Enhancing Chimeric Antigen Receptor T Cell Therapies for HematologicMalignancies: Beyond CART 19

总体项目摘要/摘要 这次更新P01的长期目标是开发嵌合抗原的下一代免疫疗法 受体(CAR)T细胞，并将这项研究转化为具有治疗潜力的新疗法 血癌。我们中心开发的汽车是有史以来第一个获得批准的细胞和基因疗法 FDA，最初于2017年治疗难治性/复发性前B细胞急性淋巴细胞白血病(ALL)，并于 2018年。然而，多发性骨髓瘤(MM)、急性髓系白血病(AML)和慢性淋巴细胞白血病(CLL) 仍然是血癌中尚未得到满足的主要医疗需求。我们的中心假设是 CAR T细胞和先进形式的人类基因组编辑的结合将使这种强大的疗法能够 覆盖范围更广的血癌患者。我们汇聚了一支杰出的干部队伍 来自多个学科的研究人员，他们合作并共同发表了多年。每个人 以疾病为重点的项目将由该领域公认的权威机构领导。为了实现我们的目标，我们有三个目标 在上一个供资期间取得进展的基础上继续密切协调的项目 基本共享资源核心。在项目1中，我们将确定治疗的临床和免疫学影响 参加两项临床试验的患者：(I)靶向CD19的CAR T细胞将接受CD5、CTLA- 4和TET2，以解决CLL和淋巴瘤，这些患者缺乏持续的效应器T功能。 在急性髓细胞白血病中，CAR T细胞治疗的中心问题是缺乏一种存在于急性髓细胞白血病上的已知表面抗原 但缺乏正常的造血功能。项目2的目标是通过以下方式为AML打开一个广泛的治疗窗口 对正常骨髓进行基因改造，使其耐受抗AML CAR T细胞的杀伤，并提供有效的 CD45特异性抗白血病CAR T细胞。经过基因编辑的工程HSC，以安装 促进用这些强大的CAR T细胞进行无毒治疗的造血系统将被开发出来。在项目中 3.总体假设是，通过(I)检测骨髓的疗效- 衍生CAR T与现行护理标准的比较(II)提高BCMA的持久性 CART结合IL-2/IL-2R正交突变技术和mRNA/脂质纳米粒疫苗技术 克服当前BCMA T细胞的次佳持久性和有效性。 P01的科学和行政核心对我们的进展至关重要，包括提供项目 管理协作和生物统计、临床安全和监测以及财政支助(核心A)，a 用于制造电池和识别用于汽车靶材的新粘结剂的GMP设施(核心B)，以及 最先进的GLP分析平台，提供所有项目(核心)中生成的样本的高维数据 c)。我们的续订应用具有潜在的范式转换影响，以改变CAR T的教训 所有这些对所有血液系统恶性肿瘤、实体癌都有有意义的疗效，并为 从癌症延伸到自身免疫性疾病。

OVERALL PROJECT SUMMARY / ABSTRACT The long-term goals of this renewal P01 are to develop next generation immunotherapy with chimeric antigen receptor (CAR) T cells and to translate this research into new therapies with curative potential for patients with blood cancer. The CAR developed at our center was the first cell and gene therapy to ever receive approval from the FDA, initially for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL) in 2017 and lymphoma in 2018. However, multiple myeloma (MM), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) remain as the major unmet medical need in blood cancers. Our central hypothesis is that therapies with combination of CAR T cells and advanced forms of human genome editing will enable this powerful therapy to reach a broader spectrum of patients with blood cancer. We have brought together a cadre of exceptional investigators from multiple disciplines who have collaborated and published together for many years. Each disease-focused project will be led by recognized authorities in the field. To achieve our goals, we have three Projects that build on progress during the previous funding period and will continue to coordinate closely with essential shared resource cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) CAR T cells targeting CD19 will be tested with genetic disruption of CD5, CTLA- 4 and TET2 to address CLL and lymphoma, which is lack of sustained effector CAR T function in these patients. In AML, the central problem in CAR T cell therapy is the lack of a known surface antigen that is present on AML but lacking from normal hematopoiesis. The goal of Project 2 is to open a wide therapeutic window for AML by genetically-modifying normal marrow to make it resistant to killing by anti-AML CAR T cells, and delivering potent anti-leukemic CAR T cells specific for CD45. Engineered HSC that are genetically edited to install a hematopoietic system facilitating non-toxic therapy with these potent CAR T cells will be developed. In Project 3, the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) testing the efficacy of marrow- derived CAR T compared to current standard of care blood-derived CAR T (ii) improving persistence of BCMA CAR T with orthogonally mutated IL-2/IL-2R technology and mRNA/lipid-nanoparticle vaccine technology to overcome suboptimal persistence and efficacy of current BCMA T cells. The Scientific and Administrative Cores for this P01 are essential for our progress including provision of project management for collaboration and biostatistics, clinical safety and monitoring, and fiscal support (Core A), a GMP facility for manufacture of cells and identification of new binders for CAR targets (Core B), and a state-of- the-art platform for GLP analysis to provide high dimensional data of the samples generated in all Projects (Core C). Our renewal application has the potential for paradigm-shifting impact to transform the lessons of CAR T for ALL into meaningful efficacy against all hematologic malignancies, solid cancers and provides direction for extending beyond cancer to autoimmune disorders.