The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model.

转基因 T 细胞疗法的临床应用使接受抗 CD19 嵌合抗原受体 (CAR)-T 治疗的白血病和淋巴瘤患者获得了前所未有的缓解率。尽管取得了临床成功，但 FDA 批准的 T 细胞疗法目前仅限于 B 细胞恶性肿瘤，并且在管理细胞因子相关毒性方面仍然存在挑战。我们设计了一种新型抗体-T 细胞受体 (AbTCR) 平台，将抗体的 Fab 结构域与 TCR 的 γ 和 δ 链结合起来作为效应结构域。我们证明了抗 CD19-AbTCR-T 细胞在体外和异种移植小鼠模型中触发抗原特异性细胞因子产生、脱粒和杀死 CD19 阳性癌细胞的能力。与 CAR 平台相比，通过在 AbTCR 上使用相同的抗 CD19 结合部分，我们证明 AbTCR 激活细胞毒性 T 细胞反应，其剂量反应与 CD28/CD3z CAR 相似，但细胞因子释放较少，并导致T 细胞具有较少的耗尽表型。此外，在与经过临床验证的基于 CD137 (4-1BB) 的 CAR CTL019 的比较研究中，我们的抗 CD19-AbTCR 在患者来源的异种移植白血病模型中显示出较少的细胞因子释放和类似的肿瘤抑制作用。