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Harnessing the thymus for long-term tumor control with hematopoietic stem cell-derived naive CAR T cells

利用造血干细胞衍生的初始 CAR T 细胞利用胸腺来长期控制肿瘤

基本信息

批准号：
10580801
负责人：
Johannes Zakrzewski
金额：
$ 54.37万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580801
关键词：
Address Adoptive Cell Transfers Affect Affinity Allogenic Antigen Receptors Antineoplastic Agents Area B-Lymphocytes Biological Biological Assay Biological Models Biology Bioreactors Bone Marrow Bypass CAR T cell therapy CD19 gene CD28 gene Cancer Patient Cause of Death Cell Lineage Cell Maintenance Cells Childhood Childhood Acute Lymphocytic Leukemia Clinical Consolidation Therapy Data Development Disease remission Engraftment Epithelium Gene Expression Gene Transfer Generations Goals Hematopoietic stem cells Homing Human Human Activities Immunity Immunologic Surveillance Immunotherapeutic agent In Vitro Injections Laboratories Longitudinal Studies Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of thymus Mediating Methods Modality Modeling Modern Medicine Molecular Mus Outcome Pathway interactions Patients Peripheral Phenotype Pre-B Acute Lymphoblastic Leukemia Procedures Production Protocols documentation Publishing Relapse Remission Induction Research Risk Reduction Signal Transduction Specificity System T cell differentiation T cell reconstitution T cell therapy T-Cell Development T-Cell Transformation T-Lymphocyte Technology Testing Thymus Gland Time Transfusion Tumor Antigens Tumor Burden Variant antigen-specific T cells cancer immunotherapy cancer therapy cell motility cellular engineering cellular transduction chemotherapy chimeric antigen receptor T cells clinical application clinically relevant conditioning cytokine release syndrome design disorder control engineered stem cells exhaustion genetic manipulation hematopoietic engraftment high risk humanized mouse image guided improved in vivo innovation intravenous administration irradiation leukemia/lymphoma manufacture minimally invasive molecular targeted therapies mouse model neoplastic cell novel overexpression patient derived xenograft model patient population pre-clinical assessment preclinical efficacy preservation rational design receptor relapse prevention relapse risk secondary lymphoid organ self-renewal single-cell RNA sequencing transgene expression translational immunology translational study tumor tumor specificity young adult

项目摘要

PROJECT SUMMARY Chimeric receptor antigen (CAR) T cells are transforming cancer treatment by providing tumor-specific, molecularly targeted therapies. However, even though current clinical applications of CAR T cell-based cancer immunotherapies such as Kymriah or Yescarta induce remission in most cases, long-term disease control, which is especially needed in pediatric and young adult cancer patients with high-risk malignancies, remains a major clinical challenge. In fact, malignant relapse continues to be the leading cause of death post CAR T cell therapy. Insufficient CAR T cell persistence in vivo is a major obstacle to reducing the risk of relapse and improving survival. We have developed a novel platform for long-lasting tumor immunosurveillance based on continuous in vivo generation of naïve CAR T cells. This proposal is driven by the hypothesis, based on our published and unpublished data, that after the completion of the initial course of intensive chemotherapy long-lasting T cell immunity to cancer antigens can be established by using hematopoietic stem and progenitor cells (HSPCs) engineered to express a tumor cell-targeting CAR and delivered into the patient’s thymus. Image-guided intrathymic injection is a minimally invasive procedure that harnesses the thymus of cancer patients as an in vivo bioreactor, thus offering an innovative and also relatively simple and low-toxic clinical method for sustainable production of highly potent naïve designer T cells from genetically manipulated HSPCs. Direct thymic engraftment of HSPCs (bypassing the bone marrow) eliminates the need for myelo-ablative conditioning while preserving the desired outcome, i.e., long-term generation of naïve antigen-specific T cells. Thymic engraftment will be facilitated by thymic irradiation combined with either cell delivery to the thymus by intrathymic injection or by enhancing the thymic homing capacity of intravenously administered HSPCs by overexpression of thymus- specific homing molecules. We will focus on CD19 CARs as a model system to establish proof of concept of our approach because CD19 CARs have become the gold standard for evaluating novel CAR technologies. Our experimental approaches include strategies designed to allow successful thymic negative selection of CD19 CAR-transduced HSPCs. Over time the project is expected to expand to include a variety of CAR specificities. CAR T cell development from HSPCs will be analyzed both in vitro and in vivo, including assays assessing thymic hematopoietic stem cell maintenance and T cell differentiation from HSPCs within the thymic epithelial microenvironment. We will demonstrate in vivo efficacy (B cell depletion and anti-tumor activity) of the most promising CAR expression system in syngeneic mouse models. Translational studies in humanized mice, including a patient-derived pediatric acute lymphoblastic leukemia model, will be performed during the final year of the project. In sum, this research will test the novel paradigm of CAR T cell development in vivo, promising to make tumor immunosurveillance by CAR T cells broadly available as post-consolidation therapy of high-risk malignancies in pediatric and young adult patient populations.

