Enhancing CD8 T Cell Function by Abrogating Inhibition by Regulatory Proteins

通过消除调节蛋白的抑制来增强 CD8 T 细胞功能

• 批准号: 7642451
• 负责人: Joseph N Blattman
• 金额: $ 15.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642451
• 关键词: Address; Adoptive Immunotherapy; Affinity; Antigens; Avidity; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Dominant-Negative Mutation; Dose; Failure; Generations; Genes; Goals; HIV Infections; Helper-Inducer T-Lymphocyte; Human; Human Virus; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Interleukin-2; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Modality; Mus; PTPN6 gene; Phosphoric Monoester Hydrolases; Principal Investigator; Production; Property; Protein Dephosphorylation; Proteins; Public Health; Regulation; Resistance; Signal Pathway; Signal Transduction; Small Interfering RNA; Supplementation; T cell regulation; T-Cell Activation; T-Lymphocyte; Therapeutic; Treatment Efficacy; Tumor Antigens; Ubiquitination; Viral; Viral Tumor Antigens; Virus; Virus Diseases; antigen processing; autocrine; genetic regulatory protein; improved; improved functioning; in vivo; leukemia; mouse model; novel; preclinical study; prevent; programs; protein degradation; response; tumor; tumor growth; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Adoptive immunotherapy with large numbers of in vitro expanded antigen-specific CDS T cells has the potential to become a novel and safe treatment modality for cancer or viral infections, but efficacy is often limited. One obstacle is insufficient in vivo survival and retention of function by donor T cells, which can often be sustained by cotransfer of CD4 helper T cells or by IL-2 administration to substitute for CD4 help. However, specific helper CD4 T cells have not been identified for many tumors, CD4 T cells are often limiting and can be pose additional problems during treatment of HIV infection, and prolonged high-dose IL-2 supplementation can be both inefficient and toxic. Another major obstacle to adoptive immunotherapy can be the failure of transferred T cells to be effectively activated by viral and tumor targets in vivo. T cells specific for tumors often have low affinity TCRs, malignant or infected targets can have impaired antigen processing machinery or accessory signals, and prolonged recognition of target cells can induce T cell tolerance. Thus, increasing the capacity of CDS T cells for IL-2 production and autocrine IL-2 mediated proliferation, reducing the threshold for CDS T cell activation, or preventing induction of tolerance in antigen-specific CDS T cells should significantly enhance the efficacy of adoptive immunotherapeutic strategies. One potential means to increase CDS T cell avidity and function or sustain autocrine IL-2 proliferation and survival is to reduce inhibitory signals in transferred CDS T cells mediated by intracellular regulatory proteins. We have identified Cbl-b, SHP-1, and SOCS-1 as potential targets to enhance CDS T cell aviditiy and function. CDS T cells from mice deficient in these genes results in increased T cell reactivity and costimulation independent IL-2 production. The major goals of this project are to determine if decreasing the negative regulation of activation signals in CDS T cells by Cbl-b, SHP-1, or SOCS-1 by expression of dominant negative versions of these proteins, or by reducing endogenous levels of these proteins via expression of specific siRNA, can improve T cell avidity and function and render these cells more effective in therapy of chronic viral infections or malignancy in mouse models. Additionally, we will determine if abrogating inhibition by these regulatory proteins can enhance the avidity, proliferation and survival of human CDS T cells in preclinical studies. Chronic viral infections and cancer represent major public health concerns. Adoptive immunotherapy with T cells has the potential to become an effective and broadly applicable approach for the treatment of viral infections and malignancy. However, the efficacy of transferred T cells is limited by insufficient in vivo survival and function. These studies will determine if genetically modifying T cells to improve function and survival can enhance adoptive immunotherapy approaches in mouse models of chronic viral infection or malignancy as well as the survival and function of human virus and tumor specific T cells in preclinical studies.

描述（由申请人提供）：使用大量体外扩增的抗原特异性CDS T细胞的连续免疫疗法有可能成为癌症或病毒感染的新型安全治疗方式，但疗效通常有限。一个障碍是供体T细胞的体内存活和功能保留不足，这通常可以通过CD 4辅助T细胞的共转移或通过IL-2给药来替代CD 4辅助来维持。然而，对于许多肿瘤，尚未鉴定出特异性辅助性CD 4 T细胞，CD 4 T细胞通常是限制性的，并且在治疗HIV感染期间可能会造成额外的问题，并且长时间的高剂量IL-2补充可能是低效和有毒的。过继性免疫治疗的另一个主要障碍可能是转移的T细胞在体内不能被病毒和肿瘤靶标有效激活。肿瘤特异性T细胞通常具有低亲和力TCR，恶性或感染的靶标可能具有受损的抗原加工机制或辅助信号，并且靶细胞的长期识别可能诱导T细胞耐受性。因此，增加CD 8 T细胞产生IL-2和自分泌IL-2介导的增殖的能力，降低CD 8 T细胞活化的阈值，或防止抗原特异性CD 8 T细胞中耐受性的诱导应显著增强过继免疫策略的功效。增加CD 8 T细胞亲合力和功能或维持自分泌IL-2增殖和存活的一种潜在手段是减少由细胞内调节蛋白介导的转移的CD 8 T细胞中的抑制信号。我们已经鉴定了Cbl-b、SHP-1和SOCS-1作为增强CDS T细胞亲合力和功能的潜在靶标。来自这些基因缺陷的小鼠的CDS T细胞导致T细胞反应性增加和共刺激非依赖性IL-2产生。该项目的主要目标是确定是否通过表达Cbl-b、SHP-1或SOCS-1的显性负性形式来降低CDS T细胞中Cbl-b、SHP-1或SOCS-1对激活信号的负性调节，或者通过表达特异性siRNA来降低这些蛋白的内源性水平，可以改善T细胞亲合力和功能，并使这些细胞在小鼠模型中的慢性病毒感染或恶性肿瘤的治疗中更有效。此外，我们将确定是否废除这些调节蛋白的抑制可以提高亲合力，增殖和生存的人CDS T细胞在临床前研究。 慢性病毒感染和癌症是主要的公共卫生问题。用T细胞的连续免疫疗法有可能成为治疗病毒感染和恶性肿瘤的有效且广泛适用的方法。然而，转移的T细胞的功效受到体内存活和功能不足的限制。这些研究将确定遗传修饰T细胞以改善功能和存活率是否可以增强慢性病毒感染或恶性肿瘤小鼠模型中的过继免疫治疗方法，以及临床前研究中人类病毒和肿瘤特异性T细胞的存活和功能。