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.

项目摘要 免疫细胞疗法是治疗癌症的一种有希望的方法，但是尽管做出了巨大的努力，临床结果仍然是不稳定的。 使用ACT与表达T细胞受体（TCR）的肿瘤特异性T细胞进行的人实体瘤试验，或 嵌合抗原受体（CAR）尚未显示出所需的治疗反应。最近我们 开发了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细胞抗实体瘤活性主要归因于特殊类型的肿瘤细胞 死亡，自体免疫，以前没有被认为是T细胞杀伤机制，但可能有助于 通过靶向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。要求1 将确定肿瘤细胞自体化的独特分子机制， 粘液瘤病毒衍生的因子与T细胞衍生的可溶性因子。目标2将确定这些方面的作用 肿瘤特异性T细胞在促进自体免疫和强大的宿主免疫以根除实体瘤时， 靶向抗原仅由~25%的肿瘤细胞表达。我们提出的研究将确定一种新的ACT 该策略被赋予消除具有非常高抗原异质性的实体瘤的能力。这 临床相关工作有望显著提高ACT在固体中的治疗指数， 这将为未来的临床试验奠定基础。