Induction of autosis to overcome resistance in adoptive cell therapy for solid tumors

诱导自体死亡以克服实体瘤过继细胞治疗中的耐药性

• 批准号: 10629835
• 负责人: Yong Lu
• 金额: $ 58.33万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629835
• 关键词: Adoptive Cell Transfers; Adoptive Immunotherapy; Antigen Targeting; Antigens; Apoptosis; Cell Death; Cells; Clinical Trials; DNA Viruses; Data; Endowment; European; Event; Exertion; Foundations; Future; Heterogeneity; Human; Immune response; Immunity; Immunocompetent; Immunologic Deficiency Syndromes; In Vitro; Leukocytes; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Mus; Myxoma virus; Nature; Oncolytic viruses; Oryctolagus cuniculus; Pathogenicity; Patients; Proto-Oncogene Proteins c-akt; Rag1 Mouse; Recurrence; Resistance; Role; SKOV3 cells; Signal Transduction; Solid Neoplasm; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Index; Tumor Antigens; Tumor Immunity; Viral load measurement; Work; cell killing; chimeric antigen receptor; chimeric antigen receptor T cells; complement C2a; effector T cell; in vivo; melanoma; mesothelin; mouse model; neoplastic cell; novel; patient derived xenograft model; pre-clinical; prevent; response; synergism; treatment response; tumor; tumor eradication; tumor heterogeneity; tumor xenograft

Project Summary Adoptive cell therapy is a promising approach to treat cancer, but despite tremendous efforts, results of clinical trials in human solid tumors using ACT with tumor-specific T cells expressing T-cell-receptors (TCR) or chimeric antigen receptors (CAR) have not demonstrated the desired therapeutic responses. Recently, we developed tumor-specific T cells loaded with the myxoma virus to overcome resistance in solid tumor ACT. We hypothesize that anti-solid tumor activity of these T cells is mainly attributed to a special type of tumor cell death, autosis, that has not been considered a T cell killing mechanism before but may contribute to the observed exciting antitumor potency by targeting both antigen-positive and antigen-negative tumor cells. Aim 1 will determine the unique molecular mechanism underlying tumor cell autosis induced by the synergy of myxoma virus-derived factor(s) with T cell-derived soluble factor(s). Aim 2 will determine the role of these tumor-specific T cells in promoting autosis and robust host immunity to eradicate solid tumors when the targeted antigen is expressed by only ~25% of tumor cells. Our proposed studies will identify a novel ACT strategy endowed with the capacity to eliminate solid tumors with very high antigen heterogeneity. This translationally relevant work holds promise to significantly advance the therapeutic index of ACT in solid tumors and could then lay the foundation for future clinical trials.

项目概要 过继细胞疗法是一种很有前景的癌症治疗方法，但尽管付出了巨大的努力，临床结果 使用 ACT 与表达 T 细胞受体 (TCR) 的肿瘤特异性 T 细胞进行人类实体瘤试验，或 嵌合抗原受体（CAR）尚未表现出所需的治疗反应。最近，我们 开发出负载粘液瘤病毒的肿瘤特异性 T 细胞，以克服实体瘤 ACT 的耐药性。我们 假设这些 T 细胞的抗实体瘤活性主要归因于一种特殊类型的肿瘤细胞 死亡、自体死亡，以前未被认为是 T 细胞杀伤机制，但可能有助于 通过针对抗原阳性和抗原阴性肿瘤细胞观察到令人兴奋的抗肿瘤效力。目标1 将确定由协同作用诱导的肿瘤细胞自噬的独特分子机制 粘液瘤病毒衍生因子与 T 细胞衍生可溶性因子。目标 2 将确定这些的作用 肿瘤特异性 T 细胞可促进自体死亡和强大的宿主免疫力，从而根除实体瘤 靶向抗原仅由约 25% 的肿瘤细胞表达。我们提出的研究将确定一种新颖的 ACT 该策略具有消除抗原异质性极高的实体瘤的能力。这 转化相关工作有望显着提高 ACT 的治疗指数 肿瘤，然后可以为未来的临床试验奠定基础。