City of Hope Lymphoma SPORE

希望之城淋巴瘤孢子的总体目标是开发新的治疗方法和预后 代表了从分子生物学和细胞免疫学的观察中获得的前沿知识 在希望之城。建议进行六项临床试验，其中五项利用药物(细胞产品、小分子、 放射性标记抗体)是由希望之城生产的，是从我们的临床前开发出来的 实验室研究。在项目1中，我们已经设计出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)抗原均有效。结合双特异性CAR T细胞 希望之城研发的CMV疫苗可能会增强CAR T细胞的持久性并允许体内控制 三种临床环境下复发/难治性非霍奇金淋巴瘤(NHL)患者的T细胞： 1)淋巴清除化疗，2)自体(自)造血细胞移植(HCT)，以及 3)异基因Hct。项目2建立在我们之前观察到的前瞻性纵向研究的基础上 淋巴瘤患者接受自体HCT，发现致病突变导致38基因预测 对TMDS/AML易感性的特征。我们现在将使用这个希望之城队列和外部验证 目的：建立汽车HCT后发生t-MDS/AML的综合风险预测模型。项目3 通过两项II期临床试验解决复发霍奇金淋巴瘤患者的不良结局：A 使用PD-1抑制剂nivolumab±ICE化疗作为通往自体HCT的桥梁的PET适应策略，以及 ATAC-BEAM，一种基于放射免疫治疗的增强型自体HCT方案。在项目4中，我们提出了一个 新型CpG寡核苷酸与反义STAT3 siRNA靶向NHL和NHL的临床研究 相关的免疫细胞。我们还在开发一种修饰的高亲和力STAT3-DNA结合序列 一种通过充当DNA诱饵来抑制STAT3的CpG寡核苷酸。孢子，也支撑着一份事业 淋巴瘤研究新手和发展研究人员的增强计划 面向有前景的试点项目的科学家的计划。孢子核心为成功提供关键支持 项目：行政核心(核心A)提供组织和方案支助； 生物统计和研究信息学核心(核心B)提供全面的统计和信息 管理专业知识；Biospecimen核心(核心C)支持与样本有关的项目 收集、加工、储存、配送。GMP制造核心(核心D)负责 新产品的流程开发、监管支持和符合cGMP的临床级别生产 研究代理；这个核心是一个无价的资源，使我们能够快速转换实验室发现 去诊所。最后，凭借丰富多样的集水区，希望之城做出了协调努力，参与 传统上在临床试验中代表性和服务不足的患者。总而言之，这个孢子 具有在改善淋巴瘤患者预后方面取得重大进展的巨大潜力。

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.