of the clove tree Syzygium aromaticum, possesses antioxidant and cytotoxic properties against cancer cells, yet its potential as an ICI remains unclear. Methods: In this study, we aimed to investigate whether CC extract modulates PD-L1 expression in cancer cells and activates T cell immunity through a co-culture system of cancer cells and T cells, as well as in hPD-L1/MC-38 tumor-bearing animal models. Results: Our findings indicate that CC extract significantly downregulated both constitutive and inducible PD-L1 expression at non-toxic concentrations for cancer cells while simultaneously enhancing cancer cell mortality and T cell activity in the co-culture system. Furthermore, the administration of CC extract to hPD-L1/MC-38 tumor-bearing mice resulted in a greater than 70% reduction in tumor growth and increased infiltration of CD8+ T cells within the tumor microenvironment. Principal component analysis identified bergenin, chlorogenic acid, and ellagic acid as active ICIs. Conclusions: These findings suggest that CC extract exerts a potent antitumor effect as an immune checkpoint blocker by inhibiting PD-L1 expression in cancer cells and disrupting the PD-1/PD-L1 interaction.
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Lorrey, Selena, Lucas P. Wachsmuth, Quinn T. Ostrom, and Peter E. Fecci. "Combination beta-adrenergic blockade and immunotherapy for the treatment of primary and metastatic brain cancer." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e14017-e14017. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e14017.
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e14017 Background: Brain tumors present a unique challenge to immunotherapeutic success, as immune responses in patients with brain tumors are suppressed both within the tumor microenvironment and peripherally. The systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Brain tumor patients, particularly those with primary brain tumors like glioblastoma, represent a population in dire need of more thoughtful, targeted treatment approaches. Through this work we present an immunosuppressive axis specifically activated in the context of intracranial malignancies that inhibits immunotherapeutic success in these patients. We demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. More specifically, beta-adrenergic signaling is known to suppress immune responses in various contexts. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. Methods: Using the SEER Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently on beta-blocker therapy. Results: We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of both glioma and melanoma brain metastases, demonstrating that combining immunotherapy and propranolol, a highly-prescribed FDA-approved beta-blocker, extended survival. Conclusions: Moving forward, we suggest that combination therapy with propranolol and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.
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Wang, Zhengyi, and Xiaoying Wu. "Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker." Cancer Medicine 9, no. 21 (September 2, 2020): 8086–121. http://dx.doi.org/10.1002/cam4.3410.
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Rasor, Brendan, Rachel Henderson, and Kin Chan. "Characteristics of hospitalizations among patients receiving immune checkpoint inhibitors at a community teaching hospital." Journal of Oncology Pharmacy Practice 26, no. 1 (March 29, 2019): 60–66. http://dx.doi.org/10.1177/1078155219836155.
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Purpose As immune checkpoint inhibitors continue to acquire new indications, it is important to understand the impact their use has on patients. This study adds to current literature by presenting an analysis of hospitalizations in this population. The primary objective was to assess the reasons for an emergency department visit or hospital admission in patients who receive immune checkpoint inhibitors. Secondary objectives included identifying the frequency of suspected or confirmed immune related adverse events, types of immune related adverse events, number of preventable admissions, duration of immunotherapy, and length of stay. Methods This study was a retrospective, multi-center, chart review of patients hospitalized after receiving an immune checkpoint inhibitor. The population included patients aged 18 and above who received at least one dose of an immune checkpoint inhibitor at a network facility and had a documented admission within one year following the initiation of immunotherapy. Descriptive statistics were performed along with inferential comparisons and a Poisson regression to determine if the immune checkpoint blocker or cancer type predicted admission or reason for admission. Results The 99 patients who met inclusion criteria had a total of 202 admissions. Of these patients, 56 (56.6%) had multiple admissions within the year following initiation of immunotherapy. The most common diagnoses on initial admissions were shortness of breath, pain, and pneumonia. A total of 104 admissions (51.5%) were considered potentially preventable. Suspected or confirmed immune related adverse events were identified in 15.6% of all admissions. There were no significant predictors of admissions or reason for admission. Conclusion Reasons for admission in the study population were comparable to those identified in the general cancer population, with immune related adverse events being associated with a minority of both total and potentially preventable admissions.
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Yu, Xiaoqing, and Xuefeng Wang. "Tumor immunity landscape in non-small cell lung cancer." PeerJ 6 (March 23, 2018): e4546. http://dx.doi.org/10.7717/peerj.4546.
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Even with the great advances in immunotherapy in recent years, the response rate to immune checkpoint inhibitor therapy for non-small cell lung cancer is only about 20%. We aimed to identify new features that would better predict which patients can benefit from an immune checkpoint blocker. This study is based on the publicly available gene expression data from The Cancer Genome Atlas lung cancer samples and the newly released mutation annotation data. We performed a comprehensive analysis by correlating patient cytolytic activity index, mutational signatures, and other immune characteristics in four stratified patient groups. The results cytolytic activity index are highly correlated with immune infiltration scores, T cell infiltration scores and TCR clonality scores in lung cancer. In addition, we observed that the mutational event signatures might play a more important role in predicting immunotherapy response in squamous cell carcinoma and two subgroups of adenocarcinomas. Our analysis illustrates the utility of integrating both tumor immune and genomic landscape for a better understanding of immune response in lung cancer.
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Lee, J., J. S. Chang, M. R. Roh, B. H. Oh, K. Y. Chung, W. S. Koom, and S. J. Shin. "PO-1224: Clinical outcomes of malignant melanoma treated with immune checkpoint blocker in Korean patients." Radiotherapy and Oncology 152 (November 2020): S644—S645. http://dx.doi.org/10.1016/s0167-8140(21)01242-1.
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Lorrey, Selena, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, and Peter Fecci. "Abstract PR-001: Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases." Cancer Research 84, no. 5_Supplement_1 (March 4, 2024): PR—001—PR—001. http://dx.doi.org/10.1158/1538-7445.brain23-pr-001.
