Gamma delta T-cell immunotherapy for T-cell acute lymphoblastic leukemia

T 细胞急性淋巴细胞白血病的 Gamma Delta T 细胞免疫疗法

• 批准号: 10593051
• 负责人: Sunil Sudhir Raikar
• 金额: $ 22.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593051
• 关键词: Acute T Cell Leukemia; Aftercare; Allogenic; Animal Cancer Model; Antigen Presentation; Antigen Targeting; Biology; Bone Marrow Transplantation; Bortezomib; CAR T cell therapy; CD28 gene; CD95 Antigens; Cancerous; Cell Line; Cell Therapy; Cell surface; Cell-Mediated Cytolysis; Cells; Cellular Stress; Cessation of life; Childhood Hematopoietic Neoplasm; Clinical; Data; Disease; Disease remission; Down-Regulation; Effectiveness; Epigenetic Process; Goals; Hematopoietic Stem Cell Transplantation; Immunocompromised Host; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Laboratories; Lentivirus Vector; Life; Ligands; Longevity; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Mediating; Mentorship; Methods; Modification; Molecular; Mus; Nature; Nelarabine; Non-Malignant; Pathway interactions; Patients; Pediatric Oncologist; Physicians; Predisposition; Process; Proteasome Inhibition; Proteasome Inhibitor; Recurrent disease; Relapse; Remission Induction; Research; Sampling; Scientist; Series; Serum; Stress; Surface; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF10A gene; TNFSF10 gene; Testing; Training; Transplantation; Treatment Protocols; Viral; Viral Vector; Work; Xenograft procedure; acute T-cell lymphoblastic leukemia cell; adeno-associated viral vector; biological adaptation to stress; bisphosphonate; cancer cell; career; cell killing; chemotherapeutic agent; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytotoxic; cytotoxicity; design; epigenetic drug; experience; experimental study; gene therapy; genetically modified cells; graft vs host disease; in vivo; ineffective therapies; innovation; interest; lentivirally transduced; leukemia; minimal risk; novel; novel strategies; overexpression; peripheral blood; pre-clinical; preclinical study; receptor; receptor expression; side effect; therapy development; tool; transgene expression; translational immunology; tumor; γδ T cells

Project Summary My long-term career goal is to become an independent physician-scientist with a research focus in developing novel cellular immunotherapeutics for pediatric blood cancers, especially T-cell acute lymphoblastic leukemia (T-ALL). My clinical experiences as a pediatric oncologist have driven my research interest to develop better therapies for these patients. This proposal outlines a series of preclinical experiments, which in combination with complementary didactics and interdisciplinary mentorship, will provide a promising platform to advance my training in immunology, cancer animal models, and cellular therapy development. This work will be completed under the exceptional mentorship team of Drs. H. Trent Spencer, Edmund K. Waller and Douglas K. Graham, given their collective expertise in cell and gene therapy, translational immunology and leukemia biology. Survival for patients with relapsed T-ALL remains extremely poor. Although allogeneic hematopoietic stem cell transplant (HSCT) provides a chance of cure, attaining disease remission is necessary prior to HSCT, but is seldom achieved. In this research, we capitalize on the promise of gamma delta (γδ) T cells which unlike the more predominant alpha beta (αβ) T cells, do not require antigen presentation and identify their targets in a major histocompatibility complex independent manner. Allogeneic γδ T cells, thus have a minimal risk of causing graft-versus-host disease and can be used to create ‘off-the-shelf’ cellular therapeutics. This is ideal to target T-ALL given the aggressive nature of relapsed disease. Inherent cytotoxic mechanisms used by γδ T cells include recognition of cellular stress molecules such as NKG2D and DNAM-1 receptor ligands and interactions with death pathway receptors Fas and TRAIL-R1/R2 on target cells. Our promising data shows that these markers are overexpressed in T-ALL, making them susceptible to γδ T-cell mediated killing. Furthermore, stress ligand expression can be upregulated by proteasome inhibition, epigenetic modification, and through use of traditional chemotherapeutic agents. We also predict that malignant T-ALL cells can be directly targeted by γδ T cells using CD5-directed chimeric antigen receptors (CARs). CAR T-cell therapy has been challenging in T-ALL given the lack of a specific target antigen on cancerous T cells. However, we have shown that expression of a CAR directed against the pan surface T-cell marker CD5, results in surface CD5 downregulation, thereby reducing the fratricidal effect among CD5-CAR T cells. Additionally, the limited persistence of γδ T cells negates the possibility of life-threatening immune suppression from T-cell aplasia, which may be seen with a CAR-based approach using αβ T cells. Thus, our overarching hypothesis is that the intrinsic cytotoxic activity of γδ T cells can be enhanced and directed towards cancerous T-ALL cells. In Aim 1, we will utilize cellular stress modulation by three distinct mechanisms to sensitize T-ALL to γδ T cell-mediated cytotoxicity, whereas in Aim 2, we will optimize the functionality of CD5-CAR γδ T cells against this disease.