项目概要嵌合受体抗原 (CAR) T 细胞通过提供肿瘤特异性、分子靶向治疗。然而，尽管目前基于 CAR T 细胞的癌症临床应用 Kymriah 或 Yescarta 等免疫疗法在大多数情况下可引起缓解，实现长期疾病控制，这患有高危恶性肿瘤的儿童和年轻成人癌症患者尤其需要，仍然是一个主要的治疗方法临床挑战。事实上，恶性复发仍然是 CAR T 细胞治疗后死亡的主要原因。 CAR T细胞体内持久性不足是降低复发风险和改善病情的主要障碍生存。我们开发了一个基于持续性肿瘤免疫监视的新型平台体内生成初始 CAR T 细胞。该提案是由假设驱动的，基于我们发布的和未发表的数据表明，在完成初始强化化疗疗程后，T细胞持久使用造血干细胞和祖细胞 (HSPC) 可以建立对癌症抗原的免疫力设计用于表达肿瘤细胞靶向 CAR 并输送到患者的胸腺中。图像引导胸腺内注射是一种微创手术，利用癌症患者的胸腺作为体内注射剂生物反应器，从而为可持续发展提供了一种创新且相对简单且低毒的临床方法从基因操纵的 HSPC 中生产高效的天然设计 T 细胞。直接胸腺 HSPC 的植入（绕过骨髓）消除了骨髓消融调理的需要，同时保留期望的结果，即长期生成幼稚抗原特异性 T 细胞。胸腺植入通过胸腺照射结合通过胸腺内注射或将细胞递送至胸腺将促进通过胸腺过度表达来增强静脉注射 HSPC 的胸腺归巢能力特定的归巢分子。我们将重点关注 CD19 CAR 作为模型系统，以建立我们的概念验证方法，因为 CD19 CAR 已成为评估新型 CAR 技术的黄金标准。我们的实验方法包括旨在允许成功胸腺阴性选择 CD19 的策略 CAR 转导的 HSPC。随着时间的推移，该项目预计将扩大到包括各种 CAR 特性。 HSPC 的 CAR T 细胞开发将在体外和体内进行分析，包括评估分析胸腺造血干细胞维持和胸腺上皮内 HSPC 分化为 T 细胞微环境。我们将展示大多数药物的体内功效（B 细胞耗竭和抗肿瘤活性）在同基因小鼠模型中具有前景的 CAR 表达系统。人源化小鼠的转化研究，包括来自患者的儿童急性淋巴细胞白血病模型，将在最后一年进行项目的。总之，这项研究将测试体内 CAR T 细胞开发的新范式，有望使 CAR T 细胞的肿瘤免疫监视广泛用作高危患者的巩固治疗后儿科和年轻成人患者群体的恶性肿瘤。