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高度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。但是，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诸如高突变负荷，肿瘤微环境（TME）和肿瘤异质性或小鼠在先天和适应性免疫调查中与人类有重大差异。响应 PAR-20-131，我们将使用新型的人源性小鼠模型（HUMICE）测试γ---二尔达t（γδT）细胞 - 基于免疫疗法。由于Vγ9Vδ2+ T细胞，最常用于γδT细胞的亚型收养免疫疗法，是私人独有的，传统的鼠标模型不是研究人类的理想选择 γδT细胞。该建议将通过研究哺乳动物模型的翻译潜力最大化 Vγ9Vδ2+ T细胞基于HUMICE的HUMICE与细胞系的HLA匹配的人黑色素瘤或患者衍生的Xenographictic（PDX）。我们的实验室已经建立了> 500个黑色素瘤PDX和> 300 黑色素瘤细胞系，代表该疾病的所有临床，遗传和生物群。在AIM 1中，我们将研究增强的γδT细胞的适应性转移。我们将测试一种新的Vγ9Vδ2+ T细胞扩展方法在嗡嗡声中。然后，我们将为γδT细胞配备DR5卡车，该车的靶向两个均可抑制细胞和黑色素瘤细胞。我们将研究治疗后TME的变化。避免潜在毒性针对DR5，我们将开发一种针对PD-L1和DR5的新型组合车。在AIM 2中，我们将刺激内源性γδT细胞进行癌症治疗。我们将使用溴氢化蛋白的焦磷酸（BRHPP）和regiquimod膨胀内源性人γδT细胞以治疗伴有黑色素瘤。我们将研究BTN3A1 MAB是否会扩大人γδT细胞并控制γδ和 Humice中的CD8+ T细胞。然后，我们将结合内源性γδT细胞的膨胀与抗PD-1 mAb 在含黑色素瘤的嗡嗡声中。我们预计Humice将使我们能够测试内源性的扩展在模型系统中首次进行癌症治疗的Vγ9Vδ2+，我们的新扩展方法是有效，可以在以后的临床试验中进行优化和测试。