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Escape from CAR T surveillance through lineage plasticity

通过谱系可塑性逃避 CAR T 监控

基本信息

批准号：
10419173
负责人：
Patricia Ernst
金额：
$ 57.87万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10419173
关键词：
Address Adoptive Cell Transfers Adult Affect Antigens B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes B-cell precursor acute lymphoblastic leukemia cell Biological Models Biology Blocking Antibodies Bone Marrow CD19 Antigens CD19 gene CRISPR/Cas technology Cancer Model Cell Communication Cell Line Cell Therapy Cells Characteristics Childhood Childhood Precursor B Lymphoblastic Leukemia Coupled Cytokine Signaling Data Development Disease remission Effectiveness Environment Epigenetic Process Epithelial Evolution Exhibits Frequencies Gene Expression Profile Genetic Genomics Hematologic Neoplasms Hematopoiesis Heterogeneity Immune Immune checkpoint inhibitor Immunologics Immunotherapeutic agent Immunotherapy Infant Inflammatory Interleukin-1 Interleukin-6 Intervention Intrinsic factor Knockout Mice Lead Lymphoma MLL gene MLL-rearranged leukemia Malignant Neoplasms Methods Modeling Mouse Strains Multiple Myeloma Myelogenous Newborn Infant Pathogenesis Patients Pattern Phenotype Production Protocols documentation Refractory Relapse Resistance Role Signal Pathway Signal Transduction Site Solid Neoplasm Study models Surface Antigens System T-Lymphocyte TCF3 gene Testing Therapeutic bcr-abl Fusion Proteins cancer cell cancer therapy chimeric antigen receptor curative treatments cytokine cytotoxic design genetically modified cells immune checkpoint blockade improved in vivo innovation leukemia molecular targeted therapies mouse model novel novel strategies phenotypic biomarker pressure prevent relapse patients response therapeutic target transplant model tumor

项目摘要

PROJECT SUMMARY Cancer cell genomic plasticity can enable resistance to cancer therapy for both solid tumors and hematologic malignancy. Escape from cytotoxic or molecularly targeted therapy through an inherent capacity to reprogram differentiation state or lineage has now been described following adoptive cell therapy or immune checkpoint blockade in adult epithelial tumors. Transfer of T cells genetically modified to express chimeric antigen receptors (CAR T cells) targeting the B cell surface antigen CD19 induces remission in 70-90% of patients with relapsed/refractory B cell acute lymphocytic leukemia (B-ALL) resulting in FDA-approval for this indication. However, a large fraction of those patients relapse within one year of treatment. This occurs with two main patterns, 1) early antigen-positive (CD19pos) relapse, attributed to poor CAR T expansion or lack of persistence, and 2) later antigen-negative relapse. Evasion of CD19-targeted immunotherapy can result from loss of all B lineage phenotypic markers with acquisition of stable, alternative phenotypes in MLL-rearranged (MLL-r), BCR-ABL driven, TCF3-ZNF384 and other subtypes of ALL. Remarkably, emergence of phenotypic switch can occur years after CD19-targeted immunotherapy. Understanding the mechanisms of immunotherapeutic resistance and identifying strategies to overcome these will be critical in improving remission depth and durability of response. Our proposal will address two major deficits in cancer models to identify factors contributing to relapse from immunotherapy: the lack of immune-intact model systems that recapitulate the lineage switching phenomenon observed using CD19-targeted immunotherapy and the lack of faithful mouse models recapitulating infant/childhood MLL-r B-ALL. This collaborative proposal brings together the extensive expertise of the Ernst group in the biology of MLL-r leukemia and hematopoiesis with the CAR T cell expertise of the Fry/Kohler groups to develop innovative new models systems to study evasion from CAR T cell therapy through lineage reprogramming. Our preliminary CAR T cell data employs immune-intact mouse models to illustrate that CD19neg relapse includes cells that exhibit gain of myeloid antigens and a myeloid transcriptional profile. On the pediatric B-ALL front, we develop a retroviral system to produce B-ALL that captures the inherent plasticity of MLL-r leukemias and switches to AML in vivo. Our proposal assesses the ability for both leukemia-intrinsic as well as extrinsic host- environmental components to influence escape from CAR T killing through lineage reprogramming. The findings of our studies, including the discovery of novel strategies to block lineage reprogramming have the potential to inform the development of similar approaches in other forms of cancer treated with cellular therapy and, potentially, immune checkpoint inhibitors. In addition, these studies may lead to a better understanding of lineage plasticity and the extent to which epigenetic heterogeneity contributes to relapse, which can directly inform the design of curative therapies.

项目总结