Augmenting the efficacy of prostate cancer-directed CAR T cell therapy by combining immune-editing, chemotherapy and androgen receptor blockade

前列腺癌（PC）是世界范围内男性第二大常见癌症。虽然原发性肿瘤通常可以成功地控制，但迫切需要新的治疗方案来治疗到目前为止无法治愈的晚期肿瘤。近年来，免疫疗法成为癌症治疗的新基石，包括靶向免疫检查点受体的单克隆抗体和靶向肿瘤相关抗原的嵌合抗原受体（CAR） T细胞。我们最近证明，我们的前列腺特异性膜抗原（PSMA）靶向CAR - T细胞在局部应用后能够根除异种移植小鼠模型中的人类PC，并且在与多西紫杉醇（DTX）化疗联合应用后，在全身应用后能够抑制肿瘤生长。我们的初步数据显示，DTX或enzalutamide处理增加了PC细胞中CCL2和CCL22的表达，并且共表达趋化因子受体CCR2和CCR4的CAR - T细胞分别向CCL2和CCL22的迁移增强。因此，我们假设，在DTX或enzalutamide治疗后，为CAR - T细胞配备趋化因子受体将改善它们向分泌CCL2/CCL22的肿瘤细胞的迁移，以及它们杀死表达psma的肿瘤细胞的能力。我们项目的目标是(i)在体外表征表达基因编辑的CCR2/ ccr4的psma靶向CAR - T细胞单独和与DTX和/或enzalutamide联合的抗肿瘤功效，以及（ii）验证表达CCR2/ ccr4的CAR - T细胞在非烧蚀性DTX和/或enzalutamide治疗下与转移性人PC细胞异种原位移植的小鼠的抗肿瘤功效。我们相信这一结果将扩大我们对PC免疫肿瘤学特征的认识，并为临床试验铺平道路。

Prostate cancer (PC) is the second most common cancer in men worldwide. Whereas primary tumors can often be successfully managed, new therapeutic options are urgently needed for advanced, thus far incurable stages of the disease. In recent years, immunotherapy became a new cornerstone in the treatment of cancer, including monoclonal antibodies that target immune checkpoint receptors and chimeric antigen receptor (CAR) T cells that target tumor-associated antigens. We recently demonstrated that our prostate-specific membrane antigen (PSMA)-targeting CAR T cells were able to eradicate human PC in a xenografted mouse model after local application, and, after systemic application, to inhibit tumor growth when combined with docetaxel (DTX) chemotherapy. Our preliminary data show that DTX or enzalutamide treatment increased CCL2 and CCL22 expression in PC cells, and that CAR T cells co-expressing the chemokine receptors CCR2 and CCR4 showed enhanced migration towards CCL2 and CCL22, respectively. We thus hypothesize that equipping CAR T cells with chemokine receptors will improve both their migration to CCL2/CCL22 secreting tumor cells as well as their ability to kill PSMA-expressing tumor cells after DTX or enzalutamide treatment. The objectives of our project are (i) to characterize the anti-tumor efficacy of gene-edited CCR2/CCR4-expressing PSMA-targeting CAR T cells alone and in combination with DTX and/or enzalutamide in vitro, and (ii) to validate the antitumor efficacy of CCR2/CCR4-expressing CAR T cells in mice xenografted orthotopically with metastasizing human PC cells upon non-ablative DTX and/or enzalutamide therapy. We believe that the results will expand our knowledge of immuno-oncological features of PC and pave the way for clinical trials.