项目摘要 我的长期职业目标是成为一名独立的医生科学家，研究重点是开发 用于儿科血癌特别是T细胞急性淋巴细胞白血病的新细胞免疫治疗剂 （T-ALL）。我作为一名儿科肿瘤学家的临床经验推动了我的研究兴趣更好地发展 治疗这些患者。该提案概述了一系列临床前实验，这些实验结合起来 与互补的教学法和跨学科的导师，将提供一个有前途的平台，以提高我的 免疫学、癌症动物模型和细胞疗法开发方面的培训。这项工作将完成 在H博士卓越的指导团队下。放大图片作者：Trent Spencer. Waller和道格拉斯K.格雷厄姆， 鉴于他们在细胞和基因治疗、转化免疫学和白血病生物学方面的集体专业知识。 复发性T-ALL患者的生存率仍然极低。虽然异基因造血干细胞 移植（HSCT）提供了治愈的机会，在HSCT之前获得疾病缓解是必要的，但 很少实现。在这项研究中，我们利用了γ δ（γδ）T细胞的前景，这与γ δ T细胞不同。 更主要的α β（αβ）T细胞，不需要抗原呈递，并在一个特定的时间内识别它们的靶点。 主要组织相容性复合体独立的方式。因此，同种异体γδ T细胞具有最小的风险， 引起移植物抗宿主病，并可用于产生“现成的”细胞治疗剂。这是理想的， 考虑到复发性疾病的侵袭性，γδ T使用的固有细胞毒性机制 细胞包括识别细胞应激分子如NKG 2D和DNAM-1受体配体， 与靶细胞上的死亡途径受体Fas和TRAIL-R1/R2相互作用。我们有希望的数据显示 这些标志物在T-ALL中过表达，使其对γδ T细胞介导的杀伤敏感。 此外，应激配体表达可通过蛋白酶体抑制，表观遗传修饰， 以及通过使用传统的化疗剂。我们还预测，恶性T-ALL细胞可以是 使用CD 5定向的嵌合抗原受体（汽车）由γδ T细胞直接靶向。CAR T细胞疗法 由于癌性T细胞上缺乏特异性靶抗原，因此在T-ALL中具有挑战性。但我们 显示针对淘选表面T细胞标记物CD 5 CAR的表达导致表面CD 5 在一些实施方案中，CD 5-CAR T细胞可以下调，从而减少CD 5-CAR T细胞之间的自相残杀效应。此外，有限的 γδ T细胞的持续存在否定了T细胞发育不全导致危及生命的免疫抑制的可能性， 这可以在使用αβ T细胞的基于CAR的方法中看到。因此，我们的首要假设是， γδ T细胞的内在细胞毒活性可以增强并针对癌性T-ALL细胞。在目标1中， 我们将通过三种不同的机制利用细胞应激调节来使T-ALL对γδ T细胞介导的 在目的2中，我们将优化CD 5-CAR γδ T细胞针对这种疾病的功能。