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.

项目概要 我的长期职业目标是成为一名独立的医师科学家，研究重点是开发 针对儿童血癌，特别是 T 细胞急性淋巴细胞白血病的新型细胞免疫疗法 （T-ALL）。我作为儿科肿瘤科医生的临床经验推动了我的研究兴趣更好地发展。 该提案概述了一系列临床前实验，这些实验结合在一起。 通过互补的教学和跨学科指导，将为我提供一个有前途的平台 这项工作将完成免疫学、癌症动物模型和细胞疗法开发方面的培训。 在 H. Trent Spencer、Edmund K. Waller 和 Douglas K. Graham 博士的杰出指导团队下， 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。 尽管使用同种异体造血干细胞，复发性 T-ALL 患者的生存率仍然极低。 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 在这项研究中，我们利用了γδ（γδ）T 细胞的前景，这与其他细胞不同。 更占优势的 αβ (αβ) T 细胞，不需要抗原呈递并在 主要以组织相容性复合体独立的方式存在，因此具有最小的风险。 引起移植物抗宿主病，可用于创建“现成的”细胞疗法。 考虑到复发性疾病的侵袭性，γδ T 使用固有的细胞毒性机制。 细胞包括识别细胞应激分子，例如 NKG2D 和 DNAM-1 受体配体， 我们有希望的数据显示了与靶细胞上死亡途径受体 Fas 和 TRAIL-R1/R2 的相互作用。 这些标记物在 T-ALL 中过度表达，使它们容易受到 γδ T 细胞介导的杀伤。 此外，应激配体的表达可以通过蛋白酶体抑制、表观遗传修饰、 通过使用传统的化疗药物，我们还预测恶性 T-ALL 细胞可以被治愈。 使用 CD5 导向的嵌合抗原受体 (CAR) 直接靶向 γδ T 细胞。 由于癌性 T 细胞缺乏特定的靶抗原，因此 T-ALL 治疗一直具有挑战性。 表明针对泛表面 T 细胞标记 CD5 的 CAR 表达，导致表面 CD5 下调，从而减少 CD5-CAR T 细胞之间的自相残杀效应。 γδ T 细胞的持续存在消除了 T 细胞再生障碍性免疫抑制危及生命的可能性， 这可以通过使用 αβ T 细胞的基于 CAR 的方法来观察。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。 我们将通过三种不同机制利用细胞应激调节来使 T-ALL 对 γδ T 细胞介导的敏感性 细胞毒性，而在目标 2 中，我们将优化 CD5-CAR γδ T 细胞对抗这种疾病的功能。