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Abstract Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment, increasing NF-kB activity and resulting in an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond to immunotherapy. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely prescribed FDA-approved beta-blocker, extended survival. Moving forward, we proffer that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies. Citation Format: Selena Lorrey, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, Peter Fecci. Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-001.
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Sue, Mayumi, Takuya Tsubaki, Yoko Ishimoto, Shinko Hayashi, Saori Ishida, Takafumi Otsuka, Yoshitaka Isumi, et al. "Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates." PLOS ONE 19, no. 6 (June 6, 2024): e0304985. http://dx.doi.org/10.1371/journal.pone.0304985.
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Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.
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Ye, Weiyu, Anna Olsson-Brown, Robert A. Watson, Vincent T. F. Cheung, Robert D. Morgan, Isar Nassiri, Rosalin Cooper, et al. "Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles." British Journal of Cancer 124, no. 10 (March 15, 2021): 1661–69. http://dx.doi.org/10.1038/s41416-021-01310-3.
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Abstract Background Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10−6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.
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Matta, Jessica, Célia Matta, Emilie Thiebault Peter, David Moulaert, Robert Drillien, Benoit Petit-Demouliere, Tania Sorg, Ghina Bou about, and Jean-Marc Limacher. "An innovative combined immunization platform for personalized cancer immunotherapy." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14225-e14225. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14225.
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e14225 Background: Activity of immune checkpoint inhibitors relies mainly on the presence of an immune response directed against neoantigens resulting from tumor specific mutations. The induction and/or amplification of such an immune response is expected to increase the activity of these therapies. We describe here a novel immunization platform developed for the purpose of personalized cancer immunotherapy. This platform integrates a DNA vector coding for neoantigens, a live modified vaccinia of strain Ankara (MVA) used as a physiologic adjuvant and anti-CTLA-4 as a locally acting early immune checkpoint blocker. Methods: Immune potency was assessed in C57BL6 mice injected subcutaneously three times five days apart with an ovalbumine (OVA) expressing DNA vector (100 µg), either alone or in combination with increasing doses of MVA (up to 2.5x107 plaque forming units, pfu) and increasing doses of anti-CTLA-4 (up to 100 µg). OVA specific immune responses were measured by ELISpot. Anti-tumor efficacy was then investigated with a similar administration scheme in a therapeutic B16F10 mice melanoma model with a DNA vector coding for the B16F10-M30 tumor neoantigen. Results: At an optimal dose of 2.5x106 pfu, MVA significantly improved OVA specific immune response up to 10 times higher as compared to vector alone. Addition of CTLA-4 blockade further increased the magnitude of response, up to 30 times higher than with vector alone. Both MVA and CTLA-4 demonstrated a bell-shaped dose dependent effect. In tumor-bearing animals, 80% experienced durable tumor-free survival when treated with the combination therapy as compared to less than 20% in untreated animals or animals treated with each component independently. Treatment appeared feasible and well-tolerated. Conclusions: Neoantigen coding DNA vector, MVA and CTLA-4 immune checkpoint blockade, when co-administered in immunocompetent C57BL6 mice, acted synergistically to induce a cellular immune response. The same approach translated into a strong anti-tumoral response in an aggressive melanoma model. This combined immunization platform appears as a potential novel way to enhance clinical benefit from current immune checkpoint inhibitors.
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Basingab, Fatemah S., Reem A. Alzahrani, Aisha A. Alrofaidi, Ahmed S. Barefah, Rawan M. Hammad, Hadil M. Alahdal, Jehan S. Alrahimi, et al. "Herpesvirus Entry Mediator as an Immune Checkpoint Target and a Potential Prognostic Biomarker in Myeloid and Lymphoid Leukemia." Biomolecules 14, no. 5 (April 27, 2024): 523. http://dx.doi.org/10.3390/biom14050523.
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Herpesvirus entry mediator (HVEM) is a molecular switch that can modulate immune responses against cancer. The significance of HVEM as an immune checkpoint target and a potential prognostic biomarker in malignancies is still controversial. This study aims to determine whether HVEM is an immune checkpoint target with inhibitory effects on anti-tumor CD4+ T cell responses in vitro and whether HVEM gene expression is dysregulated in patients with acute lymphocytic leukemia (ALL). HVEM gene expression in tumor cell lines and peripheral blood mononuclear cells (PBMCs) from ALL patients and healthy controls was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Tumor cells were left untreated (control) or were treated with an HVEM blocker before co-culturing with CD4+ T cells in vitro in a carboxyfluorescein succinimidyl ester (CFSE)-dependent proliferation assay. HVEM expression was upregulated in the chronic myelogenous leukemia cell line (K562) (FC = 376.3, p = 0.086) compared with normal embryonic kidney cells (Hek293). CD4+ T cell proliferation was significantly increased in the HVEM blocker-treated K562 cells (p = 0.0033). Significant HVEM differences were detected in ALL PBMCs compared with the controls, and these were associated with newly diagnosed ALL (p = 0.0011) and relapsed/refractory (p = 0.0051) B cell ALL (p = 0.0039) patients. A significant differentiation between malignant ALL and the controls was observed in a receiver operating characteristic (ROC) curve analysis with AUC = 0.78 ± 0.092 (p = 0.014). These results indicate that HVEM is an inhibitory molecule that may serve as a target for immunotherapy and a potential ALL biomarker.
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Patel, Vaibhav G., Qian Qin, Bo Wang, Mahalya Gogerly-Moragoda, George Mellgard, Xiaobo Zhong, Anish B. Parikh, et al. "Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15068-e15068. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15068.
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e15068 Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.
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Hu, Y., X. Liu, M. Ran, T. Yang, T. Li, Y. Wu, Y. Lin, Z. Qian, and X. Gao. "Simultaneous delivery of immune stimulatory gene and checkpoint blocker via targeted nanoparticles to strengthen antitumor immunity." Materials Today Nano 17 (March 2022): 100151. http://dx.doi.org/10.1016/j.mtnano.2021.100151.
