BACKGROUND Prostate cancer is one of the most common adult malignancies in men, and nearly all patients with metastatic prostate cancer can develop and receive resistance to primary androgen deprivation therapy (ADT), a state known as metastatic castration-resistant prostate cancer (mCRPC). Recent reports demonstrated the great breakthroughs made by the chimeric antigen receptor T (CAR-T) cell therapy, which is significantly different from traditional T cells therapies. In spite of the progress of CAR-T technology in the treatment of lymphoma, leukemia, and other blood system tumor, there are still many difficulties in the treatment of solid tumors by CAR-T technology. METHODS In this report, we designed a panel of IL23mAb-PSMA-CARs, including PSMA-CAR, IL23mAb-T2A-PSMA-CAR, IL23mAb-PSMA-CAR, and PSMA-CAR (soluble IL23mAb). And we studied the function of these CARs in mice model. RESULTS Co-culture experiments with different CAR T cells have normal lysis function in vitro. The duo-CAR T cells co-expressing the IL-23mAb and PSMA-mAb had a significant higher population than the rest three different CAR T cells in co-culturing experiments at day 28, 35 and 42. A panel of cytokines were differentially secreted at higher amounts in IL23mAb-T2A-PSMA-CAR T cells than CAR T cells in other groups. In NOD/SCID IL-2 gamma (NSG) mice model, IL23mAb-T2A-PSMA-CAR T cells functioned significantly better than CAR T cells from the other groups and eradicated the tumor from these mice starting at day 14 post T cells injection and regained the body weight immediately. In IL23mAb-T2A-PSMA-CAR mice, CD45RO+ CD8+ T cells and CD127+ CD4+ CAR T cells were significantly increased. RNA sequencing revealed a difference expression pattern of genes in IL23mAb-T2A-PSMA-CAR mice. A reverse infusion experiment under the same model further proved the tumor eradication function of IL23mAb-T2A-PSMA-CAR T cells. CONCLUSIONS We found that IL-23mAb combined PSMA CARs worked better than PSMA CAR only in Prostate Cancer Eradication, and we further discussed the mechanisms among different IL-23mAb combined PSMA CARs in Prostate Cancer Eradication.

中文翻译：

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在临床前模型中将IL-23和PSMA靶向的duo-CAR T细胞用于前列腺癌的根除。

背景技术前列腺癌是男性中最常见的成人恶性肿瘤之一，几乎所有转移性前列腺癌患者都可以发展并接受对原发性雄激素剥夺疗法（ADT）的抵抗，该状态称为转移性去势抵抗性前列腺癌（mCRPC）。最近的报道表明，嵌合抗原受体T（CAR-T）细胞疗法取得了巨大突破，这与传统的T细胞疗法有显着差异。尽管CAR-T技术在治疗淋巴瘤，白血病和其他血液系统肿瘤方面取得了进步，但是在通过CAR-T技术治疗实体瘤方面仍然存在许多困难。方法在本报告中，我们设计了一组IL23mAb-PSMA-CAR，包括PSMA-CAR，IL23mAb-T2A-PSMA-CAR，IL23mAb-PSMA-CAR和PSMA-CAR（可溶性IL23mAb）。并且我们研究了这些CAR在小鼠模型中的功能。结果与不同的CAR T细胞共培养实验具有正常的体外裂解功能。在第28、35和42天的共培养实验中，共同表达IL-23mAb和PSMA-mAb的duo-CAR T细胞的种群明显高于其余三个不同的CAR T细胞。 IL23mAb-T2A-PSMA-CAR T细胞中的含量高于其他组中的CAR T细胞。在NOD / SCID IL-2γ（NSG）小鼠模型中，IL23mAb-T2A-PSMA-CAR T细胞的功能明显优于其他组的CAR T细胞，并且从注射T细胞后第14天开始消除了这些小鼠的肿瘤，立即恢复体重。在IL23mAb-T2A-PSMA-CAR小鼠中，CD45RO + CD8 + T细胞和CD127 + CD4 + CAR T细胞显着增加。RNA测序揭示了IL23mAb-T2A-PSMA-CAR小鼠中基因的差异表达模式。在相同模型下的反向输注实验进一步证明了IL23mAb-T2A-PSMA-CAR T细胞的肿瘤根除功能。结论我们发现IL-23mAb联合PSMA CAR仅在前列腺癌根除中比PSMA CAR更好，并且我们进一步讨论了不同IL-23mAb联合PSMA CAR在前列腺癌根除中的机制。