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: 9341075
• 负责人: Michael C Jensen
• 金额: $ 56.04万
• 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/9341075
• 关键词: Acute Lymphocytic Leukemia; Adoptive Transfer; Aftercare; Allogenic; Alpha Cell; Antibodies; Antitumor Response; Ataxia Telangiectasia Patients; Autologous; B lymphoid malignancy; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Behavior; Blood; CD19 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Therapy; Cell surface; Cells; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Complication; Derivation procedure; Development; Disease remission; Dose; Engineered Gene; Engineering; Enrollment; Epidermal Growth Factor Receptor; Erbitux; Failure; Formulation; Frequencies; Gene Transfer; Genes; Genetic; Hematopoietic Stem Cell Transplantation; Human; Immunotherapy; In Vitro; Infusion procedures; Malignant Neoplasms; Measures; Memory; Methods; Minor; Modality; Modification; Molecular; Non-Hodgkin' s Lymphoma; Patients; Phase I Clinical Trials; Phenotype; Pre-Clinical Model; Prior Chemotherapy; Progress Reports; Property; Recovery; Refractory; Relapse; Reporting; Reproducibility; Risk; Safety; T cell therapy; T memory cell; T-Lymphocyte; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Tumor Escape; Variant; Work; antitumor effect; bacterial H antigen; base; betacell therapy; cancer cell; cancer therapy; cellular engineering; chemotherapy; chimeric antigen receptor; cohort; design; graft vs host disease; in vivo; leukemia; leukemia/lymphoma; neoplastic cell; patient subsets; phase I trial; pre-clinical; public health relevance; receptor; response; targeted treatment; 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）：过继性 T 细胞疗法的一项进步是通过引入编码合成嵌合抗原受体 (CAR) 的基因，赋予患者 T 细胞对肿瘤细胞表面分子的反应性。对少数晚期 B 细胞恶性肿瘤患者的研究表明，在一部分患者中表达 CD19 特异性 CAR 的 T 细胞具有强大的抗肿瘤作用，表明这种方法可以为治疗带来重大进展。然而，并非所有患者都有反应，而且反应持续时间仍不确定。先前的研究尚未严格定义给予患者的 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，并可以解释许多患者缺乏疗效的原因。我们的团队致力于阐明人类 T 细胞的细胞内在特性，这些特性在基因改造和过继转移后提供可重复的体内行为，并优化 CAR 的设计以实现肿瘤识别和安全性。我们启动了 CD19 CAR-T 细胞疗法的第一个临床试验，其中向每位患者施用的 T 细胞产品均按照确定的优化组合物进行配制。初步结果显示，晚期化疗难治性 NHL 患者在输注小剂量 CD19 CAR-T 细胞后，肿瘤明显消退。该提案将在这些成就的基础上，将 CD19 CAR T 细胞疗法发展成为一种可重复、广泛有效且安全的 B 细胞恶性肿瘤疗法。具体目标是： 目标 1. 评估在难治性 B 细胞淋巴瘤或白血病患者中过继转移以确定的细胞产品组合物施用的 CD19 CAR-T 细胞后的安全性、抗肿瘤功效和肿瘤逃逸机制。目标 2. 评估 HLA 匹配相关或不相关同种异体 HCT 后，TM 细胞衍生的 CD19 CAR-T 细胞用于治疗 ALL 和 CLL 的抗肿瘤反应的安全性和持久性。目标 3：进行 I 期临床试验，以确定是否可以通过输注抗 EGFR mAb Erbitux 在体内删除过继转移的共表达截短的人 EGFR 的 CD19 CAR-T 细胞。