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Lorrey, Selena, Lucas Wachsmuth, Quinn Ostrom, and Peter Fecci. "SYST-05 BETA-ADRENERGIC BLOCKADE LICENSES THE USE OF IMMUNOTHERAPY IN PRIMARY AND METASTATIC BRAIN TUMORS." Neuro-Oncology Advances 5, Supplement_3 (August 1, 2023): iii28—iii29. http://dx.doi.org/10.1093/noajnl/vdad070.112.
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Abstract Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just at the tumor but also outside the CNS. The systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Brain tumor patients, particularly those with metastatic disease, represent a patient population that is on the rise and in need of targeted treatment approaches. Through this work we present a novel axis of immunosuppression in brain tumor patients and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently on beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of both glioma and melanoma brain metastases, demonstrating that combining immunotherapy and propranolol, a widely-prescribed FDA-approved beta-blocker, extended survival. Moving forward, we suggest that combination therapy with propranolol and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.
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Vladimirova, L. Yu, A. Eh Storozhakova, I. L. Popova, S. N. Kabanov, N. A. Abramova, M. A. Teplyakova, N. M. Tikhanovskaya, et al. "Some aspects of nivolumab administration in treatment for metastatic melanoma (clinical cases)." Meditsinskiy sovet = Medical Council, no. 9 (August 7, 2021): 64–74. http://dx.doi.org/10.21518/2079-701x-2021-9-64-74.
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The development of a new direction in anticancer medical therapy – the use of immune checkpoint inhibitors targeting PD-1/ PD-L1 and CTLA-4 – has significantly changed the approach to tumor treatment in the last few years. The PD1 blocker nivolumab in major registered clinical trials improved overall survival, including in metastatic melanoma, with a favorable toxicity profile. However, its efficacy in patients with brain metastases from melanoma was poorly studied, since the inclusion criteria for most clinical trials do not envisage recruiting such patients. The immune-mediated toxicity of immune checkpoint inhibitors is currently well enough studied. However, cases of cutaneous toxicity are quite rare and present certain difficulties for differential diagnosis and treatment. This article presents two cases of effective nivolumab treatment in patients with generalized BRAFwt and BRAFmut cutaneous melanoma. The first case is of interest due to the presence of brain metastases in the patient. Nivolumab therapy helped achieving complete regression of intracranial metastases with the long-term effect. The second case, in addition to effective treatment, demonstrates a rare manifestation of skin toxicity – vitiligo on the face and upper extremities.
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Khalil, Roukiah, Ryan J. Green, Kavya Sivakumar, Payal Varandani, Srinivas Bharadwaj, Shyam S. Mohapatra, and Subhra Mohapatra. "Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer." Cancers 15, no. 12 (June 7, 2023): 3089. http://dx.doi.org/10.3390/cancers15123089.
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Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)—a herbal compound—and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.
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Xie, Bin, Hongkui Chen, Xin Hou, and Danyi Wen. "Abstract 1391: PBMC humanized mouse model for ImmunoOncology drug evaluation." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1391. http://dx.doi.org/10.1158/1538-7445.am2022-1391.
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Abstract Since the first immune checkpoint blocker Ipilimumab was approved by US FDA in 2011, more and more immune therapeutic drugs popped up. Humanized PBMC reconstitution in immune deficient mice is becoming a good model for evaluating therapeutic antibodies, especially the BsAb with one arm of anti-CD3 that mediates immune cells and another arm targeting a tumor antigen. However, limited window of dosing regimen triggered by graft-versus-host-disease (GvHD) after 30-40 days of reconstitution, and insufficient tumor-infiltrated immune cells naturally from reconstituted circulatory system hindered the widely application of the model in immunotherapy in development of multiple immune checkpoint inhibitors or immune agonists. To overcome this, LIDE has developed a unique human PBMC-cancer cells co-inoculated model instead. In our platform, cancer-priming PBMCs were mixed with the fresh cancer cells in MatriGel, co-inoculated into NCG mice to form a huPBMC well-infiltrated tumor tissue for immunotherapy. Our platform has been successfully helped evaluate biological function of PD1, Tigit, PVRIG, CD73, CD47, CD38, CD40, GITR Antibodies, Tgfb1/PDL1 BsAb, DLL3/CD3 BsAb in multiple cancers, such as melanoma, breast cancer and lung cancer. Citation Format: Bin Xie, Hongkui Chen, Xin Hou, Danyi Wen. PBMC humanized mouse model for ImmunoOncology drug evaluation [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 1391.
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Kozhevnikov, Alexander, Ashot Mkrtumyan, Polina Serrgeevna Feoktistova, Daria Filonenko, Natalya Polshina, Ekaterina Volkova, Katerina Grechukhina, Irina Bykonya, and Lyudmila Zhukova. "Predictors of endocrine immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICI) in routine clinical practice." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e14713-e14713. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e14713.
