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: 10368969
• 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/10368969
• 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; Lead; 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; Process; Proteasome Inhibition; Proteasome Inhibitor; Recurrent disease; Relapse; Research; Sampling; Scientist; Series; Serum; Stress; Surface; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF10 gene; Testing; Therapeutic; Training; Transplantation; Treatment Protocols; Viral; Work; Xenograft procedure; acute T-cell lymphoblastic leukemia cell; adeno-associated viral vector; base; 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; 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内科科学家，专注于 治疗儿童血癌，特别是T细胞急性淋巴细胞白血病的新细胞免疫疗法 (t-all)。作为一名儿科肿瘤学家，我的临床经验促使我的研究兴趣得到更好的发展 这些病人的治疗方法。这项提案概述了一系列临床前试验，这些试验结合在一起 通过互补的教学和跨学科的指导，将提供一个有前途的平台来推进我的 在免疫学、癌症动物模型和细胞疗法开发方面的培训。这项工作将会完成 在H·特伦特·斯宾塞博士、埃德蒙·K·沃勒和道格拉斯·K·格雷厄姆博士的杰出指导下， 鉴于他们在细胞和基因治疗、翻译免疫学和白血病生物学方面的集体专长。 复发T-ALL患者的存活率仍然非常低。虽然异基因造血干细胞 移植(HSCT)提供了治愈的机会，在HSCT之前达到疾病缓解是必要的，但 很少实现。在这项研究中，我们利用了伽马三角洲(γδ)T细胞的前景，这与 更主要的α-β(αβ)T细胞，不需要抗原提呈，并在 主要组织相容性复合体的独立方式。同种异体γδT细胞，因此风险最低 导致移植物抗宿主疾病，并可用于创造“现成”的细胞疗法。这是理想的 目标T-ALL考虑到复发性疾病的侵袭性。γδT固有的细胞毒机制 细胞包括识别细胞应激分子，如NKG2D和dNaM-1受体配体和 与靶细胞上死亡途径受体Fas和TRAIL-R1/R2的相互作用我们有希望的数据显示 这些标记物在T-ALL中过度表达，使它们容易受到γδT细胞介导的杀伤。 此外，蛋白酶体抑制、表观遗传修饰、 并通过使用传统的化疗药物。我们还预测，恶性T-ALL细胞可以 由γδT细胞使用CD5导向的嵌合抗原受体(CARS)直接靶向。CAR T细胞疗法已经 在T-ALL中一直具有挑战性，因为肿瘤T细胞上缺乏特定的靶抗原。然而，我们有 显示针对PAN表面T细胞标记CD5的CAR的表达导致表面CD5 下调，从而减少CD5-CAR T细胞之间的杀伤效应。此外，有限的 γδT细胞的持久性否定了T细胞再生障碍性疾病对危及生命的免疫抑制的可能性。 这可以在使用αβT细胞的基于CAR的方法中看到。因此，我们的首要假设是 γδT细胞的固有细胞毒活性可以被增强，并针对肿瘤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使T-ALL对γδT细胞介导的T-ALL敏感 在目标2中，我们将优化CD5-CARγδT细胞的功能，以对抗这种疾病。