Cirella Assunta, Bolaños Elixabet, Di Trani Claudia Augusta, de Andrea Carlos E, Sánchez-Gregorio Sandra, Etxeberria Iñaki, Gonzalez-Gomariz Jose, Olivera Irene, Brocco Davide, Glez-Vaz Javier, Luri-Rey Carlos, Azpilikueta Arantza, Rodríguez Inmaculada, Fernandez-Sendín Myriam, Egea Josune, Eguren Iñaki, Sanmamed Miguel F, Palencia Belen, Teijeira Alvaro, Berraondo Pedro, Melero Ignacio
Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.
Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
Cancer Immunol Res. 2023 Feb 3;11(2):184-198. doi: 10.1158/2326-6066.CIR-22-0373.
IL12-based local gene therapy of cancer constitutes an active area of clinical research using plasmids, mRNAs, and viral vectors. To improve antitumor effects, we have experimentally tested the combination of mRNA constructs encoding IL12 and IL18. Moreover, we have used a form of IL18 [decoy-resistant IL18 (DR-18)] which has preserved bioactivity but does not bind to the IL18 binding protein decoy receptor. Both cytokines dramatically synergize to induce IFNγ release from mouse splenocytes, and, if systemically cotransferred to the liver, they mediate lethal toxicity. However, if given intratumorally to B16OVA tumor-bearing mice, the combination attains efficacy against the directly treated tumor and moderate tumor-delaying activity on distant noninjected lesions. Cotreatment was conducive to the presence of more activated CD8+ T cells in the treated and noninjected tumors. In keeping with these findings, the efficacy of treatment was contingent on the integrity of CD8+ T cells and cDC1 dendritic cells in the treated mice. Furthermore, efficacy of IL12 plus DR-18 local mRNA coinjection against distant concomitant tumors could be enhanced upon combination with anti-PD-1 mAb systemic treatment, thus defining a feasible synergistic immunotherapy strategy.
基于白细胞介素12（IL12）的癌症局部基因治疗是一个活跃的临床研究领域，使用质粒、信使核糖核酸（mRNA）和病毒载体。为了提高抗肿瘤效果，我们通过实验测试了编码IL12和IL18的mRNA构建体的组合。此外，我们使用了一种形式的IL18 [抗诱饵IL18（DR-18）]，它保留了生物活性，但不与IL18结合蛋白诱饵受体结合。两种细胞因子显著协同作用，诱导小鼠脾细胞释放干扰素γ（IFNγ），并且，如果全身共转移至肝脏，它们会介导致命毒性。然而，如果瘤内给予荷B16OVA肿瘤的小鼠，该组合对直接治疗的肿瘤具有疗效，并且对远处未注射的病灶具有中度的肿瘤延迟活性。联合治疗有利于在治疗的和未注射的肿瘤中存在更多活化的CD8 + T细胞。与这些发现一致，治疗效果取决于治疗小鼠中CD8 + T细胞和cDC1树突状细胞的完整性。此外，IL12加DR-18局部mRNA共注射对远处伴随肿瘤的疗效在与抗程序性死亡蛋白1（PD-1）单克隆抗体全身治疗联合时可增强，从而确定了一种可行的协同免疫治疗策略。
