CAR T cell therapy for T cell lymphoma

T细胞淋巴瘤的CAR T细胞疗法

• 批准号: 10247739
• 负责人: MALCOLM K. BRENNER
• 金额: $ 25.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247739
• 关键词: Adult; Allogenic; Antigen Receptors; Antigen Targeting; Antigens; Attenuated; B lymphoid malignancy; B-Lymphocyte Subsets; CAR T cell therapy; CD19 gene; CD28 gene; CD5 Antigens; CD7 gene; CRISPR/Cas technology; Cell Line; Cells; Childhood; Clinical; Clinical Research; Clinical Trials; Development; Disease remission; Down-Regulation; Ensure; Escape Mutant; Experimental Models; Future; Generations; Goals; Hematologic Neoplasms; Immunotherapy; In Vitro; In complete remission; Individual; Investigation; Lymphoblastic lymphoma; Lymphocyte; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Methodology; Modeling; Patients; Peer Review; Peripheral; Pre-Clinical Model; Prognosis; Protocols documentation; Recurrent disease; Refractory; Refractory Disease; Relapse; Reproducibility; Research; Residual state; Resistance; Retroviral Vector; Risk; Signal Transduction; Specificity; Stem cell transplant; Structure; Surface; T-Cell Lymphoma; T-Cell Receptor; T-Cell and NK-Cell Neoplasm; T-Lymphocyte; Testing; Variant; Xenograft procedure; base; cancer immunotherapy; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; clinical application; cytotoxicity; design; effector T cell; first-in-human; genome editing; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; preclinical development; preservation; receptor; success; targeted treatment; therapy resistant; tool; tumor; vector

PROJECT SUMMARY Patients with primary refractory or relapsed T-cell lymphoma typically have a poor prognosis and limited options for effective targeted therapy. This contrasts with the clinical success of using CD19-specific chimeric antigen receptors (CARs) in immunotherapies for B-cell malignancies. Thus, to begin to achieve the long- term goal of devising a CAR-T cell platform that can be safely and effectively applied in patients with T-cell lymphoma, new Project 2 has selected CD5 as a novel target antigen for CAR-transduced cells. This common surface marker of normal T cells is also expressed by an estimated 85% of T-cell malignancies and functions as a transmembrane inhibitory receptor that attenuates signaling from the antigen receptor of T cells and a subset of B cells. Importantly, CD5-specific CAR-T cell fratricide (self-killing) is limited in our experimental model, allowing the CAR-modified cells to expand normally, after which they display potent and selective cytotoxicity against malignant T cells. Nonetheless, we reasoned that a second target antigen might be helpful, as antigen loss during treatment is a major obstacle to truly successful therapy, in patients receiving CD19-specific CAR-T cells, for example. CD7 was judged the best candidate as it is expressed at a high level on >90% of T-lymphoblastic lymphomas and >60% of mature lymphomas including those lacking CD5. Although in preliminary studies CD7-specific CARs showed strong activity against CD7+ target cells, the transduced T cells did not rapidly downregulate CD7, leading to enhanced fratricide that abrogated further expansion. This pitfall was eliminated by targeted depletion of the antigen in the CAR-modified T cells, a step that did not compromise either expansion or antitumor activity. Given these positive findings, we hypothesize that CD5-specific CAR-T cells can be safely used to target CD5+ T-cell lymphomas and induce complete remissions, and that CD7- cells will continue to expand and function in even in the presence of CD7-directed CARs by T cells. We propose to test each strategy in the following specific aims. Aim 1: Manufacture the GMP-grade vector and develop the SOPs needed for a clinical trial of CD5-specific CAR-T cells in T-cell lymphoma, and obtain all necessary local and federal regulatory approval. Aim 2: Conduct and evaluate a clinical trial using CD5 CAR-T cells to induce remissions in individuals with residual T-cell lymphoma who would then become eligible for allogeneic stem cell transplant. Aim 3: Express the CD7-specific CAR on CD7- effector T cells as a means to increase the range of targetable tumors and overcome CD5 antigen escape. Our proposed studies of CD5-specific CARs and the preclinical development of a CD7-specific CAR will do much to substantiate and advance our CAR-based platform for the treatment of T-cell malignancies and would provide a scientific basis for further optimization.

项目摘要 原发性难治性或复发性T细胞淋巴瘤的患者的预后较差，并且有限 有效靶向治疗的选择。这与使用CD19特异性嵌合的临床成功形成对比 B细胞恶性肿瘤免疫疗法中的抗原受体（CAR）。因此，开始实现长期 设计一个可以安全有效地应用于T细胞患者的CAR-T细胞平台的术语目标 淋巴瘤，新项目2已选择CD5作为CAR转导细胞的新型靶抗原。这 正常T细胞的常见表面标记也以估计的85％的T细胞恶性肿瘤和 充当跨膜抑制受体，可减弱T细胞抗原受体的信号传导 和B细胞的子集。重要的是，我们 实验模型，允许CAR修饰的细胞正常扩展，之后它们显示出强大的和 针对恶性T细胞的选择性细胞毒性。但是，我们认为第二个靶抗原可能 有帮助，因为治疗期间的抗原损失是真正成功治疗的主要障碍 例如，CD19特异性CAR-T细胞。 CD7被认为是最好的候选人，因为它在高水平上表达 > 90％的T淋巴细胞淋巴瘤和> 60％的成熟淋巴瘤（包括缺乏CD5）上的淋巴瘤。 尽管在初步研究中，CD7特异性汽车对CD7+靶细胞的活性很强，但 转导的T细胞并未迅速下调CD7，导致进一步废除的杂化剂 扩张。通过靶向抗原在CAR修饰的T细胞中靶向耗竭来消除这种陷阱，这是一个步骤 这不会损害膨胀或抗肿瘤活性。考虑到这些积极的发现，我们假设 该CD5特异性CAR-T细胞可安全地用于靶向CD5+ T细胞淋巴瘤并诱导完整 还原，即使存在CD7定向 T细胞的汽车。我们建议在以下特定目标中测试每个策略。 目标1：制造GMP级矢量并开发CD5特异性临床试验所需的SOP T细胞淋巴瘤中的CAR-T细胞，并获得所有必要的本地和联邦法规批准。 AIM 2：使用CD5 CAR-T细胞进行和评估一项临床试验，以诱导患有 残留的T细胞淋巴瘤，后来有资格接受同种异体干细胞移植。 AIM 3：在CD7效应T细胞上表达CD7特异性汽车，以增加目标的范围 肿瘤并克服CD5抗原逃生。 我们提出的对CD5特异性汽车的研究以及CD7特异性汽车的临床前开发 可以证实和推进我们基于汽车的T细胞恶性肿瘤的平台，并将 为进一步优化提供科学基础。