Gamma delta T cell based melanoma therapies

总结 我们的长期目标是开发高度可翻译的动物模型来测试癌症 免疫疗法动物模型在癌症研究中至关重要。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 应答，如高突变负荷、肿瘤微环境（TME）和肿瘤异质性，或 小鼠在先天性和适应性免疫应答方面与人类有很大的不同。响应于 PAR-20-131，我们将使用我们的新型人源化小鼠模型（HuMice）来测试γ-δ T（γδT）细胞。 基于免疫疗法。由于Vγ 9 V δ2+ T细胞，一种最常用于免疫调节的γδT细胞亚型， 过继性免疫治疗是灵长类动物所特有的，传统的小鼠模型不适合研究人类 γδT细胞。该提案将通过研究最大限度地提高哺乳动物模型的翻译潜力 在具有来自细胞系或细胞系的HLA匹配的人黑素瘤的HuMice中基于Vγ 9VS 2+ T细胞的疗法 患者来源的异种移植物（PDX）。我们的实验室已经建立了>500个黑色素瘤PDX和>300个 黑色素瘤细胞系，其代表疾病的所有临床、遗传和生物学组。目标1： 将研究增强型γδT细胞的过继转移。我们将测试新的Vγ9Vδ2+ T细胞扩增方法 在HuMice。然后，我们将用DR 5-CAR装备γδT细胞，其靶向骨髓来源的抑制性T细胞和骨髓来源的抑制性T细胞。 细胞和黑色素瘤细胞。我们将研究治疗后TME的变化。为了避免潜在的毒性 为了靶向DR 5，我们将开发一种靶向PD-L1和DR 5的新型组合CAR。在目标2中， 将刺激内源性γδT细胞用于癌症治疗。我们将使用溴代焦磷酸（BrHPP） 和瑞喹莫特来扩增内源性人γδT细胞以治疗携带黑色素瘤的HuMice。我们将 研究BTN 3A 1 mAb是否扩增人γδT细胞并支配γδ和γ δ T细胞的抗肿瘤功能。 HuMice中的CD 8 + T细胞。然后，我们将联合收割机扩增内源性γδT细胞与抗PD-1单克隆抗体结合， 黑色素瘤荷鼠我们希望HuMice能够让我们测试内源性的扩张， 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.