Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70-targeted allogeneic CAR T cells. Significance: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors.

中文翻译：

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CD70 靶向同种异体 CAR T 细胞治疗晚期透明细胞肾细胞癌

透明细胞肾细胞癌（ccRCC）的治疗方法仍然有限；然而，嵌合抗原受体（CAR）T 细胞疗法可能提供新的治疗选择。 CTX130是一种同种异体CD70靶向CAR T细胞产品，专为治疗晚期或难治性ccRCC而开发。我们报告说，CTX130 显示出良好的临床前增殖和细胞毒性特征，并且完全消退了 RCC 异种移植肿瘤。我们还报告了 16 名复发/难治性 ccRCC 患者在一项 I 期、多中心、首次人体临床试验中接受 CTX130 的结果。没有患者出现剂量限制性毒性，81.3%的患者实现了疾病控制。一名患者在 3 年后仍保持持久的完全缓解。最后，我们报告了下一代 CAR T 构建体 CTX131，其中对 CTX130 的协同效力编辑可改善临床前研究的扩展和功效。这些数据代表了使用 CD70 靶向同种异体 CAR T 细胞治疗 ccRCC 和其他 CD70+ 恶性肿瘤的概念证明。意义：尽管 CAR T 细胞在血液恶性肿瘤中的作用已得到充分证实，但实体瘤的临床经验却令人失望。该临床试验首次在 RCC 患者中实现完全缓解，增强了 CAR T 细胞在实体瘤治疗中的潜在益处。