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(申请人提供)：供者T细胞在异基因造血干细胞移植中起着至关重要的作用。首先，天然的和病原体特异性的供体记忆T细胞(TM)保护受者免受感染。第二，供者T细胞介导移植物抗白血病(GVL)效应。在MHC相合的同种异体干细胞移植中，GVL诱导的T细胞以次要组织相容性抗原(MIHAS)为靶标。不幸的是，MIHA反应性T细胞也攻击非恶性宿主组织，导致移植物抗宿主病(GVHD)。一个长期而又难以捉摸的目标是开发保存GVL和免疫重建的方法，同时将GVHD降至最低。第二个目标是克服GVL耐药性。事实上，复发的疾病是移植后死亡的最大原因。白血病复发必须与同种异体反应性T细胞、白血病细胞和宿主的特性有关。要了解这些因素是如何导致复发的，需要临床上相关的模型，在这些模型中，每种因素的影响都可以分离出来。了解复发的一个主要障碍是无法在具有所有(或甚至几个)导致GVL的同种异体特异性的多克隆T细胞中进行追踪。第二个障碍是缺乏临床相关和基因可操作的白血病。我们有了新的数据，揭示了面对强大的同种免疫，白血病复发之间的脱节，在这个模型中，容易追踪的多克隆GVL诱导T细胞以相关的和基因可操纵的白血病为靶点。我们推测，如果在供者体内诱导CD8+TM对白血病细胞表达的MIHAS产生反应，GVL将会增强。正如我们所希望的那样，来自MiHA疫苗的供者的CD8+TM是GVL的有效介导者，对抗由逆转录病毒转移BCR-ABL和NUP98-HOXA9融合基因诱导的GVL抵抗的BBC-CML模型。MIHA特有的TM经历了戏剧性的扩张。然而，相当一部分小鼠死于MBC-CML。这是相当出乎意料的，特别是进行性MBC-CML小鼠保留了大量MIHA反应的CD8细胞。我们将使用这个模型来检验两个关于GVL耐药性的非排他性假设：1)GVL耐药白血病亚克隆的同种免疫选择；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，这是唯一介导GVL的T细胞。MBC-CML是人类BC-CML/AML的基因复制和表型复制，由于它是由逆转录病毒诱导的，因此很容易产生基因修饰的白血病。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。这些研究解决了一个真正的临床问题。我们有一项正在进行的临床试验，白血病患者接受CD34选择的移植物，辅以TM，通过使用PI共同开发的试剂耗尽CD45RA+TN而纯化。在随后的研究中，我们计划纳入捐赠者MIHA疫苗接种。这些研究将用这种方法确定GVL耐药机制，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。