From the Past to the Future: Chimeric Antigen Receptor T cells for Lymphoid Malignancies

从过去到未来：嵌合抗原受体 T 细胞治疗淋巴恶性肿瘤

• 批准号: 10713200
• 负责人: Joseph Anthony Fraietta
• 金额: $ 44.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713200
• 关键词: Ablation; Acute Lymphocytic Leukemia; Address; Adopted; Adoptive Immunotherapy; Antigen Receptors; Antigens; Autoimmune Diseases; Automobile Driving; Award; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Cell Leukemia; B-Cell NonHodgkins Lymphoma; Biological Assay; Biological Markers; Biology; Blood; CAR T cell therapy; CBL gene; CD19 Antigens; CD19 gene; CRISPR/Cas technology; CTLA4 gene; Cell Culture Techniques; Cell physiology; Cells; Characteristics; Chemoresistance; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Collaborations; Critical Pathways; Data; Development; Disease remission; Dose; Engineering; Exhibits; Flow Cytometry; Future; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Hematological Disease; Heterogeneity; Human; Immune; Immunologics; Immunotherapy; Infiltration; Infusion procedures; Investigation; Knock-out; Laboratories; Lead; Libraries; Link; Lupus; Lymphocyte; Malignant Lymph Node Neoplasm; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediator; Modeling; Outcome; PRDM1 gene; PTPN6 gene; Pathway interactions; Patients; Population; Proliferating; Property; Proteins; Public Health; Publishing; Reagent; Receptor Signaling; Recurrent disease; Refractory; Relapse; Research; Resistance; Resolution; Safety; Sampling; Science; Series; Serum; Specific qualifier value; Structure; T cell therapy; T-Cell Development; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Translating; Treatment Failure; Tumor Tissue; Veins; Work; Xenograft Model; biobank; cancer immunotherapy; cellular engineering; chimeric antigen receptor; chimeric antigen receptor T cells; clinically actionable; cohort; cytokine; design; exhaust; experience; experimental study; first-in-human; follow-up; genome editing; head-to-head comparison; immune checkpoint; improved; improved outcome; in vivo; inhibitor; innovation; leukemia; manufacture; manufacturing process; mouse model; multiple omics; neoplastic cell; new technology; next generation; novel; pre-clinical; prevent; programmed cell death protein 1; refractory cancer; resistance mechanism; response; safety assessment; success; synthetic biology; tool; trafficking; treatment optimization; tumor; vector

Summary/Abstract (PROJECT 1) Chimeric antigen receptor (CAR) T cells directed to the CD19 protein (CART19) have revolutionized the treatment of a variety of B cell malignancies, with complete remission rates as high as 97% in certain types of advanced leukemia. Many of these responses are sustained, but poor CAR T cell expansion and persistence following infusion and antigen-negative escape are common mechanisms of treatment failure. It is critical to investigate factors driving successful CAR T cell function in responding patients. Previous studies have indicated that in lymphoid malignancies, durable remission is associated with activation of specific T cell pathways and only some patients experience therapeutic levels of CAR T cell expansion and antitumor activity. During the previous award period, we successfully developed a comprehensive understanding of the T cell-intrinsic and - extrinsic mechanisms of resistance as well as tumor cell-intrinsic mechanisms that lead to relapse. Here we propose extensive next-generation analyses to understand properties of optimal CAR T cell therapy, elucidate mechanisms of resistance, and develop strategies to overcome resistance and enhance CAR T cell activity to cure more patients with hematologic diseases. We will take advantage of already established successful collaborations with core laboratories possessing expertise in cell manufacturing, gene editing, and state-of-the- art correlative science platforms to explore a number of innovative aims. In Aim 1, we will carry out an extensive analysis of T cell receptor (TCR) rearrangements, vector copy number, T cell subsets analyzed by flow cytometry, serum cytokines and biomarkers (~7,000), and transcriptional landscapes of CAR T cells in blood as well as tumor tissues and formulate multi-omics models linking correlative data and outcome. In Aim 2, we have designed a high-impact clinical trial to knockout CD5, an unconventional negative immune checkpoint molecule and inhibitor of antigen-receptor signaling, with the goal of increasing the therapeutic index of 3-day manufactured CART19 cells for relapsed/refractory B-cell malignancies. Finally, in Aim 3, we will carry out functional analyses of genes implicated in potentiating CAR T cell proliferation, persistence, and antitumor function to develop `best-in-class' products for ALL, CLL, and NHL. Using a structured, multi-pronged strategy, we hope to ameliorate resistance to CAR T cell-based therapies for B-cell malignancies and clinically advance several next-generation synthetic biology tools. This work is expected to open therapeutic horizons in the field of adoptive immunotherapy for cancer and offer new research prospects that could be translated to improving the treatment of other cancers and autoimmune disorders.

摘要/摘要（项目一）