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e14713 Background: Endocrine irAEs have been reported in association with various ICI and are characterized by their correlation with improved survival outcomes. A growing clinical comprehension of endocrine irAEs has facilitated the development of effective treatment strategies involving hormone replacement, which has been shown to enhance patients' quality of life. This study aims to evaluate outcomes in patients (pts) experiencing endocrine irAEs and identify predictive factors for their occurrence. Methods: This retrospective cohort study comprised 214 adult pts with solid malignant tumors who underwent ICI, either as monotherapy or in combination with other chemotherapeutic agents, at the SBIH Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM. Results: Between June 2016 and January 2023, 214 pts were included in the study (46.3% female, 53.7% male). The median age was 62.6 years (range 32–91). At the data cut-off (1 February 2024) the median overall survival (OS) for the analyzed population was 34,5 months (95%CI 21,15-43,91). No significant difference in median OS was observed between pts with overall endocrine irAEs and those exhibiting specific manifestations, such as hypocortisolism and destructive diabetes mellitus. However, thyroid irAEs were associated with improved median OS: 27.5 months compared to 22.6 months in those without (p=0.037); RR=1.39 (95%CI 1.025-1.89; p=0.036). The grade of endocrine irAEs did not impact the survival benefit. A significant association was observed between age group and endocrine irAEs (Pearson’s χ2=9.92, p=0.019), with a left-skewed age distribution due to a higher proportion of participants aged 32–44 years among those developing endocrine irAEs. Pts with nodular goiter had a 2.91 times higher risk of developing thyroiditis (95%CI 1.03–8.25), although this did not reach statistical significance (p=0.067). Calcium channel blockers were associated with an increased risk of developing thyroid irAEs (RR=1.54, 95%CI 1.09–2.19; p=0.036). Antihistamine use was a robust predictor of hypothyroidism with a RR=1.68 (95%CI 1.05–2.7, p=0.04). Initial derived neutrophil-to-lymphocyte ratio (dNLR) ≥3 predict the development of endocrine irAEs (Pearson χ2=4.02; p=0.045) as well as dNLR>2.2 (Pearson χ2=4.22, p=0.04). Conclusions: Thyroid irAEs are correlated with improved OS. Predictors of endocrine irAEs may include young age (32-44 years), calcium channel blocker or antihistamine use, dNLR ≥3, or dNLR >2.2. Prospective trials are warranted to validate these findings.
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Vergne-Santiago, Norma, Ernesto Jos E. Sola Sanchez, and Michelle Marie Mangual Garcia. "Immune Check Point Inhibitors Triggering Non Autoimmune Polyendocrinopathy." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A136—A137. http://dx.doi.org/10.1210/jendso/bvab048.275.
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Abstract The superlative therapeutic response of cancer immunotherapy is activation of the immune system against cancer cells. Currently, one of the most considered immune system enhancer are the immunomodulatory antibodies well known as checkpoint inhibitor therapy. Among this type of treatment, programed cell death-1 receptor blocker, is one of the most sought-after therapies on demand now a day. Notwithstanding the important clinical benefits of this therapeutic modality, serial autoimmune adverse effects and variety of atypical presentations of life-threatening endocrinopathies are expected to occur. We present a case of a 78-year-old man with dyslipidemia and lung CA who was referred to our clinic after developing electrolyte disturbances with associated dizziness and fatigue one month after Pembrolizumab therapy initiation. Physical exam was unremarkable. Laboratory data was consistent with mild hyponatremia, hyperkalemia and adequate fasting blood sugar levels. Aldosterone levels were extremely low, ACTH levels were extremely high with inappropriate low total cortisol response and negative 21-Hydroxylase antibodies. Diagnosis of primary adrenal insufficiency was established and Fludrocortisone 0.05 mg PO daily therapy was started with further resolution of hyponatremia and initial symptoms. In addition, concurrent primary hyperthyroidism along with thyroid RAIU-Scan results were consistent with thyroiditis, but TSI and TPO’s antibody levels were unexpectedly negative. Eventually, a suspicious thyroid nodule was identified requiring biopsy. Initial FNA results showed a follicular lesion of undetermined significance followed by a benign finding when repeated after six months. During follow up, patient’s primary hyperthyroidism converted to severe primary hypothyroidism without any intervention for her prior hyperthyroidism. Patient’s TPO’s levels remain undetectable and his current status is post-thyroiditis with residual primary hypothyroidism. Primary adrenal insufficiency also persist and its antibodies have not yet been identified either. It is known that autoimmunity can predispose to the development of primary adrenal and thyroid disorders in patients undergoing PD-1 receptor blockers therapy against cancer. Both disorders are increasingly recognized and reported as one of the most common adverse effects presenting in patients treated with these agents. However, to our knowledge, cases of non-immune related adverse effects are barely documented. This case of uncommon endocrine manifestations related to checkpoint inhibitors therapy is meritorious of being reported since it should raise awareness in the medical community for prompt identification of signs and symptoms, as well as to offer adequate management, accurate treatment and provide a better standard of care.
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Oren, Ohad, Eric H. Yang, Julian R. Molina, Kent Bailey, and Stephen Kopecky. "BETA-BLOCKER USE IS ASSOCIATED WITH INCREASED ALL-CAUSE MORTALITY IN LUNG CANCER PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITORS." Journal of the American College of Cardiology 75, no. 11 (March 2020): 3519. http://dx.doi.org/10.1016/s0735-1097(20)34146-2.
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Grewal, Udhayvir Singh, Kruti Bhagirath Vora, Aparna Raj Parikh, Amit Mahipal, and Sakti Chakrabarti. "Efficacy and safety of neoadjuvant immune checkpoint inhibitors in patients with localized mismatch repair deficient colorectal cancer: A systematic review." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 149. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.149.
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149 Background: Clinical data demonstrating remarkable anti-tumor activity of immune checkpoint inhibitors (ICI) in patients with mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) and preclinical data suggesting enhanced efficacy of ICIs in the neoadjuvant setting than in the adjuvant setting led to numerous studies with neoadjuvant ICI in various tumor types including in dMMR CRC. We performed a systematic literature review of the published studies reporting the efficacy and safety of neoadjuvant ICIs in patients with localized dMMR CRC. Methods: Medline and Embase were searched for eligible case reports, case series, and clinical trial reports. Eligibility criteria included: 1. patients aged 18 years or older, 2. localized dMMR CRC, and 3. received neoadjuvant therapy primarily with ICI. Patients receiving radiation or chemotherapy along with ICI were excluded. The systematic review was conducted according to the PRISMA harms guidelines. Results: The database search yielded 143 citations which were reviewed by 3 authors (UG, KV, and SC), and 14 citations fulfilled all criteria for inclusion. The analysis included 173 patients with colon cancer (CC) and 19 with rectal cancer (RC). Among the patients with CC, 41 (24 %) received single-agent programmed death 1 (PD-1) blocker, and 132 (76 %) received dual blockade with an anti-PD-1 agent plus an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agent. Resection was performed in 171/173 (99%) patients, and 117/171 (69%) achieved complete pathological response (pCR). After median follow-up ranging between 8 and 15 months, none of the patients experienced cancer relapse. Among patients with RC, 16/19 (84%) received a PD-1 blocker, and 3 (16%) received dual PD-1 plus CTLA-4 blocker. Complete clinical response (cCR) was reported in 14/19 (74%) patients, and of the 5 patients who underwent surgery, 4 (80%) achieved pCR. All patients remained progression-free after median follow-up ranging from 6 to 12 months. Cancer progression or death on neoadjuvant ICI was not reported in any studies with CC or RC patients, and only two studies reported grade 3+ toxicity in 3% of CC patients. Conclusions: Neoadjuvant therapy with ICIs results in a remarkably high rate of clinical and pathological tumor regression with negligible safety concerns in patients with dMMR localized CRC. Well-designed clinical trials with long-term follow-up are needed to evaluate the organ-sparing potential of neoadjuvant ICI therapy in patients with dMMR CRC.
