SPORE in Lymphoma

整体项目总结 这个孢子更新提案的首要目标是设计和测试新的细胞形式。 T细胞和NKT细胞介导的免疫治疗治疗非霍奇金淋巴瘤 淋巴瘤(HL)。一支由分子生物学家、免疫学家和临床研究人员组成的杰出团队 富有成效的翻译研究的典范历史，并得到四个共享核心资源的支持， 已被招募参与这项工作。应对不可持续的完全缓解和持续的挑战 不可接受的治疗相关毒性比率，该项目的研究人员提出了四种不同的 一系列研究，每一项都涉及早期临床试验。1)使用高度特异的T和自然杀伤T 以多种淋巴瘤抗原为靶点的(NKT)细胞免疫疗法。这一目标将在每个 使用天然或嵌合抗原受体(CARS)或两者兼而有之的项目。2)提高T的效力 淋巴瘤的NKT细胞免疫疗法。这将需要免疫调节剂5-氮胞苷来 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CARS (项目2)；增加一辆非裂解共刺激汽车，以提供更多的“信号-2”元素，以改善 EBV特异性T细胞的表达和持久性(项目3)；使用CD19-CAR增强肿瘤 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。研究人员将使用一种经过修改的倒置细胞因子受体来 与肿瘤部位的免疫抑制分子相互作用，同时传递积极的共刺激信号 (项目1)；将利用一种新的共刺激CAR来使T细胞在存在的情况下保持激活 免疫抑制分子(项目3)；并将利用NKT细胞克服 免疫抑制微环境以提高应答率(项目4)。4)制作T细胞和NKT细胞 免疫疗法的适用范围更广。这种孢子的制造实践中的创新将 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)以及使用银行的NKT细胞作为“非-The-the-the- 货架“产品(项目4)。在这些拟议研究的结论中，我们将评估临床 几种新的非霍奇金淋巴瘤和霍奇金淋巴瘤免疫治疗方法的可行性和安全性，并获得了有价值的见解 与靶向免疫治疗后的临床结果相关的免疫变量。这些 这些成就将是朝着开发新的淋巴瘤治疗方法迈出的实质性步骤，这些治疗方法是 既有效力，又有广泛的可及性。

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.