Department Hematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany.
Leibniz Institute for Immunotherapy, Division Genetic Immunotherapy, and Chair for Genetic Immunotherapy, University Regensburg, 93053 Regensburg, Germany.
Cells. 2022 Nov 30;11(23):3839. doi: 10.3390/cells11233839.
The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as "fourth generation" CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on the TRUCK technology, we aimed to generate CAR T-cells with a CAR-inducible artificial, self-limiting autocrine loop. To this end, we engineered CAR T-cells with CAR triggered secretion of type-1 interferons (IFNs). At baseline, IFNα and IFNβ CAR T-cells showed similar capacities in cytotoxicity and cytokine secretion compared to conventional CAR T-cells. However, under "stress" conditions of repetitive rounds of antigen stimulation using BxPC-3 pancreas carcinoma cells as targets, anti-tumor activity faded in later rounds while being fully active in destructing carcinoma cells during first rounds of stimulation. Mechanistically, the decline in activity was primarily based on type-1 IFN augmented CAR T-cell apoptosis, which was far less the case for CAR T-cells without IFN release. Such autocrine self-limiting loops can be used for applications where transient CAR T-cell activity and persistence upon target recognition is desired to avoid lasting toxicities.
嵌合抗原受体 (CAR) T 细胞的出现加速了癌症免疫疗法领域的发展，使难治性血液恶性肿瘤患者获得持久缓解。通用细胞因子介导杀伤 (TRUCKs) 的 T 细胞重定向，通常称为“第四代”CAR T 细胞，旨在在 CAR 诱导的 T 细胞激活时释放工程载药。基于 TRUCK 技术，我们旨在生成具有 CAR 诱导的人工、自我限制的自分泌环的 CAR T 细胞。为此，我们设计了 CAR T 细胞，使其能够在 CAR 触发下分泌 1 型干扰素 (IFN)。在基线水平，与传统的 CAR T 细胞相比，IFNα 和 IFNβ CAR T 细胞在细胞毒性和细胞因子分泌方面具有相似的能力。然而，在使用 BxPC-3 胰腺癌细胞作为靶标进行重复抗原刺激的“应激”条件下，在随后的刺激轮次中抗肿瘤活性减弱，而在第一轮刺激中完全活跃地破坏癌细胞。从机制上讲，活性下降主要基于 1 型 IFN 增强的 CAR T 细胞凋亡，而对于没有 IFN 释放的 CAR T 细胞则不太可能发生这种情况。这种自分泌自我限制循环可用于需要在靶标识别时短暂的 CAR T 细胞活性和持久性以避免持续毒性的应用。
