Gamma delta T cell based melanoma therapies

摘要 我们的长期目标是开发用于测试癌症的高度可翻译的动物模型 免疫疗法。动物模型在癌症研究中一直是必不可少的。然而，小鼠肿瘤 移植或肿瘤遗传模型缺乏研究人类抗肿瘤的关键成分 高突变负荷、肿瘤微环境(TME)和肿瘤异质性或 在先天免疫反应和获得性免疫反应方面，老鼠与人类有很大的不同。作为对.的回应 PAR-20-131后，我们将使用我们的新型人源化小鼠模型(HuMice)来测试伽玛-德尔塔T(γδT)细胞- 以免疫疗法为基础。由于Vγ9Vδ2+T细胞是γδT细胞中最常用的一个亚型 过继免疫疗法，是灵长类动物独有的，传统的小鼠模型不适合研究人类 γδT细胞。这一建议将通过研究使哺乳动物模型的翻译潜力最大化 以Vγ9Vδ2+T细胞为基础的人黑色素瘤治疗 患者来源的异种移植(PDX)。我们的实验室已经建立了&gt；500黑色素瘤PDX和&gt；300 黑色素瘤细胞系，代表该病的所有临床、遗传和生物学群体。在目标1中，我们 将研究增强型γδT细胞的过继转移。我们将测试一种新的Vγ9Vδ2+T细胞扩增方法 在胡米斯。然后，我们将为γδT细胞配备针对髓系来源抑制的DR5-CAR 细胞和黑色素瘤细胞。我们将研究治疗后TME的变化。避免潜在的毒性 针对DR5，我们将开发一种针对PD-L1和DR5的新型组合汽车。在目标2中，我们 将刺激内源性γδT细胞用于癌症治疗。我们将使用溴代丙烷焦磷酸(BrHPP) Resiquimod扩增内源性人γδT细胞治疗荷HuMice黑色素瘤。我们会 BTN3A1单抗是否能扩增人γδT细胞并调控γδ和BTN3A1mAb的抗肿瘤作用 HuMice小鼠体内CD8+T细胞。然后我们将内源性γδT细胞的扩增与抗PD-1单抗相结合 携带黑色素瘤的HuMice。我们预计HuMice将允许我们测试内源性 Vγ9Vδ2+首次在模型系统中用于癌症治疗，我们的新扩展方法是 有效，并可能在未来的临床试验中进行优化和测试。

SUMMARY Our long-term objective is to develop highly translatable animal models for testing cancer immunotherapies. Animal models have been essential in cancer research. However, mouse tumor transplantation or tumor genetic models lack critical components for studying human anti-tumor responses such as high mutational load, tumor microenvironment (TME) and tumor heterogeneity or mice have major differences from humans in innate and adaptive immune responses. In response to PAR-20-131, we will use our novel humanized mouse models (HuMice) to test gamma-delta T (γδT) cell- based immunotherapies. Since Vγ9Vδ2+ T cells, a subtype of γδT cells that are most commonly used in adoptive immunotherapy, are unique to primates, traditional mouse models are not ideal to study human γδT cells. This proposal will maximize translational potential of mammalian models by studying Vγ9Vδ2+ T cells-based therapy in HuMice with HLA-matched human melanomas from cell lines or patient-derived xenografts (PDX). Our laboratories have established >500 melanoma PDX and >300 melanoma cell lines, which represent all clinical, genetic and biologic groups of the disease. In Aim 1, we will study adoptive transfer of enhanced γδT cells. We will test a new Vγ9Vδ2+ T cell expansion method in HuMice. We will then equip γδT cells with DR5-CAR that targets both myeloid derived suppressive cells and melanoma cells. We will study alterations in the TME after treatment. To avoid potential toxicity of targeting DR5, we will develop a novel combinatorial CAR that targets PD-L1 and DR5. In Aim 2, we will stimulate endogenous γδT cells for cancer therapy. We will use bromohydrin pyrophosphate (BrHPP) and resiquimod to expand endogenous human γδT cells to treat melanoma bearing HuMice. We will study whether BTN3A1 mAbs expand human γδT cells and govern antitumor functions of both γδ and CD8+ T cells in HuMice. We will then combine expansion of endogenous γδT cells with anti-PD-1 mAbs in melanoma-bearing HuMice. We expect that HuMice will allow us to test expansion of endogenous Vγ9Vδ2+ for cancer therapy for the first time in a model system and our new expansion methods are effective and may be optimized and tested in future clinical trials.