Gamma delta T cell based melanoma therapies

基于 Gamma Delta T 细胞的黑色素瘤疗法

基本信息

批准号：
10540374
负责人：
Meenhard F Herlyn
金额：
$ 63.27万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-13 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540374
关键词：
Adoptive Cell Transfers Adoptive Immunotherapy Adoptive Transfer Affect Affinity Aftercare Agonist Alleles Animal Model Animals Antigen Presentation Antigens Antitumor Response Autologous Transplantation B-Lymphocytes Biological Biological Models Blood CD34 gene CD8-Positive T-Lymphocytes Cell Line Cell Maturation Cells Cellular immunotherapy Clinical Clinical Trials Data Diphosphates Disease Fetal Liver Future Genetic Genetic Models Goals Growth Factor HLA Antigens HLA-A gene Hematopoietic Human Immune system Immunophenotyping Implant Infiltration Innate Immune Response Laboratories Liquid substance Melanoma Cell Methods Modeling Monoclonal Antibodies Mus Mutation Myeloid Cells Myeloid-derived suppressor cells Natural Killer Cells Neoplasm Transplantation Normal Cell Organ Patients Primates Proteins Receptor Cell Solid Neoplasm Study models T cell therapy T-Lymphocyte TLR7 gene TNFRSF10B gene Testing Thymus Gland Time Toxic effect Treatment Efficacy Treatment outcome adaptive immune response anti-PD-1 anticancer research cancer immunotherapy cancer therapy chimeric antigen receptor chimeric antigen receptor T cells combinatorial cytokine human fetal hematopoietic stem cells humanized mouse immune checkpoint improved in vivo isopentenyl pyrophosphate mast cell melanoma mouse model neoplastic cell novel novel therapeutics patient derived xenograft model preservation programmed cell death ligand 1 programmed cell death protein 1 reconstitution resiquimod response tissue tropism translational potential treatment comparison tumor tumor heterogeneity tumor microenvironment tumor-immune system interactions γδ T cells

项目摘要

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.

概括我们的长期目标是开发用于测试癌症的高度可转化的动物模型然而，动物模型在癌症研究中至关重要。移植或肿瘤遗传模型缺乏研究人类抗肿瘤的关键成分反应，例如高突变负荷、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反应方面与人类存在重大差异。 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-δT（γδT）细胞- 基于 Vγ9Vδ2+ T 细胞（γδT 细胞的一种亚型）的免疫疗法。过继免疫疗法是灵长类动物所独有的，传统的小鼠模型并不适合研究人类该提案将通过研究最大限度地发挥哺乳动物模型的转化潜力。 HuMice 中基于 Vγ9Vδ2+ T 细胞的疗法，采用 HLA 匹配的人类黑色素瘤细胞系或我们的实验室已经建立了超过 500 个黑色素瘤 PDX 和超过 300 个。黑色素瘤细胞系，代表该疾病的所有临床、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新的 Vγ9Vδ2+ T 细胞扩增方法。然后，我们将为 γδT 细胞配备针对骨髓源性抑制的 DR5-CAR。我们将研究治疗后 TME 的变化，以避免潜在的毒性。针对 DR5，我们将开发一种针对 PD-L1 和 DR5 的新型组合 CAR 在目标 2 中，我们。将刺激内源性 γδT 细胞进行癌症治疗。我们将使用焦磷酸溴醇 (BrHPP)。和 resiquimod 来扩展内源性人 γδT 细胞来治疗携带 HuMice 的黑色素瘤。研究 BTN3A1 mAb 是否能够扩增人类 γδT 细胞并控制 γδ 和 γδ 的抗肿瘤功能 HuMice 中的 CD8+ T 细胞随后将内源性 γδT 细胞的扩增与抗 PD-1 mAb 结合起来。在携带黑色素瘤的 HuMice 中，我们期望 HuMice 能够让我们测试内源性的扩增。 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，并且可以在未来的临床试验中进行优化和测试。