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.

项目摘要嵌合受体抗原（CAR）T细胞通过提供肿瘤特异性，转化癌症治疗分子靶向疗法。但是，即使目前的基于CAR T细胞的癌症的临床应用在大多数情况下，Kymriah或Yescarta等免疫疗法会诱导长期疾病控制，这会缓解，这在患有高危恶性肿瘤的小儿和年轻成人癌症患者中，尤其需要临床挑战。实际上，恶性继电器仍然是CAR T细胞治疗后死亡的主要原因。体内汽车T细胞的持久性不足是降低缓解风险和改善风险的主要障碍生存。我们已经开发了一个新型平台，用于基于连续的持续肿瘤免疫监视体内生成幼稚的汽车T细胞。该提议是由我们发表的假设驱动的，未发表的数据，在最初的强化化学疗法长期持久的T细胞完成后完成后可以通过使用造血茎和祖细胞（HSPC）来确定对癌症抗原的免疫力设计为表达肿瘤细胞靶向的汽车，并将其送入患者的胸腺。图像引导胸膜注射是一种微创手术，将癌症患者的胸腺作为体内生物反应器，因此为可持续性提供了创新且相对简单且相对简单且低毒的临床方法从遗传操纵的HSPC中生产高潜在的幼稚的设计师T细胞。直接胸腺 HSPC的植入（绕过骨髓）消除了对骨髓燃烧性调节的需求保留所需的结果，即长期生成幼稚的抗原特异性T细胞。胸腺植入将通过胸腺照射制备，并通过胸膜注射或通过增强胸腔过表达的静脉内给药HSPC的胸腺归巢能力特定的归巢分子。我们将专注于CD19汽车作为模型系统，以建立我们的概念证明方法是因为CD19汽车已成为评估新型汽车技术的黄金标准。我们的实验方法包括旨在成功的胸腺阴性CD19的策略汽车转导的HSPC。随着时间的流逝，该项目将扩展到包括各种汽车规格。 HSPC的CAR T细胞开发将在体外和体内分析，包括评估评估胸腺上皮内的HSPC的胸腺造血干细胞维持和T细胞分化微环境。我们将展示最多的体内效率（B细胞部署和抗肿瘤活动）合成小鼠模型中有希望的汽车表达系统。人性化小鼠的翻译研究，包括患者来源的儿科急性淋巴细胞白血病模型将在最后一年进行项目。总而言之，这项研究将测试体内CAR T细胞发育的新型范式，承诺将使CAR T细胞的肿瘤免疫监视，作为高危后固结疗法广泛使用小儿和年轻患者人群的恶性肿瘤。