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独立的身体科学家，研究重点是发展 小儿血液癌的新型细胞免疫疗法，尤其是T细胞急性淋巴细胞白血病 （高的）。我作为儿科肿瘤学家的临床经验使我的研究兴趣促进了更好的发展 这些患者的疗法。该建议概述了一系列临床前实验，这些实验结合了 有了完整的教学和跨学科的心态，将提供一个有望的平台来推动我的 免疫学，癌症动物模型和细胞疗法发育的培训。这项工作将完成 在DRS的杰出心态下。 H. Trent Spencer，Edmund K. Waller和Douglas K. Graham， 鉴于他们在细胞和基因疗法，转化免疫学和白血病生物学方面的集体专业知识。 接力T-ALL患者的生存率仍然非常差。虽然同种异性造血干细胞 移植（HSCT）提供了治愈的机会，在HSCT之前需要达到疾病的缓解，但IS 很少实现。在这项研究中，我们利用了伽玛三角洲（γδ）T细胞的承诺 更多的主要αβ（αβ）T细胞不需要抗原表现，并确定其目标 主要的组织相容性复杂独立的方式。同种异体γδT细胞，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”细胞疗法。这是理想的选择 Target T-All赋予了继电器疾病的侵略性。 γδT使用的固有细胞毒性机制 细胞包括识别细胞应激分子，例如NKG2D和DNAM-1受体配体，以及 与靶细胞上的死亡通路接收器FAS和TRAIL-R1/R2的相互作用。我们的承诺数据显示 这些标记在T-all中过表达，使它们容易受到γδT细胞介导的杀戮的影响。 此外，可以通过蛋白酶体抑制作用，表观遗传修饰，可以更新胁迫配体表达， 并通过使用传统的化学治疗剂。我们还预测，恶性T-ALL细胞可以是 使用CD5定向的嵌合抗原受体（CAR）直接靶向γδT细胞。汽车T细胞疗法具有 考虑到取消T细胞上缺乏特定的靶抗原，我们在T-All中受到了挑战。但是，我们有 表明针对PAN表面T细胞标记CD5的汽车的表达导致表面CD5 下调，从而降低了CD5-CAR T细胞之间的杂化作用。另外，有限 γδT细胞的持久性否定了威胁生命的免疫抑制的可能性 使用αβT细胞的基于汽车的方法可以看出。那就是我们的总体假设是 γδT细胞的内在细胞毒性活性可以增强并针对取消的T-ALL细胞。在AIM 1中， 我们将通过三种不同的机制利用细胞应力调制，以将T-ALL感知到γδT细胞介导 细胞毒性，而在AIM 2中，我们将优化CD5-CARγδT细胞的功能，可针对该疾病。