Activating Native Tumor Immunity with IL-33 Armored CARs

摘要 与液体癌不同，目前的CAR T细胞免疫疗法对实体癌几乎没有效果，主要是因为 肿瘤微环境的免疫抑制性质。接受注射的CAR T细胞和 肿瘤相关细胞杀死和/或中和另一个细胞的倾向很大程度上有利于肿瘤。异质 肿瘤或能够释放或下调CAR靶向抗原的肿瘤也可以逃脱功能障碍的消除 CAR T细胞效应器。我们最近发现，传递双重细胞因子的CAR T细胞可以征募和激活 内源性T细胞、NK细胞和髓系细胞可发动有效的抗肿瘤免疫反应。进一步 研究表明，穿孔素和干扰素γ在CAR T细胞中是必不可少的，支持辅助作用 CAR T细胞能动员内源性免疫细胞，最终控制肿瘤生长。CAR T细胞介导的细胞免疫 通过3种不同的CAR T细胞构建和4种细胞因子载体的双重细胞因子传递有效地控制了肿瘤的生长。 体内肿瘤模型：原发和转移性黑色素瘤和原发结肠癌小鼠模型，以及 重要的是，它不受抗原丢失的影响。这表明双重细胞因子平台具有潜在的 普遍适用于多种实体肿瘤类型。在本应用程序中，我们假设CAR T细胞 双重细胞因子的传递具有广泛的应用前景，因为它抵消了免疫抑制、先天免疫抑制和获得性免疫抑制 免疫细胞诱导广泛的内源性抗肿瘤反应，不依赖于CAR效应器的潜力。我们会 通过确定CAR T细胞存活和分布动力学(目标1)来检验这一假设，确定共同的 免疫抑制、免疫刺激和效应白细胞群的肿瘤特异性变化 从CAR细胞因子治疗前后免疫原性低和强的肿瘤中分离出来(目标2)，以及 确定它们在激活内源性肿瘤免疫中的作用(目标3)。已确定的细胞和机制 将通过各种CAR靶向支持Super2+IL-33平台的进一步改进和临床翻译 用于实体肿瘤的CAR T细胞疗法的构建。

ABSTRACT Unlike liquid cancers, current CAR T cell immunotherapies have little effect against solid cancers, largely due to the immunosuppressive nature of the tumor microenvironment. The race between administered CAR T cells and tumor associated cells to kill off and/or neutralize the other is tipped heavily in favor of the tumor. Heterogeneous tumors or tumors able to shed or downregulate CAR-targeted antigens can also escape elimination by functional CAR T cell effectors. We recently found that CAR T cells delivery of dual cytokines can enlist and activate endogenous T cells, NK cells and myeloid cells to mount an effective anti-tumor immune response. Further investigation revealed that perforin and IFNγ are dispensable in CAR T cells, supporting an accessory role for CAR T cells in mobilizing endogenous immune cells to ultimately control tumor growth. CAR T cell-mediated dual cytokine delivery was effective in controlling tumor growth with 3 different CAR T cell constructs and 4 in vivo tumor models: primary and metastatic melanoma and primary colon cell carcinoma mouse models, and importantly was impervious to antigen loss. This suggests that the dual cytokine platform has potential for universal application against multiple solid tumor types. In this application, we hypothesize that CAR T cell delivery of dual cytokines has broad application because it counteracts immunosuppressive innate and adaptive immune cells to elicit a broad endogenous anti-tumor response independent of CAR effector potential. We will test this hypothesis by identifying CAR T cell survival and distribution dynamics (Aim 1), identify the common and tumor-specific changes in immunosuppressive, immunostimulatory and effector leukocyte populations isolated from poorly and strongly immunogenic tumors pre- and post-CAR cytokine treatment (Aim 2), and determine their roles in activating endogenous tumor immunity (Aim 3). The cellular and mechanisms identified will support further improvement and clinical translation of the Super2+IL-33 platform with various CAR targeting constructs for CAR T cell therapies for solid tumors.