西班牙应用医学研究中心Ignacio Melero课题组研究发现，将瞬时工程改造的瘤内过继转移IL-12 mRNA表达在CD8⁺T细胞中可提高抗肿瘤效应。相关论文2019年11月21日在线发表在《癌细胞》上。

为了克服不良反应，研究人员设计了肿瘤特异性CD8⁺T细胞来瞬时表达IL-12。肿瘤内注射而非静脉内注射的工程化T细胞不仅导致被注射病变位置的完全排斥，也导致远端伴随肿瘤的完全排斥。通过与激动剂抗CD137 mAb共同注射或通过CD137配体的瞬时共表达，进一步提高了疗效。这种治疗以依赖于cDC1树突状细胞的方式诱导内源性CD8⁺T细胞免疫应答的表位扩散。 可以将小鼠和人肿瘤浸润性T淋巴细胞培养物进行瞬时IL-12工程改造，以达到明显的免疫治疗效果。

据介绍，白细胞介素12（IL-12）逆转录病毒基因转移到T细胞中可显著增强过继转移后的抗肿瘤效应，但临床已显示出严重的不良副作用。

附：英文原文

Title: Intratumor Adoptive Transfer of IL-12 mRNA Transiently Engineered Antitumor CD8+ T Cells

Author: Iaki Etxeberria, Elixabet Bolaos, Jose I. Quetglas, Alena Gros, Alberto Villanueva, Jara Palomero, Alfonso R. Sánchez-Paulete, Jose María Piulats, Xavier Matias-Guiu, Irene Olivera, Maria C. Ochoa, Sara Labiano, Saray Garasa, Inmaculada Rodriguez, August Vidal, Uxua Mancheo, Sandra Hervás-Stubbs, Arantza Azpilikueta, Itziar Otano, M. Angela Aznar, Miguel F. Sanmamed, Susana Inogés, Pedro Berraondo, álvaro Teijeira, Ignacio Melero

Issue&Volume: November 21, 2019

Abstract: Retroviral gene transfer of interleukin-12 (IL-12) into T cells markedly enhancesantitumor efficacy upon adoptive transfer but has clinically shown unacceptable severeside effects. To overcome the toxicity, we engineered tumor-specific CD8+ T cells to transiently express IL-12. Engineered T cells injected intratumorally,but not intravenously, led to complete rejections not only of the injected lesionbut also of distant concomitant tumors. Efficacy was further enhanced by co-injectionwith agonist anti-CD137 mAb or by transient co-expression of CD137 ligand. This treatmentinduced epitope spreading of the endogenous CD8+ T cell immune response in a manner dependent on cDC1 dendritic cells. Mouse and humantumor-infiltrating T lymphocyte cultures can be transiently IL-12 engineered to attainmarked immunotherapeutic effects.

DOI: 10.1016/j.ccell.2019.10.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30480-5