Zarrabi Kevin K, Narayan Vivek, Mille Patrick J, Zibelman Matthew R, Miron Benjamin, Bashir Babar, Kelly William Kevin
Department of Medical Oncology and Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA.
Department of Medical Oncology, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Ther Adv Urol. 2023 Jun 15;15:17562872231182219. doi: 10.1177/17562872231182219. eCollection 2023 Jan-Dec.
Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, 'on-target, off-tumor' immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer.
前列腺癌是男性中最常见的癌症，也是美国男性癌症相关死亡的第二大主要原因。随着多种新型疗法的出现，前列腺癌的治疗模式不断演变，这些疗法提高了生存率；然而，治疗相关的毒性很常见，持久缓解仍然很少见。免疫检查点抑制剂在一小部分前列腺癌患者中显示出适度的活性，但对大多数晚期疾病男性患者没有产生影响。前列腺特异性膜抗原（PSMA）的发现及其对前列腺癌特异性的认识，使其被确定为理想的肿瘤相关抗原，并重新唤起了人们对前列腺癌免疫治疗的热情。双特异性T细胞衔接器（BiTEs）和嵌合抗原受体（CAR）T细胞疗法形式的T细胞免疫疗法在治疗各种血液系统恶性肿瘤方面取得了显著成功，目前正在前列腺癌患者中进行测试，药物设计以各种靶配体为中心，不仅包括PSMA，还包括其他配体，如前列腺六跨膜上皮抗原1（STEAP1）和前列腺干细胞抗原（PSCA）。本综述将重点关注围绕靶向PSMA的T细胞疗法的数据。两类T细胞重定向疗法的早期临床研究均已证明具有抗肿瘤活性；然而，这类药物存在多个挑战，包括剂量限制性毒性、“靶向、脱瘤”免疫相关毒性，以及在复杂且明显具有免疫抑制作用的肿瘤微环境中维持持续免疫反应的困难。反思近期试验的经验对于理解免疫逃逸机制以及在前列腺癌中开发这些药物的局限性至关重要。新一代BiTE和CAR T细胞构建体，单独或作为联合治疗的一部分，目前正在进行研究，通过药物设计的改进来克服这些障碍。药物开发方面的持续创新可能会促进T细胞免疫疗法的成功实施，给前列腺癌的治疗带来变革性变化。
