Institute of Molecular and Cellular Biology SB RAS, Novosibirsk, Russia; Novosibirsk State University, Novosibirsk, Russia.
Institute of Molecular and Cellular Biology SB RAS, Novosibirsk, Russia.
Eur Urol. 2020 Mar;77(3):299-308. doi: 10.1016/j.eururo.2019.08.014. Epub 2019 Aug 28.
Progress achieved in the treatment of prostate cancer (PCa) with surgical, radiation, and hormonal therapies has drastically reduced mortality from this disease. Yet, patients with advanced PCa have few, if any, curative options. Recent success in treating patients with hematological malignancies of B-cell origin using T cells engineered to express chimeric antigen receptors (CARs) has inspired multiple groups worldwide to adapt this approach to the problem of late-stage PCa.
To summarize the available clinical results for CAR T-cell therapy of PCa and discuss future technological advancements in the CAR T-cell field that may help patients with metastatic PCa.
A literature review was conducted of clinical trial data, abstracts presented at recent oncology conferences, as well as reports highlighting critical bottlenecks of CAR T-cell therapy that became apparent from preclinical and clinical studies.
Current understanding of why CAR T-cell therapy may fail, particularly in the context of solid cancers, is as follows. First, a CAR design that provides potent activity and persistence of engineered T cells in the hostile tumor microenvironment is a must. The choice of the targetable epitope(s) is critical to counteract tumor antigen escape. Preclinical and clinical evidence indicates that the efficacy of CAR T-cell therapy can be enhanced significantly in combination with other therapeutic approaches. We propose that several improvements to CAR design and patient conditioning, such as unbiased identification of novel PCa-specific CAR targets, use of next-generation (multispecific, resistant to the tumor microenvironment, and with prolonged persistence) CAR T-cell products, and combination therapies may translate into improved patient outcomes and more durable responses.
Although significant preclinical experience of testing CAR T cells in solid cancer models has identified important technological and biological bottlenecks, information from clinical trials, particularly those focusing on the PCa, will be instrumental to the rational design of advanced CAR T therapies that will be both safe and effective in patients with advanced PCa.
So far, chimeric antigen receptor (CAR) T-cell therapy has not shown significant activity in patients with metastatic prostate cancer (PCa). CAR T-cell products used for such trials represent one of the pioneering efforts to adapt this technology to the problem of metastatic PCa. In retrospect, both CAR design and cell composition appear to have been suboptimal to expect strong patient responses. Given the impressive results of CAR-based approaches observed in preclinical models of solid cancers, emerging CAR T-cell products are expected to be more successful in the clinic. Here, we discuss the challenges that need to be overcome to boost the efficacy of PCa-targeted CAR T-cell therapy and call for dialogue between clinicians and cell biologists to address these challenges.
手术、放疗和激素治疗在前列腺癌（PCa）治疗方面取得的进展，极大地降低了该病的死亡率。然而，晚期 PCa 患者几乎没有治愈的选择。最近，使用嵌合抗原受体（CAR）修饰的 T 细胞成功治疗 B 细胞来源的血液恶性肿瘤，激发了全球多个团队将该方法应用于晚期 PCa 问题。
总结 CAR T 细胞治疗 PCa 的现有临床结果，并讨论 CAR T 细胞领域的未来技术进步，这些进步可能有助于转移性 PCa 患者。
对临床试验数据、最近肿瘤学会议上的摘要以及强调从临床前和临床研究中明显出现的 CAR T 细胞治疗关键瓶颈的报告进行了文献回顾。
目前对 CAR T 细胞治疗失败的原因的理解如下，特别是在实体瘤的背景下。首先，CAR 设计必须提供在恶劣的肿瘤微环境中具有强大活性和持久性的工程 T 细胞。靶向表位的选择对于对抗肿瘤抗原逃逸至关重要。临床前和临床证据表明，CAR T 细胞治疗的疗效可以通过与其他治疗方法联合显著增强。我们提出，对 CAR 设计和患者预处理进行一些改进，例如使用下一代（多特异性、抵抗肿瘤微环境且具有持久效力）CAR T 细胞产品和联合疗法，以及无偏识别新型 PCa 特异性 CAR 靶点等，可能会改善患者的预后并产生更持久的反应。
尽管在实体瘤模型中测试 CAR T 细胞的大量临床前经验确定了重要的技术和生物学瓶颈，但来自临床试验的信息，特别是针对 PCa 的临床试验信息，对于合理设计在晚期 PCa 患者中既安全又有效的先进 CAR T 疗法至关重要。
到目前为止，嵌合抗原受体（CAR）T 细胞疗法在转移性前列腺癌（PCa）患者中并未显示出显著的活性。用于此类试验的 CAR T 细胞产品代表了将该技术应用于转移性 PCa 问题的开创性努力之一。回想起来，CAR 设计和细胞组成似乎都不太理想，无法预期患者会有强烈的反应。鉴于在实体瘤的临床前模型中观察到的基于 CAR 的方法令人印象深刻的结果，预计新出现的 CAR T 细胞产品在临床上会更成功。在这里，我们讨论了需要克服的挑战，以提高针对 PCa 的 CAR T 细胞治疗的疗效，并呼吁临床医生和细胞生物学家之间进行对话，以解决这些挑战。
