SPORE in Lymphoma

总体项目摘要 这项SPORE更新提案的总体目标是设计和测试新形式的蜂窝网络， 治疗非霍奇金淋巴瘤（NHL）或霍奇金淋巴瘤的由T细胞和NKT细胞介导的免疫疗法 淋巴瘤（HL）。一个杰出的干部分子生物学家，免疫学家和临床研究人员， 生产性转化研究的典范历史，并得到四个共享核心资源的支持， 为这项工作招募。为了应对无法持续的完全缓解所带来的持续挑战， 不可接受的治疗相关毒性率，本项目的研究人员提出了四种不同的 研究线，每一个涉及一个早期阶段的临床试验。1)使用高特异性T和自然杀伤T (NKT)针对多种淋巴瘤抗原的细胞免疫疗法。这一目标将在每一个 项目使用天然或嵌合抗原受体（汽车）或两者。2)为了增加T的效力 和NKT细胞免疫疗法治疗淋巴瘤。这将需要免疫调节剂，5-氮杂胞苷， 增加肿瘤抗原表达（项目1）;开发针对T细胞淋巴瘤的独立靶点的汽车 （项目2）;添加非溶解性共刺激CAR以提供增加的“信号-2”元件，以改善细胞的免疫功能。 EBV特异性T细胞的表达和持续存在（项目3）;以及使用CD 19-CAR来增强肿瘤细胞的增殖和分化。 识别并提供额外的共刺激（项目4）。3)克服免疫逃避策略 淋巴瘤细胞及其微环境。研究者将使用改良的倒置细胞因子受体， 与肿瘤部位的免疫抑制分子相互作用，同时传递阳性共刺激信号 （项目1）;将开发一种新的共刺激CAR，使T细胞在存在 免疫抑制分子（项目3）;并将利用NKT细胞的能力，克服 免疫抑制微环境以提高反应率（项目4）。4)制造T和NKT细胞 免疫治疗更广泛适用。该SPORE的制造实践创新将 继续改进每个项目取得成功所需的技术，包括进一步减少 T细胞制备的长度和复杂性（项目1-3）以及使用库中的NKT细胞作为“非细胞”， 货架”产品（项目4）。在这些拟议的研究结束时，我们将评估临床 NHL和HL的几种新型免疫治疗方法的可行性和安全性，并获得了有价值的见解 与靶向免疫治疗后临床结果相关的免疫变量。这些 这些成就将代表朝着开发新的淋巴瘤治疗迈出实质性的一步， 既有效又容易获得。

OVERALL PROJECT SUMMARY The overarching goal of this SPORE renewal proposal is to devise and test novel forms of cellular immunotherapy mediated by T cells and NKT cells to treat non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). A distinguished cadre of molecular biologists, immunologists and clinical investigators with exemplary histories of productive translational research, and supported by four shared core resources, has been recruited for this effort. To address the persistent challenges of unsustained complete remissions and unacceptable rates of treatment-related toxicity, investigators in this program have proposed four distinct lines of research, each involving an early-phase clinical trial. 1) Use highly specific T and natural killer T (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) To increase the potency of the T and NKT cell immunotherapies for lymphoma. This will entail an immunomodulatory agent, 5-azacytidine, to increase tumor antigen expression (Project 1); developing CARs for independent targets on T cell lymphoma (Project 2); adding a nonlytic costimulatory CAR to supply increased “signal-2” elements to improve the expession and perisistence of EBV-specific T cells (Project 3); and use of a CD19-CAR to enhance tumor recognition and provide added costimulation (Project 4). 3) Overcome the immune evasion tactics of lymphoma cells and their microenvironment. Investigators will use a modified inverted cytokine receptor to interact with immunosuppressive molecules at the tumor site while delivering positive costimulatory signals (Project 1); will exploit a novel costimulatory CAR to enable T cells to sustain their activation in the presence of immunosuppressive molecules (Project 3); and will take advantage of the ability of NKT cells to overcome the immunosuppressive microenviornment to boost response rates (Project 4). 4) Make T and NKT cell immunotherapy more broadly applicable. Innovations in the manufacturing practices of this SPORE will continue to improve the technologies required for the success of each project, including further reductions in the length and complexity of T-cell preparation (Projects 1-3) and use of banked NKT cells as an “off-the- shelf” product (Project 4). At the conclusion of these proposed studies, we will have evaluated the clinical feasibility and safety of several novel immunotherapy approaches to NHL and HL, and gained valuable insight into the immune variables that correlate with clinical outcome after targeted immunotherapy. These achievements will represent substantive steps toward the development of novel lymphoma treatments that are both potent and widely accessible.