SPORE in Lymphoma

总体项目摘要 这种孢子更新的长期目标是在实验室中开发，并在临床上测试新的细胞 由遗传修饰的免疫效应细胞介导的治疗非霍奇金淋巴瘤（NHL）的免疫疗法 和霍奇金淋巴瘤（HL）。我们组建了一个由实验室科学家和临床医生组成的综合团队， 研究人员具有良好的生产性转化研究记录，由四个共享核心支持 资源为了解决次优的长期淋巴瘤控制和不可接受的持续挑战， 淋巴瘤治疗相关毒性的发生率，该项目的研究人员提出了三个项目，每个项目 涉及早期临床试验。所有项目都涉及以下五个不同的研究领域：1）高度使用 靶向多种淋巴瘤抗原的特异性T或NKT细胞免疫疗法。这一目标将在 每个项目使用天然或嵌合抗原受体（汽车）或两者。2)增加T的效力 或用于淋巴瘤的NKT细胞免疫疗法。该主题包括靶向多种抗原（项目1和 3），制造改变以增加T细胞适应性（项目2）和添加组成型IL 7受体以改善T细胞适应性（项目3）， 爱泼斯坦巴尔病毒特异性T细胞的表达和持久性（项目3）。3)克服免疫力 淋巴瘤细胞及其微环境的逃避策略。项目1将利用NKT的能力 细胞来克服免疫抑制微环境，以提高反应率。项目2将使用 同种免疫防御受体，从肿瘤微环境中清除同种反应性细胞并延长生存期 库中的CAR T细胞。项目3研究人员将利用组成型IL 7受体使T细胞能够维持 在免疫抑制分子存在下的活化和扩增，并且还将评估组合 （4）通过使用库的T细胞和NKT细胞免疫疗法，使T细胞和NKT细胞免疫疗法更广泛地适用于 正常供体细胞为了使细胞立即可用，我们将评估几种库存细胞来源 包括库存的NKT细胞作为“现成”产品（项目1），αβ TCR的敲低（项目2）， 库中的EBV特异性T细胞（项目3）。5)确保转移的库存免疫效应物不被免疫细胞排斥。 宿主免疫系统我们将通过以下方式使输注的免疫效应物能够抵抗宿主的免疫应答; 评估β 2微球蛋白（B2 M）的敲低以减少MHC 1类表达，以及MHC II类表达 不变链（项目1）;添加新的同种免疫防御受体（项目2）;或利用 CD 30 CAR靶向同种异体反应性T细胞的能力（项目3）。在完成这些研究后，我们 将评估几种具有遗传修饰的免疫效应物的策略的临床活性和安全性 NHL和HL中的细胞，并深入了解与临床结果相关的免疫和肿瘤因素。 这些研究的成功完成应该会增加这些细胞的效力并改善其可及性。 淋巴瘤的免疫疗法

OVERALL PROJECT SUMMARY The long-term goal of this SPORE renewal is to develop in the laboratory, and test in the clinic novel cellular immunotherapies mediated by genetically modified immune effector cells to treat non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). We have assembled an integrated team of laboratory scientists and clinical investigators with strong track records of productive translational research supported by four shared core resources. To address the persistent challenges of suboptimal long term lymphoma control and unacceptable rates of treatment-related toxicity in lymphoma, investigators in this program have proposed three projects, each involving early-phase clinical trials. All projects address the following five distinct lines of research: 1) Use highly specific T or NKT cell immunotherapies to target multiple lymphoma antigens. This objective will be pursued in each project using either native or chimeric antigen receptors (CARs) or both. 2) Increase the potency of the T or NKT cell immunotherapies for lymphoma. This theme includes targeting multiple antigens (Projects 1 and 3), manufacturing changes to increase T cell fitness (Project 2) and adding a constitutive IL7 receptor to improve the expression and persistence of Epstein Barr Virus-specific T cells (Project 3). 3) Overcome the immune evasion tactics of lymphoma cells and their microenvironment. Project 1 will take advantage of the ability of NKT cells to overcome the immunosuppressive microenvironment to boost response rates. Project 2 will use an alloimmune defense receptor to remove alloreactive cells from the tumor microenvironment and prolong survival of banked CAR T cells. Project 3 investigators will exploit a constitutive IL7 receptor to enable T cells to sustain activation and expansion in the presence of immunosuppressive molecules and will also evaluate combination therapy with Panobinostat (4) Make T and NKT cell immunotherapy more broadly applicable by using banked normal donor cells. To make cells immediately available, we will evaluate several sources of banked cells including banked NKT cells as an “off-the-shelf” product (Project 1), knock down of αβ TCR (Project 2) and banked EBV specific T cells (Project 3). 5) Ensure transferred banked immune effectors are not rejected by the host immune system. We will enable infused immune effectors to be resistant to the host immune response by; evaluating knock down of ß2 microglobulin (B2M) to diminish MHC Class 1 expression, and of the MHC Class II invariant chain (Project 1); adding a novel alloimmune defense receptor (Project 2); or taking advantage of the ability of a CD30 CAR to target alloreactive T cells (Project 3). At the conclusion of these proposed studies, we will have evaluated the clinical activity and safety of several strategies with genetically modified immune effector cells in NHL and HL and gained insight into immune and tumor factors that correlate with clinical outcome. Successful completion of these studies should increase the potency and improve accessibility of these cellular immunotherapies for lymphoma.