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Methods in Medicine, Computational and Mathematical. "Retracted: Value of a Signature of Immune-Related Genes in Predicting the Prognosis of Melanoma and Its Responses to Immune Checkpoint Blocker Therapies." Computational and Mathematical Methods in Medicine 2023 (June 28, 2023): 1. http://dx.doi.org/10.1155/2023/9781954.
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Zhang, Chi, Fei Wang, and Rubayat Khan. "LMAP-07 POTENTIAL MECHANISM OF IMMUNE ESCAPE RELATED TO TUMOR-ASSOCIATED MACROPHAGE IN GLIOBLASTOMA AFTER COMBINED THERAPY WITH RADIOTHERAPY AND IMMUNE CHECKPOINT BLOCKER." Neuro-Oncology Advances 5, Supplement_3 (August 1, 2023): iii10. http://dx.doi.org/10.1093/noajnl/vdad070.038.
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Abstract Immune checkpoint blockers (ICBs) have revolutionized the treatment of cancer. Radiotherapy (RT) has been demonstrated to increase the survival benefit of ICBs in some cancers through its local and systemic immunomodulation, although its efficacy in glioblastoma (GBM) is very limited. With a thorough investigation of the immune responses to single and dual treatment utilizing single-cell RNA-seq analyses on the synergy of RT and anti-PD-L1 antibody (aPD-L1), we studied the potential mechanism of immune escape in GBM even when RT and ICB are combined. Our findings demonstrated a statistically significant longer survival of mice treated with RT and aPD-L1 combined than either single modality of treatment in an orthotopic syngeneic GBM model achieving a 70% cure rate. In the tumor tissues collected from the mouse brain that failed dual treatment, i.e., immune escaped, immune cell profiling still demonstrated much lower T regulatory cells and higher CD8+ cytotoxic T cells infiltrated to tumor, and elevated CD8+/CD4+ and CD8+/Treg ratios in the dual therapy group compared to single therapies, as expected with synergistic effects of dual treatment. RT with aPD-L1 markedly reduced CD8+ and CD4+ T exhaustion cells and elevated T-memory cells in comparison to single modality groups. Nevertheless, compared to the RT alone or no treatment control group, dual therapy failed to decrease the proportion of Arginase1-positive glioma-associated macrophages (GAM) in macrophage/monocytes in tumor microenvironment, which were considerably increased if treated with aPD-L1 only. Moreover, the combination of RT with aPD-L1 did not alter immunosuppressive gene expression in the macrophage/monocyte groups. In conclusion, our research demonstrated that RT and aPD-L1 together may elicit a potent and durable antitumor immune response in the GBM mouse model through regulating lymphocytes but not macrophages. Our findings point to the urgent need for research into GAM-modulating drug and their potential to prevent immunological escape.
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Lee, Seok-Min, and Byungheon Lee. "Abstract 599: Identification of lymphocyte activation gene 3 binding peptides using phage displayed peptide libraries for cancer immunotherapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 599. http://dx.doi.org/10.1158/1538-7445.am2022-599.
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Abstract Treatment with immune checkpoint blockades against cytotoxic T lymphocyte associated protein-4, programmed cell death-1, and programmed death-ligand 1 is currently giving improved results to many cancer patients. Nevertheless, a significant proportion of cancer patients treated with immune checkpoint blockades are still largely unsatisfied with the benefits of these drugs. One of the reasons is that cancer cells also use other immune checkpoints such as lymphocyte activation gene-3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains, and T-cell immunoglobulin and mucin-domain containing-3. LAG-3 negatively regulates activated T cells. In this study, we screened phage displayed-peptide libraries for peptides that selectively bind to LAG-3. After five rounds of screening, we selected a candidate peptide and named it LAG3Pep. LAG3Pep preferentially bound to human LAG-3-transfected HEK 293T cells over mock-transfected cells and phorbol myristate acetate/ionomycin/chloroquine-stimulated Jurkat T cells over unstimulated cells. LAG3Pep also bound to splenocytes isolated from tumor-bearing mice, suggesting the reactivity across human and mouse LAG-3. Pull-down of Jurkat T cell lysates using biotin-labeled LAG3Pep yielded a protein band of LAG-3. A competition by the pre-treatment of Jurkat T cells with a LAG-3-blocking antibody inhibited the cell binding of LAG3Pep. In addition, LAG3Pep inhibited the binding of LAG-3 protein to THP-1 cells expressing HLA-DR, a well-known LAG-3 ligand. Moreover, LAG3Pep recovered IL2 production by stimulated Jurkat T cells, which were suppressed by fibrinogen-like protein 1, another ligand of LAG-3, in the culture medium of HepG2 tumor cells. These results show that LAG3Pep selectively binds to LAG-3 and has a potential as a LAG-3 blocker for cancer immunotherapy. Citation Format: Seok-Min Lee, Byungheon Lee. Identification of lymphocyte activation gene 3 binding peptides using phage displayed peptide libraries for cancer immunotherapy [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 599.
