GVL Resistance: Immune selection, T cell ignorance and T cell exhaustion

GVL 抵抗：免疫选择、T 细胞无知和 T 细胞耗竭

• 批准号: 8477401
• 负责人: Warren D Shlomchik
• 金额: $ 39.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-06 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477401
• 关键词: Accounting; Acute leukemia; Address; Allogenic; Biology; Blast Phase; Blood; Blood Cells; Bone Marrow; CD34 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Clinical; Clinical Trials; Complementary DNA; Data; Gene-Modified; Generations; Genes; Genetic; Goals; HOXA9 gene; Hematopoietic Stem Cell Transplantation; Human; Immune; Infection; Infusion procedures; Intrinsic factor; Knockout Mice; Light; Malignant Neoplasms; Mediating; Mediator of activation protein; Methods; Minor Histocompatibility Antigens; Modeling; Mus; NUP98 gene; Non-Malignant; Outcome; Pathway interactions; Patients; Peptides; Persons; Phenocopy; Play; Population; Property; Radiation therapy; Reagent; Recurrent disease; Relapse; Residual Neoplasm; Resistance; Retroviridae; Role; Secondary to; Specificity; Stem cells; System; T cell response; T cell therapy; T memory cell; T-Cell Leukemia; T-Lymphocyte; Testing; Time; Tissues; Transgenic Mice; Transplant Recipients; Transplantation; Vaccinated; Vaccination; Work; base; cancer cell; cell killing; chemotherapy; clinically relevant; exhaustion; graft vs host disease; immune resistance; improved; isoimmunity; killings; leukemia; leukemic stem cell; magnetic beads; mortality; mouse model; pathogen; public health relevance; reconstitution; resistance mechanism; response; tool

DESCRIPTION (provided by applicant): Donor T cells play a vital role in allogeneic hematopoietic stem cell transplantation (alloSCT). First, na?ve and pathogen-specific donor memory T cells (TM) protect recipients from infection. Second, donor T cells mediate the graft-versus leukemia (GVL) effect. In MHC-matched alloSCT, GVL-inducing T cells target minor histocompatibility antigens (miHAs). Unfortunately, miHA-reactive T cells also attack nonmalignant host tissues, causing graft-vs-host disease (GVHD). A longstanding and elusive goal has been to develop approaches that preserve GVL and immune reconstitution while minimizing GVHD. A second goal is to overcome GVL- resistance. Indeed, relapsed disease is the greatest cause of post-transplant mortality. Leukemia relapse must relate to properties of alloreactive T cells, leukemia cells and the host. Understanding how these contribute to relapse requires clinically relevant models in which effects of each can be isolated. A major barrier to understanding relapse has been an inability to track among polyclonal T cells with all (or even a few) of the allospecificities that contribute to GVL. A second obstacle has been the lack of clinically relevant and genetically manipulable leukemias. We have new data that shed light on the disconnect between leukemia relapse in the face of potent alloimmunity in a model wherein easily trackable polyclonal GVL-inducing T cells target a relevant and genetically manipulable leukemia. We hypothesized that GVL would be augmented if CD8+ TM reactive against miHAs expressed by leukemia cells were induced in the donor. As we hoped, the CD8+ TM from miHA-vaccinated donors were potent mediators of GVL against a GVL-resistant model of blast crisis CML (mBC-CML) induced by the retroviral transfer of bcr-abl and NUP98-HOXA9 fusion cDNAs. MiHA- specific TM underwent dramatic expansion. However, a substantial fraction of mice succumbed to mBC-CML. This was quite unexpected, especially as mice with progressive mBC-CML retained a large number of miHA- reactive CD8 cells. We will use this model to test two nonexclusive hypotheses regarding GVL resistance: 1) alloimmunity selects for GVL-resistant leukemia subclones; and 2) the T cell response is restricted by T cell- extrinsic or -intrinsic factors. Our system has unique strengths that make it ideal for these studies. Using MHCI tetramers we can track the miHA-specific polyclonal T cells which are the only T cells that mediate GVL. mBC- CML is genocopy and phenocopy of human BC-CML/AML and because it is induced by retrovirus, we can readily create gene-modified leukemias. We have also assembled key gene-modified mice and reagents that block T cell inhibitory pathways. These studies address a real clinical concern. We have an ongoing clinical trial wherein leukemia patients receive CD34-selected grafts supplemented with TM purified by the depletion of CD45RA+ TN using a reagent co-developed by the PI. In a subsequent study we plan to incorporate donor miHA-vaccination. These studies will identify GVL resistance mechanisms with this approach and similar resistance mechanisms are likely in play in alloimmune responses without donor vaccination.

