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.

项目概要 癌细胞基因组可塑性可以使实体瘤和癌症治疗产生耐药性 血液系统恶性肿瘤。通过逃避细胞毒性或分子靶向治疗 重新编程分化状态或谱系的固有能力现在已描述如下 成人上皮肿瘤的过继细胞疗法或免疫检查点阻断。转移 T 经过基因改造以表达针对 B 的嵌合抗原受体（CAR T 细胞）的细胞 细胞表面抗原 CD19 可诱导 70-90% 的复发/难治性 B 患者缓解 细胞急性淋巴细胞白血病（B-ALL）导致 FDA 批准该适应症。然而， 这些患者中很大一部分在治疗一年内复发。发生这种情况主要有两个 模式，1) 早期抗原阳性 (CD19pos) 复发，归因于 CAR T 扩增不良或缺乏 持续性，以及 2) 后来抗原阴性复发。逃避 CD19 靶向免疫治疗 可能是由于所有 B 谱系表型标记的丢失以及获得稳定的替代性标记所致 MLL 重排 (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 靶向后数年 免疫疗法。了解免疫治疗耐药的机制和 确定克服这些问题的策略对于改善缓解深度和 响应的持久性。 我们的提案将解决癌症模型中的两个主要缺陷，以确定因素 导致免疫治疗复发：缺乏完整的免疫模型系统 概括使用 CD19 靶向免疫疗法观察到的谱系转换现象 以及缺乏重现婴儿/儿童 MLL-r B-ALL 的忠实小鼠模型。这 合作提案汇集了恩斯特小组在生物学领域的广泛专业知识 借助 Fry/Kohler 团队的 CAR T 细胞专业知识，研究 MLL-r 白血病和造血作用 开发创新的新模型系统来研究逃避 CAR T 细胞治疗的方法 谱系重编程。我们的初步 CAR T 细胞数据采用免疫完整的小鼠模型 说明 CD19neg 复发包括表现出获得髓样抗原和 骨髓转录谱。在儿科 B-ALL 方面，我们开发了一种逆转录病毒系统 产生 B-ALL，捕获 MLL-r 白血病的固有可塑性，并在 体内。我们的建议评估了白血病内在和外在宿主的能力 环境成分影响通过谱系逃避 CAR T 杀伤 重新编程。我们的研究结果，包括发现新的阻断策略 谱系重编程有可能为类似方法的开发提供信息 通过细胞疗法和潜在的免疫检查点治疗其他形式的癌症 抑制剂。此外，这些研究可能有助于更好地理解谱系可塑性和 表观遗传异质性对复发的影响程度，可以直接告知 治疗方案的设计。