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Fjæstad, Klaire Yixin, Anne Mette Askehøj Rømer, Victor Goitea, Astrid Zedlitz Johansen, Marie-Louise Thorseth, Marco Carretta, Lars Henning Engelholm, Lars Grøntved, Niels Junker, and Daniel Hargbøl Madsen. "Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment." Oncogene 41, no. 9 (January 11, 2022): 1364–75. http://dx.doi.org/10.1038/s41388-021-02170-0.
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AbstractThe development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.
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Peng, Zeyu, Xiaodong F. Liu, Shukai Xia, Jinyu Liu, Hongyan Li, Yuxiang Liu, Hugh M. Davis, Mingjiu Chen, and Mark Z. Ma. "Abstract 5522: BSI-060T, a high affinity, fully human anti-siglec-15 antibody as an alternative immune checkpoint blocker." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5522. http://dx.doi.org/10.1158/1538-7445.am2022-5522.
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Abstract Background: Siglec-15 is a single-pass type I membrane protein that plays an important role in the immune-suppressive tumor microenvironment (TME). Siglec-15 has low expression levels in most normal human tissues but it is highly expressed in a subset of myeloid cells of the TME and over-expressed in some solid tumors. Siglec-15 on tumor associated macrophages and tumor cells inhibits T cell proliferation and pro-inflammatory cytokine release. Therefore, targeting Siglec-15 may overcome a suppressive TME and enhance the anti-tumor activity of other immune checkpoint inhibitors. Experimental procedures: Humanized mice were used immunized with recombinant Siglec-15-ECD-Fc. The Biosion proprietary H3 (High-throughput, High-content and High-efficiency) antibody screening platform was used to identify a lead anti-Siglec-15 mAb candidate-BSI-060T. Siglec-15 expression in head and neck, lung and other cancer types was assessed by immunohistochemistry (IHC) in conjunction with PD-L1. The ex vivo release of suppression of T cell activity was determined by stimulating human peripheral blood mononuclear cells with a suboptimal dose of immobilized OKT3 in the presence of recombinant human Siglec-15-Fc with and without BSI-060T. A pharmacokinetic study was carried out in cynomolgus monkeys to determine the exposure of BSI-060T over time. Tumor inhibition of BSI-060T was evaluated in Siglec-15 humanized mice that were inoculated with MC38 cells overexpressing human Siglec-15. Summary: BSI-060T is a fully human IgG1κ monoclonal antibody that binds to Siglec-15 protein with high affinity and blocks the interaction between Siglec-15 and its putative receptor LRRC4C. BSI-060T shows cross-reactivity to monkey and mouse Siglec-15. In ex vivo T cell response assays, BSI-060T exhibits strong activity on reverting Siglec-15-mediated inhibition of CD8+ and CD4+ T cell proliferation and interferon-γ release. In a humanized Siglec-15 mouse syngeneic tumor model, BSI-060T shows significant inhibition of tumor growth. BSI-060T also exhibits excellent monkey PK. In addition, an IHC assay has been developed and used to identify tumor types overexpressing Siglec-15. This assay will be used for patient recruitment in early clinical development and has the potential to be a companion diagnostic in the future. Conclusion: BSI-060T exhibits best-in-class biophysical properties and functional characteristics, supporting the initiation of development activities including manufacturing and IND-enabling studies. Citation Format: Zeyu Peng, Xiaodong F. Liu, Shukai Xia, Jinyu Liu, Hongyan Li, Yuxiang Liu, Hugh M. Davis, Mingjiu Chen, Mark Z. Ma. BSI-060T, a high affinity, fully human anti-siglec-15 antibody as an alternative immune checkpoint blocker [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 5522.
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von Vietinghoff, Sibylle. "Wie beeinflussen Nierenschäden unter Checkpointinhibitortherapie die Prognose?" Kompass Autoimmun 4, no. 1 (2022): 10–11. http://dx.doi.org/10.1159/000521521.
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<b>Background:</b> Immune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors. <b>Methods:</b> Patients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value. <b>Results:</b> Among 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality. <b>Conclusions:</b> In this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.
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Liu, Demi X., Jun Zhou, Chenpan Nie, Annie X. An, Henry Q. X. Li, and Jingjing Wang. "Abstract 617: MEK inhibitor rescued the efficacy of PD-1 blocker in STK11/LKB1 mutated colorectal cancer model." Cancer Research 82, no. 12_Supplement (June 15, 2022): 617. http://dx.doi.org/10.1158/1538-7445.am2022-617.
