Targeted therapy of B cell malignances with CAR-T cells of defined composition

使用特定成分的 CAR-T 细胞靶向治疗 B 细胞恶性肿瘤

• 批准号: 8827126
• 负责人: Michael C Jensen
• 金额: $ 57.94万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827126
• 关键词: Acute Lymphocytic Leukemia; Adoptive Transfer; Aftercare; Allogenic; Antibodies; Antigen Receptors; Antitumor Response; Autologous; B lymphoid malignancy; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Behavior; Blood; CD19 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Therapy; Cell surface; Cells; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Complication; Derivation procedure; Development; Disease remission; Dose; Drug Formulations; Engineered Gene; Engineering; Enrollment; Epidermal Growth Factor Receptor; Erbitux; Failure; Frequencies; Gene Transfer; Genes; Genetic; Hematopoietic stem cells; Human; Immunotherapy; In Vitro; Infusion procedures; Measures; Memory; Methods; Minor; Modality; Modification; Molecular; Non-Hodgkin' s Lymphoma; Patients; Phase I Clinical Trials; Pre-Clinical Model; Prior Chemotherapy; Progress Reports; Property; Recovery; Refractory; Relapse; Reporting; Risk; Safety; Stem cell transplant; T cell therapy; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Tumor Escape; Variant; Work; bacterial H antigen; base; cancer cell; cancer therapy; cellular engineering; chemotherapy; cohort; design; graft vs host disease; in vivo; leukemia; leukemia/lymphoma; neoplastic cell; pre-clinical; public health relevance; receptor; response; tumor

DESCRIPTION (provided by applicant): An advance in adoptive T cell therapy is the ability to endow patient's T cells with reactivity for tumor cell surface molecules through the introduction of genes that encode synthetic chimeric antigen receptors (CARs). Studies of small numbers of patients with advanced B cell malignancies have demonstrated potent antitumor effects of T cells that express a CD19-specific CAR in a subset of patients, suggesting this approach could provide a major advance in therapy. However, not all patients respond and the duration of response remains uncertain. Prior studies have not rigorously defined the phenotypic composition or frequency of CAR T cells administered to patients, which has resulted in variations in potency and in vivo persistence, and could explain the lack of efficacy in many patients. Our group has focused on elucidating cell intrinsic properties of human T cells that provide for reproducible in vivo behavior after genetic modification and adoptive transfer, and on optimizing the design of CARs for tumor recognition and safety. We initiated the first clinical tril of CD19 CAR- T cell therapy in which the T cell products administered to every patient were formulated in a defined optimized composition. The initial results have revealed profound tumor regressions in patients with advanced chemotherapy refractory NHL after infusion of small doses of CD19 CAR-T cells. This proposal will build on these accomplishments and develop CD19 CAR T cell therapy into a reproducible, broadly effective and safe therapy for B cell malignancies. The specific aims are: Aim 1. To evaluate the safety, antitumor efficacy, and mechanisms of tumor escape after adoptive transfer of CD19 CAR-T cells administered in a defined cell product composition in patients with refractory B cell lymphoma or leukemia. Aim 2. To evaluate the safety and durability of antitumor responses of CD19 CAR-T cells derived from TM cells for therapy of ALL and CLL after HLA matched related or unrelated allogeneic HCT. Aim 3: To perform a phase I clinical trial to determine if adoptively transferred CD19 CAR-T cells that co-express a truncated human EGFR can be deleted in vivo by infusion of the anti-EGFR mAb, Erbitux.

描述（由申请人提供）：通过引入编码合成嵌合抗原受体（CAR）的基因，通过引入基因，可以使患者的T细胞具有反应性，以使患者的T细胞具有反应性。对少量B细胞恶性肿瘤患者的研究表明，T细胞在一部分患者中表达CD19特异性汽车的T细胞有效抗肿瘤作用，这表明这种方法可以为治疗提供了重大进展。但是，并非所有患者都反应，并且反应持续时间仍然不确定。先前的研究并未严格定义对患者施用的CAR T细胞的表型组成或频率，这导致了效力和体内持久性的变化，并且可以解释许多患者缺乏疗效。我们的小组的重点是阐明人类T细胞的细胞固有特性，这些细胞可在遗传修饰和收养后提供可再现的体内行为，并优化汽车设计以识别肿瘤识别和安全性。我们启动了CD19 CAR-T细胞疗法的第一个临床三LIL，其中用定义的优化组合物配制了针对每个患者的T细胞产物。最初的结果表明，在输注小剂量的CD19 CAR-T细胞后，晚期化学疗法难治性NHL患者的肿瘤消退深刻。该建议将基于这些成就，并将CD19 CAR T细胞疗法发展为可重复的，广泛的，安全且安全的治疗B细胞恶性肿瘤。具体目的是：目标1。评估在难治性B细胞淋巴瘤或白血病患者中定义的细胞产物组成中给药的CD19 CAR-T细胞的过继转移后的安全性，抗肿瘤功效和肿瘤逃逸机制。 AIM 2。评估来自TM细胞的CD19 CAR-T细胞的抗肿瘤反应的安全性和耐用性，用于在HLA匹配相关或不相关的同种异体HCT之后对所有和CLL进行治疗。 AIM 3：进行I期临床试验以确定是否可以通过输注抗EGFR MAB Erbitux在体内删除截短的人类EGFR的经过转移的CD19 CAR-T细胞。