The Importance of T cell Survival in Tumor Immunity

T 细胞存活在肿瘤免疫中的重要性

• 批准号: 7759639
• 负责人: Andrew D Weinberg
• 金额: $ 27.04万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759639
• 关键词: Adoptive Transfer; Agonist; Antibodies; Applications Grants; CD4 Positive T Lymphocytes; Cancer Patient; Cell Survival; Cells; Clinic; Clinical; Clinical Trials; Data; Equilibrium; Family member; Generations; Genomics; Grant; Immune; Immune response; Immune system; Immunity; Immunology; Immunotherapy; Individual; Interferon Type I; Interleukin-12; Knowledge; Learning; Link; Malignant Neoplasms; Mediating; Memory; Methods; Molecular; Mus; Natural Killer Cells; Pathway interactions; Peripheral; Phase I Clinical Trials; Production; Property; Proteins; Signal Transduction; T memory cell; T-Lymphocyte; TNFRSF1A gene; Testing; Treatment Efficacy; Tumor Immunity; Tumor Necrosis Factor Receptor; base; clinically relevant; cytokine; design; in vivo; memory CD4 T lymphocyte; neoplastic cell; research study; response; tumor; tumor immunology

A key component to enhance immune-based strategies in cancer-bearing individuals is to increase the survival of effector T cells specific for tumor Ag(s), which leads to increased tumor-specific memory. In cancer-bearing hosts it is important to maintain high levels of tumor Ag-specific T cells, because it is difficult to eliminate every last tumor cell. In essence this creates an ongoing battle between the tumor cells and the immune system and it is essential that the immune system win for the host to survive. Learning how to tip the balance in favor of effector T cell survival will be an important strategy for enhancing immunity in cancer- bearing individuals. A recent clinical trial dramatically increased the survival of adoptively transferred tumor Ag-specific T cells in cancer patients and this increase in T cell survival correlated with increased clinical responses. Thus, understanding the mechanisms involved in the T cell survival pathway is crucial to developing new strategies aimed at potentiating tumor immunity in cancer patients. Our group has been studying the biologic function of the TNF-receptor family member, OX40, which has been shown by our group and others to enhance CD4 and CDS T cell survival leading to increased memory. In particular, we have shown that OX40 engagement in tumor-bearing hosts enhances anti-tumor immunity leading to destruction of tumors. We have found that mice cured of tumors through OX40 engagement have tumor-specific memory T cells capable of eliciting potent anti-tumor immunity upon adoptive transfer into naive mice. Therefore we propose to study the mechanism(s) involved with anti-OX40 mediated T cell survival in tumor-bearing hosts to further understand the link between increased tumor Ag-specific T cell survival and immune-mediated therapeutic efficacy. The specific aims of the grant application are as follows: 1) To understand the contribution that IL-12 makes to anti-OX40 enhanced tumor-specific T cell memory, 2) To elucidate the molecular basis for anti-OX40 enhancement of CD4 and CDS T cell survival, and 3) To determine clinically relevant ways to elicit synergy between anti-OX40 and innate cytokines to enhance tumor-specific T cell memory and destruction of tumors. The knowledge gained from this grant will help us design more effective ways to enhance tumor immunotherapy, and ultimately gain a greater understanding of anti-OX40-specific therapy. OX40-specific augmentation of the immune system has recently increased in relevance, because we have produced clinical grade anti-OX40 antibody and treated the first three cancer patients with this antibody as part of a phase I clinical trial.

在癌症患者中增强免疫策略的一个关键组成部分是增加免疫原性。 对肿瘤Ag（s）特异的效应T细胞的存活，这导致肿瘤特异性记忆增加。在 在癌症患者中，维持高水平的肿瘤Ag特异性T细胞是很重要的，因为这是困难的。 消灭所有的肿瘤细胞实质上，这在肿瘤细胞和肿瘤细胞之间创造了一场持续的战斗。 免疫系统是免疫系统的重要组成部分，免疫系统赢得宿主的生存至关重要。学习如何给小费 有利于效应T细胞存活的平衡将是增强癌症免疫力的重要策略- 轴承个人。最近的一项临床试验大大提高了过继转移肿瘤的存活率， 癌症患者中Ag特异性T细胞和T细胞存活率的增加与临床 应答因此，了解T细胞存活途径中涉及的机制对于 开发旨在增强癌症患者肿瘤免疫力的新策略。 我们小组一直在研究肿瘤坏死因子受体家族成员OX 40的生物学功能， 我们的研究小组和其他人已经证明，增强CD 4和CD 8 T细胞的存活，从而增加记忆力。 特别是，我们已经表明，OX 40参与荷瘤宿主增强抗肿瘤免疫 导致肿瘤的破坏。我们发现，通过OX 40参与治疗肿瘤的小鼠， 肿瘤特异性记忆T细胞，其在过继转移到 幼稚的老鼠因此，我们建议研究抗OX 40介导的T细胞介导的免疫应答的机制。 在荷瘤宿主中的存活率，以进一步了解增加的肿瘤Ag特异性T细胞 存活率和免疫介导的治疗功效。拨款申请的具体目的如下： 1)为了理解IL-12对抗OX 40增强肿瘤特异性T细胞记忆的贡献，2） 阐明抗OX 40增强CD 4和CD 8 T细胞存活的分子基础，以及3） 确定临床相关的方法，以引起抗OX 40和先天性细胞因子之间的协同作用， 肿瘤特异性T细胞记忆和肿瘤的破坏。从这笔赠款中获得的知识将帮助我们 设计更有效的方法来增强肿瘤免疫治疗，并最终获得更好的理解 抗OX 40特异性治疗。最近，免疫系统的OX 40特异性增强增加， 相关性，因为我们已经产生了临床级抗OX 40抗体，并治疗了前三种癌症 作为I期临床试验的一部分。