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Abstract Introduction: The mechanism of action of primary resistance to PD-1 blockade is largely unknown, however STK11/LKB1 alterations have been reported to have a significant role in primary resistance to PD-1/PD-L1 axis inhibitors in KRAS-mutant lung adenocarcinoma. It is importsnt to identify treatments which can rescue the efficacy of PD-1 blocker in STK11/LKB1-mutant patients. We have developed a STK11 knockout (KO) model using the CT26 colorectal cancer syngeneic line which harbors a KRAS mutation and evaluated the response to checkpoint inhibitor alone and in combination with MEK inhibitors. Method: CT26-STK11KOwas developed by CRISPR/Cas9 technology and STK11/LTB1 deletion was verified by Western Blot. To test the response of the cell line to anti-PD-1 treatment (10mg/kg), we engrafted CT26-WT and CT26-STK11KO tumor lines into BALB/c mice. Tumor growth inhibition (TGI) was assessed as TGI%=(1-Ti/Vi) x100%; Ti as the mean tumor volume of the treatment group on the measurement day; Vi as the mean tumor volume of control group at the measurement day. At termination FACS analysis of different major types of immune cells was performed. Combination with MEK inhibitors, including Trametinib (1mg/kg) was also evaluated. Results: In comparison to CT26-WT tumor growth, PD-1 blocker could not inhibit CT26-STK11KO tumor progression. However, Combinational treatment of Trametinib and anti-PD-1 antibody delayed CT26-STK11KO tumor growth. In CT26-WT tumor bearing mice, anti-PD-1 monotherapy increased total CD45+ immune cells, suggesting an ongoing immune response; significantly increased the ratio between M1 and M2, which might be an indicator for enhanced type I T cell response. CD8+ T cell infiltration in CT26-STK11KO tumors was dramatically decreased associated with increased percentage of G-MDSC which may have contributed to the loss of response to anti-PD-1 treatment. MET inhibitor, Trametinib, decreased G-MDSC and restored CD8+ T cell infiltration and PD-1 blocker efficacy in CT26-STK11KO tumor. Conclusions: We successfully generated a CT26-STK11KO cell line which was valuable for evaluation of PD-1 blocker and MEK inhibitor in STK11/LTB1 deficient tumor, in which Trametinib could rescue the efficacy of PD-1 treatment in CT26-STK11KO tumor via inhibiting G-MDSC. Taken together, our data suggest that altered immune cell infiltration, particularly increased G-MDSCs, in tumor microenvironment might be the reason for poor PD-1 blocker efficacy in CT26-STK11KO tumor. Citation Format: Demi X. Liu, Jun Zhou, Chenpan Nie, Annie X. An, Henry Q.X. Li, Jingjing Wang. MEK inhibitor rescued the efficacy of PD-1 blocker in STK11/LKB1 mutated colorectal cancer model [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 617.
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Mori, Takuya, Hiroaki Tanaka, Sota Deguchi, Yoshihito Yamakoshi, Yuichiro Miki, Mami Yoshii, Tatsuro Tamura, et al. "Clinical efficacy of nivolumab is associated with tertiary lymphoid structures in surgically resected primary tumors of recurrent gastric cancer." PLOS ONE 17, no. 1 (January 7, 2022): e0262455. http://dx.doi.org/10.1371/journal.pone.0262455.
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Nivolumab, an immune checkpoint blocker, has been approved for advanced gastric cancer (GC), but predictive factors of nivolumab’s efficacy in patients with GC, especially immune cells such as tissue-resident memory T cells or those forming tertiary lymphoid structures (TLS), remain unclear. Tissue samples were obtained from surgically resected specimens of patients with GC who were treated with nivolumab as third-line or later treatment. Immunohistochemical staining was performed to detect the presence of TLS and CD103+ T cells and assess the association between TLSs and response to nivolumab treatment. A total of 19 patients were analyzed. In patients with partial response (PR) to nivolumab, numerous TLS were observed, and CD103+ T cells were found in and around TLS. Patients with many TLS experienced immune-related adverse events more often than those with few TLS (p = 0.018). The prognosis of patients with TLS high was better than those with TLS low. Patients with a combination of TLS high and CD103 high tended to have a better prognosis than other groups. Our results suggested that TLS status might be a predictor of nivolumab effectiveness.
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Al-Khateeb, Wasef, John Jarad, Yuri Kim, and Robert Battisti. "Long-term nivolumab treatment possibly associated with aseptic meningitis." BMJ Case Reports 17, no. 2 (February 2024): e258141. http://dx.doi.org/10.1136/bcr-2023-258141.
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Nivolumab is a programmed death-1 receptor blocker within the family of medications called immune checkpoint inhibitors (ICIs). Although generally well tolerated, cases of immune‐related adverse events (irAEs) have been reported. We present a case of a man being treated with nivolumab for renal cell carcinoma who presented to the emergency department with problems of headache, fever and disorientation. After extensive evaluation, a diagnosis of immunotherapy-induced aseptic meningitis was considered more probable than infectious. Due to stable clinical status, no treatment was initiated, and the patient’s condition improved spontaneously. The patient was discharged home. To date, only a handful of prior cases of nivolumab-induced meningitis have been reported. Our case demonstrates that irAEs can occur years after the initiation of ICIs. This was a milder presentation of a neurological irAE that resolved spontaneously with watchful waiting, showing that irAEs are likely an evolving spectrum of disease for which clinicians should be aware.
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Michot, Jean-Marie, Abhay Patki, Marina Maglakelidze, Regis Costello, Martin Donchev, Vincent Ribrag, and Igori Vinogradov. "Open-Label Phase 2 Study Results of FS118, a LAG-3/PD-L1 Bispecific Antibody, in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma." Blood 144, Supplement 1 (November 5, 2024): 1731. https://doi.org/10.1182/blood-2024-202538.
