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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：
10365031
负责人：
Johannes Zakrzewski
金额：
$ 59.26万
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/10365031
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 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 Epithelial Gene Expression Gene Transfer Generations Goals Gold Hematopoietic stem cells Homing Human Human Activities Immunity Immunologic Surveillance Immunology Immunotherapeutic agent In Vitro Injections Intravenous Laboratories Life 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 Research Signal Transduction Specificity Sum System T cell differentiation T cell reconstitution T cell therapy T-Cell Development T-Cell Receptor T-Lymphocyte Technology Testing Thymus Gland Time Tumor Antigens Tumor Burden Variant antigen-specific T cells base cancer immunotherapy cancer therapy cell transformation cellular engineering cellular transduction chemotherapy 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 irradiation leukemia/lymphoma minimally invasive molecular targeted therapies mouse model neoplastic cell novel overexpression patient derived xenograft model patient population pre-clinical preclinical efficacy preservation prevent rational design receptor relapse risk secondary lymphoid organ self-renewal single-cell RNA sequencing transgene expression 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，分子靶向治疗然而，尽管目前基于CAR T细胞的癌症的临床应用免疫疗法如Kymriah或Yescarta在大多数情况下诱导缓解，长期疾病控制，尤其需要在儿童和年轻成人癌症患者的高风险恶性肿瘤，仍然是一个主要的临床挑战事实上，恶性复发仍然是CAR T细胞治疗后死亡的主要原因。 CAR T细胞在体内的持续性不足是降低复发风险和改善预后的主要障碍。生存我们已经开发了一种基于连续免疫监测的持久肿瘤免疫监测的新平台。体内产生幼稚CAR T细胞。这一建议是由假设驱动的，基于我们发表的和未发表的数据表明，在完成强化化疗的初始疗程后，可以通过使用造血干细胞和祖细胞（HSPC）建立对癌抗原的免疫，工程化以表达肿瘤细胞靶向CAR并递送到患者的胸腺中。图像引导胸腺内注射是一种微创手术，生物反应器，从而提供了一种创新的，也是相对简单和低毒性的临床方法，用于可持续的从基因操作的HSPC中产生高效的天然设计T细胞。直接胸腺 HSPC的移植（绕过骨髓）消除了对骨髓清除性预处理的需要，保持期望的结果，即，长期产生幼稚抗原特异性T细胞。胸腺植入通过胸腺照射结合胸腺内注射细胞递送至胸腺或通过过表达胸腺-胸腺肽来增强静脉内施用的HSPC的胸腺归巢能力，特定的归巢分子我们将专注于CD 19汽车作为模型系统，以建立我们的概念验证。这是因为CD 19汽车已成为评估新型CAR技术的金标准。我们实验方法包括设计成允许成功的胸腺阴性选择CD 19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特异性。将在体外和体内分析来自HSPC的CAR T细胞发育，包括评估CAR T细胞的测定。胸腺造血干细胞维持和胸腺上皮内HSPC的T细胞分化微环境我们将证明大多数人的体内功效（B细胞耗竭和抗肿瘤活性）。在同基因小鼠模型中有希望的CAR表达系统。在人源化小鼠中的转化研究，包括一个病人来源的小儿急性淋巴细胞白血病模型，将在最后一年进行本项目总之，这项研究将测试体内CAR T细胞发育的新模式，有望使CAR T细胞的肿瘤免疫监视广泛用作高风险患者的巩固后治疗，儿童和年轻成人患者人群中的恶性肿瘤。