Enhancement of T cell therapy by incorporating adjunct treatment strategies

通过结合辅助治疗策略增强 T 细胞治疗

基本信息

批准号：
9903003
负责人：
Ronald George Blasberg
金额：
$ 8.01万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903003
关键词：
Acute Address Animal Cancer Model Animal Model Animals Antibodies Antigens Autologous Back Basic Science Binding Biological Response Modifier Therapy Biology CAR T cell therapy CD19 gene CXCL12 gene CXCR4 gene Cell surface Chimeric Proteins Chronic Lymphocytic Leukemia 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 Tolerance Immune response Immunocompetent Immunologic Adjuvants Immunotherapy Industry Infrastructure Interdisciplinary Study Investments Magnetic Resonance Imaging Malignant neoplasm of prostate Memorial Sloan-Kettering Cancer Center Metastatic Prostate Cancer Monitor Mus NOD/SCID mouse Parents Patients Penetration Positron-Emission Tomography Prostate Proteins Records Renaissance Reporter Research SLEB2 gene Signal Pathway Signal Transduction Solid Neoplasm System T cell response T cell therapy T-Cell Activation T-Lymphocyte Text Transgenic Mice Transgenic Organisms Translating Xenograft procedure base cancer immunotherapy checkpoint modulation checkpoint receptors chimeric antigen receptor chimeric antigen receptor T cells clinical application design experience imaging study imaging system immune checkpoint blockade immune function immunoregulation improved inhibitor/antagonist neoplastic cell novel pre-clinical preclinical study programs prostate cancer model real-time images response success trafficking treatment response treatment strategy tumor tumor progression

项目摘要

PROJECT SUMMARY (unchanged from parent R01) 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（与父 R01 相同）嵌合抗原受体 (CAR) T 细胞疗法是 MSKCC 的一项活跃的基础研究和临床项目，治疗急慢性淋巴细胞白血病（CD19 CAR 特异性）和晚期转移性白血病前列腺癌（PSMA CAR 特异性）自体 T 细胞的研究包括监测后者的 T 细胞运输。我们的建议对这些正在进行的研究进行了补充。 MSKCC 的研究人员探讨了在 CAR 导向的 T 细胞疗法中添加免疫调节的好处。我们的主要目标是验证可用于同时监测 CAR-的报告成像系统定向 T 细胞肿瘤靶向、激活和持久性（组成型报告基因 1）和 T 细胞激活（NFAT- 诱导型报告基因 2），加上小动物模型中的肿瘤进展或消退（组成型报告基因 3）我们还建议开发一种对前列腺癌具有免疫耐受性的新型转基因小鼠群体。人类 PSMA 和我们的多重报告系统（但该小鼠保留了正常的免疫功能）；菌落将承载原位同基因 MycCap 小鼠肿瘤，我们还将研究已建立的人类。 NOD SCID 小鼠前列腺（原位）异种移植物。我们的次要目标与解决生物学和治疗问题有关，即：免疫调节策略可以增强过继性 CAR 导向的 T 细胞治疗，包括：a) 是否。抑制 PD-1/PD-1L 受体“检查点”，或抑制 CXCR4/CXCL12 信号传导，或抑制 TGFβ1 信号传导是否会改善 PSMA CAR 导向的 T 细胞靶向、激活和 b) 综合抑制上述免疫调节效应物是否会导致协同改善 PSMA CAR 导向的 T 细胞靶向、激活和治疗反应。建议使用报告系统（目标1）和转基因免疫能力宿主动物（目标2）来验证我们的假设是通过在适当的动物模型中进行实时成像来实现的。我们的中心主题和假设是：1）T 细胞肿瘤靶向的同时成像和监测，前列腺癌小动物模型中的激活和持久性以及肿瘤进展（或消退） 2) T细胞从肿瘤块中排除在小鼠和人类前列腺癌动物中都是可行的；模型；3) 免疫调节疗法（如上所述）将逆转 T 细胞从肿瘤中的排斥，改善 PSMA CAR 导向的 T 细胞肿瘤靶向、激活和治疗反应；4) 使用上述免疫调节效应物的联合抑制将导致协同改善 PSMA CAR 定向 T 细胞肿瘤靶向、激活和治疗反应还值得我们注意。在转导的人类 T 细胞中比较了几种基于人类 PET 的报告系统，适用于未来的临床研究（基于 PET 的生产商不属于此应用程序的一部分）。