Escape from CAR T surveillance through lineage plasticity

通过谱系可塑性逃避 CAR T 监控

• 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
• 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

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.

项目摘要 癌细胞基因组可塑性可以使实体瘤和癌症治疗能够抗药性 血液系统恶性肿瘤。逃避通过细胞毒性或分子靶向治疗 现在已经描述 成人上皮肿瘤中的收养细胞疗法或免疫检查点阻滞。 t的转移 基因修饰的细胞以表达靶向B的嵌合抗原受体（CAR T细胞） 细胞表面抗原CD19诱导70-90％的复发/难治性患者的缓解 细胞急性淋巴细胞性白血病（B-all），导致FDA批准为此适应症。然而， 这些患者在治疗后一年内复发的很大一部分。这是两个主要的 模式，1）早期抗原阳性（CD19POS）复发，归因于较差的汽车t膨胀或缺乏 持久性和2）后来的抗原阴性复发。逃避CD19靶向免疫疗法 可能是由于稳定的替代方案而丧失所有B谱系表型标记 MLL重新编织（MLL-R），BCR-ABL驱动，TCF3-ZNF384和其他亚型的表型 全部。值得注意的是，表型转换的出现可能发生在CD19靶向后的几年 免疫疗法。了解免疫治疗性抗性的机制和 确定克服这些策略对于改善缓解深度和 响应的耐用性。 我们的建议将解决癌症模型中的两个主要缺陷，以识别因素 导致免疫疗法复发：缺乏免疫独立模型系统 概括使用CD19靶向免疫疗法观察到的谱系开关现象 缺乏忠实的小鼠模型，概括了婴儿/童年时期MLL-R B-all。这 协作提案汇集了恩斯特小组在生物学方面的广泛专业知识 MLL-R白血病和造血的含量，弗莱/科勒组的CAR T细胞专业知识 开发创新的新模型系统，以研究从汽车T细胞疗法逃避到 谱系重编程。我们的初步汽车T细胞数据采用免疫独立的小鼠模型 为了说明CD19Neg复发包括表现出髓样抗原和A的细胞 髓样转录轮廓。在小儿B-All Front上，我们开发了一个逆转录病毒系统 生产B-所有人捕获MLL-R白血病的固有可塑性并切换到AML 体内。我们的建议评估白血病intrinsic和外部宿主的能力 - 环境成分会影响逃避途中通过血统杀死的逃脱 重新编程。我们的研究结果，包括发现阻止的新型策略 谱系重编程有可能告知开发类似方法 通过细胞疗法治疗的其他形式的癌症和免疫检查点 抑制剂。此外，这些研究可能会更好地了解谱系可塑性和 表观遗传异质性有助于复发的程度，这可以直接告知 治疗疗法的设计。