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Introduction Patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) after two lines of systemic therapy and after CD19 CAR-T cells have poor prognosis and new therapies are needed. There are no approved immune checkpoint blockers (ICB) for DLBCL. Immune checkpoint blockers anti-PD1 have demonstrated modest activity in R/R DLBCL and new optimized immunotherapies are required. DLBCL are tumors known to express high levels of immune checkpoints PD-L1 and LAG-3. FS118 is a novel ICB, tetravalent bispecific IgG1 antibody, which consists of an anti-PD-L1 IgG1 with a distinct LAG-3 binding capability with a terminal half-life of ~4 days. In a Phase 1, previously conducted in both US (IND Number:137281) and Europe (EudraCT Number: 2021-002946-33), FS118, was well tolerated up to dosage 20 mg/kg intravenously (IV) QW with no dose limiting toxicities (DLT) observed and demonstrated antitumor activity. Established recommended Phase 2 dose was 10 mg/kg IV QW and was investigated in FS118-21201 study (EudraCT 2021-003406-47) enrolling non-small cell lung cancer patients (Cohort A, n=21) and DLBCL patients (Cohort C, n=10). Methods FS118-21201 is a Phase 2 open-label basket study of FS118 in adult patients. The study design consists of multiple single-arm tumor-specific cohorts and is primarily designed to assess efficacy. Secondary objectives were assessment of tolerability of FS118 and PK parameters. Key inclusion criteria for cohort C were patients with measurable R/R DLBCL who previously received at least 2 systemic regimens, where one therapy line must have included anti-CD20 immuno-chemotherapy regimen and one therapy line must have included CD19 CAR-T cells where this is the institution's standard of care, unless contraindicated. Patients received FS118 IV, 10 mg/kg QW, until disease progression or unacceptable toxicity, for a maximum of 24 months. Patients achieving a durable complete response (CR) could discontinue the treatment after at least 24 QW administrations and 8 QW administrations after CR. Results. In cohort C, as of 23 Jun 2024, 10 patients with R/R DLBCL were treated. Median (range) age of 5 males and 5 females (6 patients of white race and 4 unknown) was 58.5 years (36-65 years). Median number of previous lines of therapy was 3.5 (range 2-7). Four (4/10, 40%) patients previously received CD19 CAR-T cells therapy. The overall response rate was 20% (2/10 evaluable patients), and both were complete responses. Responders (n=2) included one patient previously treated with CD19 CAR-T cells therapy. One of the responders (CD19 CAR-T cells pre-treated) had a duration of response for >64.9 weeks and other had a duration of response for 8.1 weeks. All patients have discontinued the study. Two patients discontinued due to confirmed CR and eight patients discontinued treatment due to progressive disease. There were no dose-limiting toxicities (DLTs) observed. No patients discontinued the treatment due to toxicity. Eight patients (8/10, 80% patients) experienced any grade treatment-emergent adverse event (TEAE). Three patients (3/10, 30% patients) experienced any grade drug-related TEAE. One patient experienced grade 3 drug related TEAE of pulmonary embolism. There were no grades 4 or 5 drug-related TEAE. Four (4/10, 40%) Patients experienced at least one serious TEAE (3 unrelated and 1 drug-related (pulmonary embolism). Conclusions In this phase 2 study, FS118 was well tolerated in patients with R/R DLBCL with no DLTs reported. FS118 is a new potential immune checkpoint blocker showing meaningful efficacy with durable responses achieved in patients with R/R DLBCL.
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Chow, Laura Quan Man, Justin F. Gainor, Nehal J. Lakhani, Hyun Cheol Chung, Keun-Wook Lee, Jeeyun Lee, Patricia LoRusso, et al. "A phase I study of ALX148, a CD47 blocker, in combination with established anticancer antibodies in patients with advanced malignancy." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2514. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2514.
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2514 Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host’s immune response. ALX148 (A) is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. ALX148 is well tolerated in combination with pembrolizumab (P) or trastuzumab (T) with no maximum tolerated dose (MTD) identified (ASCO 2018 #3068, SITC 2018 #P335). Safety and antitumor activity of ALX148 (10 mg/kg QW) in combination with T or P are reported in patients (pts) including those with anti-HER2 or checkpoint inhibitor (CPI) relapsed/refractory diseases. Methods: Patients with malignancy including non-small cell lung cancer (NSCLC: CPI resistant/refractory or PD-L1 tumor proportion score <50%) and head and neck squamous cell carcinoma (HNSCC: progressed on platinum therapy) received A+P. Patients with HER2 malignancy including gastric/gastroesophageal junction (GEJ) cancer (progressed on T + fluoropyrimidine-based therapy) received A+T. Safety, response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed. Preliminary data from fully enrolled cohorts are reported as of 20 Jan 2019 (safety)/28 Jan 2019 (efficacy). Results: Seventy-nine pts received A+P (All, n=50; NSCLC, n=23; HNSCC, n=20) or A+T (All, n=29; Gastric/GEJ, n=23) as of data cutoff. Forty-seven pts reported mostly low grade treatment related adverse events. The most common were fatigue (11%), AST increase (9%), ALT increase (8%), anemia (8%), and platelets decreased (6%). In select tumor histologies, anticancer activity was observed in initial response-evaluable pts [NSCLC (n=23) 1PR, 8SD; HNSCC (n=17) 3PR, 4SD; and Gastric/GEJ (n=21) 4PR, 6SD]. Preliminary results indicate favorable ALX148 PK and CD47 target occupancy profiles, and positive effects on tumor infiltrating immune cells. Results will be updated at presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics to date. Objective responses were observed in patients with late line NSCLC, HNSCC, and Gastric/GEJ, including disease relapsed/refractory to prior CPI and HER2-targeted therapies. Clinical trial information: NCT03013218.
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Ali, Mohamed H. M., Salman M. Toor, Fazle Rakib, Raghvendra Mall, Ehsan Ullah, Kamal Mroue, Prasanna R. Kolatkar, Khalid Al-Saad, and Eyad Elkord. "Investigation of the Effect of PD-L1 Blockade on Triple Negative Breast Cancer Cells Using Fourier Transform Infrared Spectroscopy." Vaccines 7, no. 3 (September 9, 2019): 109. http://dx.doi.org/10.3390/vaccines7030109.
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Interactions between programmed death-1 (PD-1) with its ligand PD-L1 on tumor cells can antagonize T cell responses. Inhibiting these interactions using immune checkpoint inhibitors has shown promise in cancer immunotherapy. MDA-MB-231 is a triple negative breast cancer cell line that expresses PD-L1. In this study, we investigated the biochemical changes in MDA-MB-231 cells following treatment with atezolizumab, a specific PD-L1 blocker. Our readouts were Fourier Transform Infrared (FTIR) spectroscopy and flow cytometric analyses. Chemometrical analysis, such as principal component analysis (PCA), was applied to delineate the spectral differences. We were able to identify the chemical alterations in both protein and lipid structure of the treated cells. We found that there was a shift from random coil and α-helical structure to β-sheet conformation of PD-L1 on tumor cells due to atezolizumab treatment, which could hinder binding with its receptors on immune cells, ensuring sustained T cell activation for potent immune responses. This work provides novel information about the effects of atezolizumab at molecular and cellular levels. FTIR bio-spectroscopy, in combination with chemometric analyses, may expedite research and offer new approaches for cancer immunology.