Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Medicine, University of Virginia, Charlottesville, Virginia, USA.
J Immunother Cancer. 2021 May;9(5). doi: 10.1136/jitc-2020-002222.
T cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative.
We generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells.
The antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs.
EATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.
嵌合抗原受体（CAR）或双特异性抗体（BsAb）的 T 细胞免疫疗法在血液恶性肿瘤中产生了令人印象深刻的反应。然而，仍存在重大障碍，包括细胞因子释放综合征、神经毒性、靶标外肿瘤效应、依赖自体 T 细胞以及大多数实体瘤治疗失败。BsAb 武装的 T 细胞提供了一种安全的替代方案。
我们使用 IgG-[L]-scFv 平台 BsAb 生成体外武装 T 细胞（EAT），其中抗 CD3（huOKT3）scFv 连接到肿瘤结合 IgG 的轻链上。评估了 EAT 上的 BsAb 密度、体外细胞毒性、细胞因子释放、体内进入肿瘤的转移以及它们在多种癌细胞系和患者来源的异种移植小鼠模型中的抗肿瘤活性。研究了 EAT 冷冻保存后的疗效，并研究了 γδ（γδ）T 细胞作为无关的替代效应 T 细胞。
使用 IgG-[L]-scFv BsAb 平台，显著提高了 BsAb 武装 T 细胞的抗肿瘤效力。与单独的 BsAb 和 T 细胞注射相比，EAT 释放的 TNF-α 更少，更快地浸润肿瘤，同时实现了强大的抗肿瘤反应。EAT 治疗的体内效力取决于武装用 BsAb 剂量、每次注射的 EAT 细胞数、EAT 剂量总数和治疗方案强度。EAT 冷冻保存后保持了抗肿瘤疗效，使用 γδ T 细胞的 EAT 安全且与 αβ T 细胞-EAT 同样有效。
EAT 对广泛的人类癌症靶标表现出强大的抗肿瘤活性，具有显著的安全性。EAT 的抗肿瘤效力取决于 BsAb 剂量、细胞数和总剂量以及方案。EAT 冷冻保存后同样有效，第三方 γδ-EAT 的可行性为自体 T 细胞来源提供了替代方案。
