Repertoire Immune Medicines, Cambridge MA, USA.
Technical University of Denmark, Copenhagen, Denmark.
Sci Adv. 2022 Apr 29;8(17):eabi8075. doi: 10.1126/sciadv.abi8075. Epub 2022 Apr 27.
Immune-activating cytokines such as interleukin-12 (IL-12) hold strong potential for cancer immunotherapy but have been limited by high systemic toxicities. We describe here an approach to safely harness cytokine biology for adoptive cell therapy through uniform and dose-controlled tethering onto the surface of the adoptively transferred cells. Tumor-specific T cells tethered with IL-12 showed superior antitumor efficacy across multiple cell therapy models compared to conventional systemic IL-12 coadministration. Mechanistically, the IL-12-tethered T cells supported a strong safety profile by driving interferon-γ production and adoptively transferred T cell activity preferentially in the tumor. Immune profiling revealed that the tethered IL-12 reshaped the suppressive tumor immune microenvironment, including triggering a pronounced repolarization of monocytic myeloid-derived suppressor cells into activated, inflammatory effector cells that further supported antitumor activity. This tethering approach thus holds strong promise for harnessing and directing potent immunomodulatory cytokines for cell therapies while limiting systemic toxicities.
免疫激活细胞因子，如白细胞介素 12（IL-12），在癌症免疫治疗方面具有巨大潜力，但由于全身毒性高而受到限制。我们在这里描述了一种通过将细胞因子均匀且剂量控制地连接到过继转移细胞表面来安全利用细胞因子生物学的方法，用于过继细胞治疗。与传统的全身 IL-12 联合给药相比，与 IL-12 连接的肿瘤特异性 T 细胞在多种细胞治疗模型中表现出更好的抗肿瘤疗效。从机制上讲，IL-12 连接的 T 细胞通过在肿瘤中优先驱动干扰素-γ产生和过继转移 T 细胞活性，具有良好的安全性。免疫分析显示，连接的 IL-12 重塑了抑制性肿瘤免疫微环境，包括触发单核细胞来源的髓样抑制细胞明显向激活的炎症效应细胞极化，进一步支持抗肿瘤活性。因此，这种连接方法在利用和指导细胞治疗中的有效免疫调节细胞因子的同时限制全身毒性方面具有巨大的潜力。
