Project 3: Modulating Androgen Receptor Signaling to Enhance the Efficacy of CAR T Cell Therapy for Advanced Prostate Cancer

项目摘要 嵌合抗原受体T细胞（CART）疗法形式的连续性细胞转移已经彻底改变了免疫学。 治疗血液恶性肿瘤，并正在慢慢进入实体瘤。对疗效的挑战 CART在前列腺癌中的安全性包括抗原异质性，免疫学上的“冷”肿瘤， 微环境，持久性差，疲惫不堪。我们开发了一种新的CART疗法， 前列腺跨膜上皮抗原1（STEAP 1），我们发现其表达更广泛， 前列腺特异性膜抗原（PSMA）在超过87%的致命转移性前列腺癌中的作用。在临床前 人在小鼠和小鼠在小鼠研究中，STEAP 1 CART证明了1）特异性和抗肿瘤性 在具有不同STEAP 1抗原密度水平的多种前列腺癌模型中的活性和2）初步的 安全的证据。STEAP 1 CART程序已被NCI实验治疗学接受 （NExT）支持临床转化为转移性去势男性首次人体研究的计划- 耐药前列腺癌（mCRPC）。此外，雄激素是众所周知的免疫抑制，但 使用CART治疗时不考虑局部雄激素浓度或患者性别。我们 目前的证据表明，靶向雄激素受体是有效的T细胞特异性免疫治疗所必需的 增强过继性细胞治疗产品的功能。此外，我们还证实了雄激素受体 信号传导抑制剂（ARSI）改善前列腺肿瘤内的抗原呈递并促进T细胞功能 微环境总之，我们的观察结果表明，CART治疗与ARSI相结合可以改善 晚期前列腺癌患者的治疗结果。据我们所知，这是第一个 结合临床前研究和CART临床试验，靶向STEAP 1治疗晚期前列腺癌 患者 这项提议的目的是了解我们是否可以通过干扰雄激素受体来改善CART功能 用ARSI发信号我们假设，我们可以提高STEAP 1 CART细胞的持久性和功能， 结合ARSI治疗。我们将在以下目标中检验这一假设：1）评估效果 AR调节对STEAP 1 CART表型和功能的影响; 2）研究炎症和ARSI是否 影响STEAP 1 CART治疗的安全性和毒性;以及3）进行I期临床试验，以评估 STEAP 1 CART单药治疗和与enzalutamide联合治疗男性的可行性、安全性和疗效 STEAP1+ mCRPC。 这些研究提供了临床前框架，用于理解ARSI和/或AR缺失如何影响 一种新型前列腺CART产品的功能。重要的是，这些研究将为安全性提供重要的见解。 和毒性，并揭示潜在的治疗毒性。

PROJECT SUMMARY Adoptive cell transfer in the form of chimeric antigen receptor T cell (CART) therapy has revolutionized the treatment of hematologic malignancies and is slowly making inroads into solid tumors. Challenges to the efficacy and safety of CARTs in prostate cancer include antigen heterogeneity, an immunologically “cold” tumor microenvironment, poor persistence, and exhaustion. We have developed a novel CART therapy targeting six transmembrane epithelial antigen of the prostate 1 (STEAP1) which we found to be expressed more broadly than prostate-specific membrane antigen (PSMA) in over 87% of lethal metastatic prostate cancers. In preclinical human-in-mouse and mouse-in-mouse studies, STEAP1 CART demonstrated 1) specificity and antitumor activity in multiple prostate cancer models with varying levels of STEAP1 antigen density and 2) preliminary evidence of safety. The STEAP1 CART program has been accepted into the NCI Experimental Therapeutics (NExT) Program to support clinical translation to a first-in-human study in men with metastatic castration- resistant prostate cancer (mCRPC). Furthermore, androgens are well known to be immunosuppressive, yet CART therapy is used without consideration of local androgen concentrations or the sex of the patient. We present evidence that targeting the androgen receptor is necessary for effective T cell-specific immunotherapy and enhances the function of adoptive cell therapy products. In addition, we demonstrate that androgen receptor signaling inhibitors (ARSI) improve antigen presentation and promote T cell function within the prostate tumor microenvironment. Together, our observations suggest that combining CART therapy with ARSI could improve therapeutic outcomes in advanced prostate cancer patients. To the best of our knowledge this is the first combination of preclinical studies and a CART clinical trial to target STEAP1 in advanced prostate cancer patients. The goal of this proposal is to understand if we can improve CART function by perturbing androgen receptor signaling with an ARSI. We hypothesize that we can improve STEAP1 CART cell persistence and function by combining it with ARSI treatment. We will test this hypothesis in the following Aims: 1) Evaluate the effect of AR modulation on STEAP1 CART phenotype and function; 2) Investigate whether inflammation and ARSI impacts safety and toxicity of STEAP1 CART therapy; and 3) Conduct a phase I clinical trial to assess the feasibility, safety, and efficacy of STEAP1 CART therapy alone and in combination with enzalutamide in men with STEAP1+ mCRPC. These studies provide the preclinical framework for understanding how ARSI and/or AR deletion impacts the function of a novel prostate CART product. Importantly, these studies will provide critical insight into the safety and toxicity of STEAP1 CART therapy alone or with ARSI and reveal potential therapeutic toxicity.