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This case describes a patient with somatic dMMR who progressed on pembrolizumab after initial response, received JNJ-081, then restarted pembrolizumab and achieved a durable exceptional second 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is pembrolizumab effective for only a subset of mCRPC patients?","Question",{"text":63,"@type":64},"Most men with metastatic castration-resistant prostate cancer show limited response, but tumors with mismatch repair deficiency (dMMR) and MSI-H exhibit a hypermutation phenotype and show predictive response to pembrolizumab.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What treatment did the patient receive after progressing on initial pembrolizumab?",{"text":68,"@type":64},"After progression on pembrolizumab, the patient enrolled in a clinical trial with JNJ-081, a PSMA-CD3 bispecific T-cell engager antibody.",{"name":70,"@type":61,"acceptedAnswer":71},"How did the patient respond after reinitiating pembrolizumab following JNJ-081?",{"text":72,"@type":64},"Upon rechallenge, the patient experienced an exceptional second response, with prostate-specific antigen dropping from 20.01 to undetectable after 6 weeks and remaining undetectable for over 11 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in a patient with mismatch repair-deficient metastatic castration-resistant prostate cancer: a case report  \nDarien E Reed-Perino  ,1,2 Michael Lai,1 Evan Y Yu,1,3 Michael T Schweizer1,3  \nTo cite: Reed-Perino DE, Lai M, Yu EY, et al. Re-sensitization topembrolizumab following PSMACD3 T-cell redirection therapy with JNJ-081 in a patient with mismatch repair-deficient metastatic castration-resistant prostate cancer: a case report. Journal for ImmunoTherapy of Cancer 2023;11:e006794 . doi:10.1136/jitc-2023-006794  \nAccepted 03 May 2023  \n© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.  \n1Division of Oncology, Department of Medicine, University of Washington, Seattle, Washington, USA 2Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA 3Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA  \nCorrespondence to  \nDr Michael T Schweizer; [schweize@uw.edu](schweize@uw.edu)  \nABSTRACT  \nWhile checkpoint inhibitor therapy has revolutionized the treatment landscape of some solid tumors, it has shown limited efficacy in metastatic castration-resistant prostate cancers (mCRPC). A small (~3–5%) but clinically distinct subset of mCRPC tumors have a DNA mismatch repair deficiency (dMMR) and develop a hypermutation phenotype with elevated tumor mutational burden and high microsatellite instability (MSI-H) . Retrospective analyses have shown dMMR/MSI-H status to be a predictive biomarker for response to pembrolizumab in prostate tumors. Here, in this report, we present a case of a patient with mCRPC harboring a somatic dMMR who had progressed on pembrolizumab after an initial response. He enrolled on a clinical trial with JNJ-081, a prostate-specific membrane antigen-CD3 bispecific T-cell engager antibody and experienced a partial response with course complicated by cytokine release syndrome. On progression, he was reinitiated on pembrolizumab and experienced an exceptional second response, with his prostate-specific antigen falling from a high of 20.01 to undetectable after 6 weeks and remaining undetectable for >11 months. To our knowledge, this represents the first reported case of bispecific T-cell engager-mediated resensitization to checkpoint inhibitor therapy in any cancer.  \nINTRODUCTION  \nCheckpoint inhibitor therapies have revolutionized the treatment of some solid tumors but have not proven to be effective for most men with metastatic castration-resistant prostate cancer (mCRPC) . A small (~3–5%) clinically distinct subset of these tumors harbor mutations in mismatch repair (MMR) genes (ie, MLH1, MSH2, MSH6 or PMS2), which in turn leads to a high tumor mutational burden (TMB) and microsatellite instability (MSI) .1 MMR deficient (dMMR) prostate tumors have aggressive pathologic and clinical features, including high Gleason scores and  \nthe presence of de novo metastatic disease at diagnosis.1 Prospective clinical studies in tumor type-agnostic dMMR/MSI-high (MSI-H) solid tumors showed high response rates and long progression-free survival with the anti-programmed cell death protein-1 (PD-1) monoclonal antibody pembrolizumab. Retrospective analyses showed dMMR/MSI-H status to be a useful predictive biomarker for response to pembrolizumab in the few prostate tumors included in these trials, whereas clinical response in unselected patients with mCRPC is exceedingly low (3–5%) .1  \nSecondary resistance mechanisms have hindered realizing the full potential of immunotherapy in mCRPC. Given that a large proportion of tumors lack T-cell infiltration, so called ‘cold tumors’, significant research has been dedicated to triggering T-cell infiltration into the tumor, creating a ‘hot tumor’. One avenue has been through bispecific antibodies comprised of two single-chain var","cbCaikB4hr3fEW5f","https://ap.wps.com/l/cbCaikB4hr3fEW5f","pdf",314665,"English","# Abstract\n# Introduction\n# Case\n## Figure 1: PSA trend","[{\"question\":\"Why is pembrolizumab effective for only a subset of mCRPC patients?\",\"answer\":\"Most men with metastatic castration-resistant prostate cancer show limited response, but tumors with mismatch repair deficiency (dMMR) and MSI-H exhibit a hypermutation phenotype and show predictive response to pembrolizumab.\"},{\"question\":\"What treatment did the patient receive after progressing on initial pembrolizumab?\",\"answer\":\"After progression on pembrolizumab, the patient enrolled in a clinical trial with JNJ-081, a PSMA-CD3 bispecific T-cell engager antibody.\"},{\"question\":\"How did the patient respond after reinitiating pembrolizumab following JNJ-081?\",\"answer\":\"Upon rechallenge, the patient experienced an exceptional second response, with prostate-specific antigen dropping from 20.01 to undetectable after 6 weeks and remaining undetectable for over 11 months.\"}]","Re-sensitization to pembrolizumab following PSMA-CD3 T-cell redirection therapy with JNJ-081: a case report | PDF",1790244022]