City of Hope Lymphoma SPORE

城市的希望淋巴瘤孢子的总体目标是开发新的疗法和药理学 代表了从分子生物学和细胞免疫学观察中获得的最前沿知识 在City of Hope提出了六项临床试验，其中五项利用试剂（细胞产物，小分子， 放射性标记的抗体），这些抗体已在City of Hope生产，并从我们的临床前研究中开发 实验室研究在项目1中，我们设计了双特异性嵌合抗原受体（CAR）T细胞， 对淋巴瘤抗原和巨细胞病毒（CMV）抗原都有反应。组合双特异性CAR T细胞 在City of Hope开发的CMV疫苗可以增强CAR T细胞的持久性， 复发性/难治性非霍奇金淋巴瘤（NHL）患者的T细胞在三种临床环境中： 1)淋巴细胞清除化疗，2）自体（auto）造血细胞移植（HCT），和 3)同种异体血细胞比容。项目2建立在我们以前在一项前瞻性纵向研究中的观察基础上， 接受自动HCT的淋巴瘤患者，揭示了导致预测性38基因突变的致病性突变， 对tMDS/AML易感性的特征。我们现在将使用这个City of Hope队列和外部验证 队列，以开发autoHCT后发生t-MDS/AML的综合风险预测模型。项目3 通过两项II期临床试验解决了复发性霍奇金淋巴瘤患者的不良结局：a 采用PD-1抑制剂纳武单抗± ICE化疗作为自体HCT的桥梁的PET适应性策略，以及 aTac-BEAM，一种基于放射免疫治疗的增强自体HCT方案。在项目4中，我们提出了一个 将CpG寡核苷酸与反义STAT 3 siRNA连接以靶向NHL的新试剂的临床试验， 相关的免疫细胞。我们还开发了一种修饰的高亲和力STAT 3-DNA结合序列， 涉及通过充当DNA诱饵来抑制STAT 3的CpG寡核苷酸。孢子，还支持职业生涯 增强计划的研究人员新的淋巴瘤研究，以及发展研究 为有前途的试点项目的科学家提供的方案。SPORE核心为 项目：行政核心（核心A）提供组织和方案支助; 生物统计学和研究信息学核心（核心B）提供全面的统计和信息 生物样本核心（核心C）支持与样本相关的项目 收集、加工、储存和分发。GMP生产核心（核心D）负责 工艺开发、监管支持和符合cGMP的临床级生产 研究药物;这一核心是一个宝贵的资源，使我们能够迅速翻译实验室发现 去诊所最后，希望之城拥有丰富多样的集水区， 传统上在临床试验中代表性不足和服务不足的患者。总之，这个孢子 在改善淋巴瘤患者的预后方面具有很大的潜力。

The overall goal of the City of Hope Lymphoma SPORE is to develop novel therapeutics and prognostics representing the forefront of knowledge gained from observations in molecular biology and cellular immunology at City of Hope. Six clinical trials are proposed, five of which utilize agents (cellular products, small molecules, radiolabeled antibodies) that have been produced at City of Hope and are developed from our preclinical laboratory studies. In Project 1, we have engineered bi-specific chimeric antigen receptor (CAR) T cells that respond to both lymphoma antigen and cytomegalovirus (CMV) antigen. Combining bi-specific CAR T cells with a CMV vaccine developed at City of Hope may enhance CAR T cell persistence and allow in vivo control of T cells in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) in three clinical settings: 1) lymphodepleting chemotherapy, 2) autologous (auto) hematopoietic cell transplantation (HCT), and 3) allogeneic HCT. Project 2 builds on our previous observations in a prospective longitudinal study of lymphoma patients undergoing auto HCT, revealing pathogenic mutations contributing to a predictive 38-gene signature of susceptibility to tMDS/AML. We will now use this City of Hope cohort and an external validation cohort to develop a comprehensive risk prediction model for developing t-MDS/AML after auto HCT. Project 3 addresses the poor outcomes for patients with relapsed Hodgkin lymphoma with two phase II clinical trials: a PET-adapted strategy using PD-1 inhibitor nivolumab ± ICE chemotherapy as a bridge to autologous HCT, and aTac-BEAM, a radioimmunotherapy-based augmented autologous HCT regimen. In Project 4, we propose a clinical trial of a novel agent linking a CpG oligonucleotide with anti-sense STAT3 siRNA to target NHL and associated immune cells. We are also developing a modified high-affinity STAT3-DNA binding sequence linked to a CpG oligonucleotide that inhibits STAT3 by acting as DNA decoy. The SPORE, also supports a Career Enhancement Program for researchers new to lymphoma research, as well as a Developmental Research Program for scientists with promising pilot projects. SPORE cores provide crucial support to the success of the projects: The Administrative Core (Core A) provides organizational and programmatic support; the Biostatistics and Research Informatics Core (Core B) imparts comprehensive statistical and information management expertise; and Biospecimen Core (Core C) supports projects as they relate to sample collection, processing, storage and distribution. The GMP Manufacturing Core (Core D) is responsible for process development, regulatory support, and cGMP-compliant clinical grade production of novel investigational agents; this core is an invaluable resource allowing us to rapidly translate laboratory discoveries to the clinic. Lastly, with a richly diverse catchment area, City of Hope has made a coordinated effort to engage patients that have been traditionally underrepresented and underserved in clinical trials. In sum, this SPORE holds high potential to make significant inroads in improving outcomes for lymphoma patients.