描述（由申请人提供）：供体 T 细胞在同种异体造血干细胞移植（alloSCT）中发挥着至关重要的作用。首先，幼稚且病原体特异性的供体记忆 T 细胞 (TM) 可以保护受体免受感染。其次，供体 T 细胞介导移植物抗白血病 (GVL) 效应。在 MHC 匹配的 alloSCT 中，诱导 GVL 的 T 细胞靶向次要组织相容性抗原 (miHA)。不幸的是，miHA 反应性 T 细胞也会攻击非恶性宿主组织，导致移植物抗宿主病 (GVHD)。一个长期且难以捉摸的目标是开发出既能保留 GVL 和免疫重建，同时又能最大限度地减少 GVHD 的方法。第二个目标是克服 GVL 耐药性。事实上，疾病复发是移植后死亡的最大原因。白血病复发必定与同种异体反应性T细胞、白血病细胞和宿主的特性有关。了解这些因素如何导致复发需要临床相关模型，其中可以分离出每种因素的影响。了解复发的一个主要障碍是无法追踪具有所有（甚至少数）有助于 GVL 的同种异体特异性的多克隆 T 细胞。第二个障碍是缺乏临床相关且基因可操纵的白血病。我们获得的新数据揭示了白血病复发与强效同种免疫之间的脱节，在该模型中，易于追踪的多克隆 GVL 诱导 T 细胞靶向相关且可基因操纵的白血病。我们假设，如果在供体中诱导针对白血病细胞表达的 miHA 的 CD8+ TM 反应，GVL 将会增强。正如我们所希望的，来自 miHA 疫苗接种供体的 CD8+ TM 是 GVL 的有效介质，对抗由 bcr-abl 和 NUP98-HOXA9 融合 cDNA 的逆转录病毒转移诱导的 GVL 耐药急变型 CML (mBC-CML) 模型。 MiHA 特定的 TM 经历了戏剧性的扩展。然而，相当一部分小鼠死于 mBC-CML。这是非常出乎意料的，特别是患有进行性 mBC-CML 的小鼠保留了大量 miHA 反应性 CD8 细胞。我们将使用该模型来检验关于 GVL 耐药性的两个非排他性假设：1）同种免疫选择 GVL 耐药性白血病亚克隆； 2) T 细胞反应受到 T 细胞外在或内在因素的限制。我们的系统具有独特的优势，使其成为这些研究的理想选择。使用 MHCI 四聚体，我们可以追踪 miHA 特异性多克隆 T 细胞，它们是唯一介导 GVL 的 T 细胞。 mBC-CML 是人类 BC-CML/AML 的基因复制和表型复制，因为它是由逆转录病毒诱导的，所以我们可以轻松创建基因修饰的白血病。我们还组装了关键的基因修饰小鼠和阻断 T 细胞抑制途径的试剂。这些研究解决了真正的临床问题。我们正在进行一项临床试验，其中白血病患者接受 CD34 选择的移植物，并补充有 TM，该TM 是通过使用 PI 共同开发的试剂耗尽 CD45RA+ TN 纯化的。在随后的研究中，我们计划纳入捐赠者 miHA 疫苗接种。这些研究将通过这种方法确定 GVL 耐药机制，并且类似的耐药机制可能在没有供体疫苗接种的同种免疫反应中发挥作用。