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: 9307774
• 负责人: Ronald George Blasberg
• 金额: $ 66.96万
• 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/9307774
• 关键词: Acute; Address; Animal Cancer Model; Animal Model; Animals; Antibodies; Antigens; Autologous; Back; Basic Science; Binding; Biological Response Modifier Therapy; Biology; CD19 gene; CXCL12 gene; CXCR4 gene; Cell Therapy; 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 response; Immunocompetent; Immunologic Adjuvants; Immunotherapy; Industry; Interdisciplinary Study; Investments; 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; chimeric antigen receptor; 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; 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).

项目总结 -- 嵌合抗原受体(CAR)T细胞疗法是MSKCC一项活跃的基础研究和临床计划， 参与急慢性淋巴细胞白血病(CD19CAR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细胞的贩运 ~(124)I-FIAU/~(18)F-FIAU和PET显像的持续性。我们的建议是对这些正在进行的研究的赞扬 并探索了在汽车导向T细胞治疗中增加免疫调节的好处。 我们的主要目标是验证可用于同时监控汽车的报告成像系统- 定向T细胞肿瘤靶向、激活和持续(构成报告1)和T细胞激活(NFAT- 诱导报告2)，加上肿瘤进展或退化(构成报告3)，在小动物模型中 前列腺癌。我们还建议开发一种新的转基因小鼠群体，该群体对 人类PSMA和我们的多种报告系统(但在其他方面保持正常的免疫功能)；这只小鼠 殖民地将容纳原位同基因的MycCap小鼠肿瘤。我们还将研究一个成熟的人类 NOD SCID小鼠的前列腺(原位)异种移植。 我们的次要目标与解决生物和治疗问题有关；即，是否 免疫调节策略可以加强过继的汽车定向T细胞治疗。它们包括：a)是否 抑制PD-1/PD-1L受体的“检查点”，抑或是CXCR4/CXCL12信号的抑制，或者 抑制转化生长因子β-1信号通路是否能改善PSMACAR导向的T细胞靶向、活化和 治疗反应；b)联合抑制上述免疫调节效应是否会导致 协同改善PSMA车载T细胞靶向、激活和治疗反应。我们 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)进行验证 我们的假设是通过在适当的动物模型中进行实时成像。 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，加上肿瘤进展(或退化)是 可行性；2)在小鼠和人前列腺癌动物体内都有T细胞从肿瘤块中排出 模型；3)免疫调节疗法(如上所述)将逆转T细胞对肿瘤的排斥，并 改善PSMA车载T细胞肿瘤的靶向、激活和治疗反应；4) 联合抑制，使用上述免疫调节效应器，将导致协同改善 PSMA车载导向T细胞肿瘤的靶向、激活和治疗反应。还应该指出的是，我们 在转导的人类T细胞中比较了几种基于PET的报告系统， 适用于未来的临床研究(基于PET的报道不是本应用的一部分)。