Imaging Immune Modulation in Chimeric Antigen Receptor (CAR) T Cell Therapy

嵌合抗原受体 (CAR) T 细胞治疗中的免疫调节成像

• 批准号: 9177127
• 负责人: Ronald George Blasberg
• 金额: $ 64.54万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177127
• 关键词: Acute; Address; Adjuvant; Animal Model; Animals; Antibodies; Antigens; Autologous; Back; Basic Science; Binding; Biological Response Modifier Therapy; Biology; CD19 gene; CXCL12 gene; CXCR4 gene; Cell surface; Chimeric Proteins; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Couples; Cytotoxic T-Lymphocytes; Data; Development; Exclusion; FOLH1 gene; Failure; Future; Genetic Engineering; Hematologic Neoplasms; Human; Image; Immune; Immune response; Immunocompetent; Immunotherapy; Industry; Interdisciplinary Study; Investments; Lymphocyte; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Memorial Sloan-Kettering Cancer Center; Metastatic Prostate Cancer; Monitor; Mus; NOD/SCID mouse; Patients; Penetration; Positron-Emission Tomography; Prostate; Proteins; Records; Renaissance; Reporter; Research; Research Infrastructure; Signal Pathway; Signal Transduction; Solid Neoplasm; System; T cell response; T cell therapy; T-Cell Activation; T-Lymphocyte; Text; Time; Transgenic Mice; Transgenic Organisms; Translating; Xenograft procedure; base; cancer immunotherapy; cellular imaging; chimeric antigen receptor; clinical application; design; experience; imaging system; immune function; immunoregulation; improved; inhibitor/antagonist; leukemia; neoplastic cell; novel; pre-clinical; preclinical study; programs; receptor; response; success; trafficking; treatment response; treatment strategy; tumor; tumor progression

PROJECT SUMMARY   Chimeric antigen receptor (CAR) T-cell therapy is an active basic research and clinical program at MSKCC, involving treatment of acute and chronic lymphocyte leukemia (CD19 CAR-specific) and advanced metastatic prostate cancer (PSMA CAR-specific) autologous T cells. The latter study includes monitoring T cell trafficking and persistence with 124I-FIAU/18F-FIAU and PET imaging. Our proposal compliments these on-going studies at MSKCC and explores the benefits of adding immune modulation to CAR-directed T cell therapy. Our primary objective is to validate reporter imaging systems that can be used to concurrently monitor CAR- directed T cell tumor targeting, activation and persistence (constitutive Reporter 1) and T cell activation (NFAT- inducible Reporter 2), plus tumor progression or regression (constitutive Reporter 3) in small animal models of prostate cancer. We also propose to develop a novel transgenic mouse colony that is immune tolerant to human PSMA and our multiple reporter systems (but otherwise retains normal immune function); this mouse colony will host orthotopic syngeneic MycCap murine tumors. We will also study an established human prostate (orthotopic) xenografts in NOD SCID mice. Our secondary objectives are related to addressing biological and therapeutic questions; namely, whether immune modulation strategies can enhance adoptive CAR-directed T cell therapy. They include: a) whether inhibition of the PD-1/PD-1L receptor “check-point”, or whether the inhibition of CXCR4/CXCL12 signaling, or whether inhibition of TGFβ1 signaling results in improved PSMA CAR-directed T cell targeting, activation and treatment response; b) whether combined inhibition of the above immune modulatory effectors results in a synergistic improvement of PSMA CAR-directed T cell targeting, activation and treatment response. We propose to use the reporter systems (Aim 1) and transgenic immune competent host animal (Aim 2) to verify our hypotheses by real-time imaging in appropriate animal models. Our central theme and hypothesis are that: 1) concurrent imaging and monitoring of T cell tumor targeting, activation and persistence, plus tumor progression (or regression) in small animal models of prostate cancer is feasible; 2) T cell exclusion from the tumor mass occurs in both murine and human prostate cancer animal models; 3) Immune modulation therapy (described above) will reverse T cell exclusion from the tumor and result in improved PSMA CAR-directed T cell tumor targeting, activation and treatment response; 4) Combined inhibition, using the above immune modulatory effectors, will result in a synergistic improvement of PSMA CAR-directed T cell tumor targeting, activation and treatment response. It should also be noted that we have compared several human PET-based reporter systems in transduced human T cells that would be suitable for future clinical studies (the PET-based reporters are not part of this application).

项目摘要   嵌合抗原受体（CAR）T细胞疗法是MSKCC的活跃基础研究和临床计划， 涉及急性和慢性淋巴细胞白血病（CD19 CAR特异性）和晚期转移的治疗 前列腺癌（PSMA CAR特异性）自体T细胞。后一项研究包括监测T细胞运输 并坚持124i-fiau/18f-fiau和宠物成像。我们的提议称赞这些正在进行的研究 在MSKCC，并探讨了在CAR指导的T细胞疗法中添加免疫调节的好处。 我们的主要目的是验证可用于同时监视CAR-的记者成像系统 定向T细胞肿瘤靶向，激活和持久性（构成报告基因1）和T细胞激活（NFAT- 诱导的报告基因2），以及肿瘤的进展或回归（构成报告基因3） 前列腺癌。我们还建议开发一种新型的转基因小鼠菌落 人类PSMA和我们的多个报告基因系统（但否则保留了正常的免疫功能）；这只鼠标 殖民地将托管原位合成的MyCCAP鼠肿瘤。我们还将研究一个已建立的人 点头SCID小鼠中的前列腺（原位）Xenographtics。 我们的次要目标与解决生物学和治疗问题有关；即，是否 免疫调节策略可以增强自适应CAR指导的T细胞疗法。它们包括：a）是否 抑制PD-1/PD-1L受体“检查点”，或者是抑制CXCR4/CXCL12信号传导还是 TGFβ1信号传导的抑制是否会改善PSMA CAR定向的T细胞靶向，激活和 治疗反应； b）上述免疫调节效应器的联合抑制是否会导致A PSMA CAR指导的T细胞靶向，激活和治疗反应的协同改善。我们 提出使用记者系统（AIM 1）和转基因免疫胜任的宿主动物（AIM 2）的提案以验证 在适当的动物模型中，我们通过实时成像提出了我们的假设。 我们的中心主题和假设是：1）同时对T细胞肿瘤靶向的成像和监测， 前列腺癌小动物模型中的激活和持久性以及肿瘤进展（或回归）是 可行的; 2）在鼠和人类前列腺癌动物中，T细胞排除在肿瘤质量之外 模型； 3）免疫调节疗法（上文描述）将逆转T细胞排除在肿瘤中， 导致PSMA导向的T细胞肿瘤靶向，激活和治疗反应的改善； 4） 使用上述免疫调节作用的联合抑制作用将导致协同改善 PSMA CAR指导的T细胞肿瘤靶向，激活和治疗反应。还应该指出的是我们 已经比较了转导的人类T细胞中的几个基于人类宠物的记者系统 适合将来的临床研究（基于宠物的记者不是本申请的一部分）。