The Importance of T cell Survival in Tumor Immunity

描述（由申请人提供）：在癌症患者中增强基于免疫的策略的一个关键组成部分是增加对肿瘤抗原特异性的效应T细胞的存活，这导致肿瘤特异性记忆增加。在携带癌症的宿主中，重要的是保持高水平的肿瘤Ag特异性T细胞，因为很难消除每一个肿瘤细胞。从本质上讲，这在肿瘤细胞和免疫系统之间造成了一场持续的战斗，免疫系统赢得宿主的生存至关重要。学习如何倾斜平衡有利于效应T细胞存活将是增强荷癌个体免疫力的重要策略。最近的一项临床试验显著增加了癌症患者中过继转移的肿瘤Ag特异性T细胞的存活率，这种T细胞存活率的增加与临床反应的增加相关。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至关重要。我们的研究小组一直在研究TNF受体家族成员OX 40的生物学功能，我们的研究小组和其他研究小组已证明OX 40可以增强CD 4和CD 8 T细胞的存活，从而增强记忆力。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。我们已经发现，通过OX 40接合治愈肿瘤的小鼠具有肿瘤特异性记忆T细胞，其能够在过继转移到幼稚小鼠中后引发有效的抗肿瘤免疫。因此，我们建议研究与抗0X 40介导的T细胞在荷瘤宿主中存活有关的机制，以进一步理解增加的肿瘤Ag特异性T细胞存活与免疫介导的治疗功效之间的联系。拨款申请的具体目的如下：1）了解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，和3）确定引发抗OX 40和先天性细胞因子之间的协同作用以增强肿瘤生长的临床相关方法。特异性T细胞记忆和肿瘤破坏。从这项资助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，并最终获得对抗OX 40特异性治疗的更深入了解。免疫系统的OX 40特异性增强最近增加了相关性，因为我们已经产生了临床级抗OX 40抗体，并作为I期临床试验的一部分用该抗体治疗了前三名癌症患者。

DESCRIPTION (provided by applicant): 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 CD8 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 CD8 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.