DC Vaccination to Enhance Adoptive T Cell Transfer

描述（由申请人提供）：细胞免疫系统具有介导癌症患者抗肿瘤反应的巨大潜力。黑色素瘤对免疫疗法的研究特别有吸引力，因为在过去的十年中已经确定了T细胞识别的几种黑色素瘤特异性抗原。在最近的临床试验中，接受离体扩增的肿瘤反应性T细胞的转移性黑色素瘤患者已经证明了令人鼓舞的临床应答，特别是当在过继细胞转移（ACT）之前与淋巴细胞清除方案组合时。然而，在许多患者中，输注的T细胞在细胞转移后长时间不增殖或存活，并且没有观察到肿瘤消退。这一观察结果表明，增加体内T细胞持久性将改善ACT后的临床反应。在我们的初步研究中，我们评估了肿瘤抗原脉冲树突状细胞（DC）作为一种免疫策略，以提高过继性T细胞反应。使用小鼠模型，我们发现DC免疫导致过继转移的T细胞的显著增殖，其介导针对大皮下肿瘤的增强的免疫应答。虽然DC在介导内源性幼稚和静息T细胞的强刺激中的作用被充分记录，但它们增加过继转移的活化T细胞的功效的能力构成了DC的新用途。我们假设这一原理在患者中适用，并且抗原特异性过继转移的T细胞与肿瘤抗原肽脉冲的DC的组合将导致转移的T细胞在体内的持久性增强，活化和功能增加，以及向肿瘤部位的运输改善，最终导致临床反应改善。在临床试验的背景下，我们在本申请中提出研究特异性DC免疫在形成过继转移的抗原特异性T细胞的持久性、功能和表型中所起的作用。该提案的目标是获得有关DC对ACT的影响的知识，并利用这些信息来改善转移性癌症患者的过继免疫治疗。该提议的具体目的是：（1）确定肽脉冲的DC免疫是否可以改变外周血中过继转移的抗原特异性T细胞的持久性、细胞表面表型和功能;（2）评估肽脉冲的DC免疫是否增强过继转移的抗原特异性T细胞在肿瘤部位浸润和发挥功能的能力：和（3）确定患者的临床反应并评估反应是否与T细胞持续性、表型、功能和肿瘤浸润程度相关。这些研究可能揭示树突状细胞和过继转移的T细胞在体内相互作用的原理，这可能允许为患者设计改进的免疫治疗策略。

DESCRIPTION (provided by applicant): The cellular immune system holds much potential for mediating antitumor responses in cancer patients. Melanoma is particularly appealing to study immunotherapy, since several melanoma-specific antigens recognized by T cells have been identified over the past decade. In recent clinical trials, metastatic melanoma patients receiving ex vivo- expanded tumor-reactive T cells have demonstrated encouraging clinical responses, particularly when combined with a lymphodepletion regimen prior to adoptive cell transfer (ACT). However, in many patients, the infused T cells did not proliferate or survive long after cell transfer and no tumor regression was observed. This observation has suggested that increasing T cell persistence in vivo will improve clinical responses following ACT. In our preliminary studies, we have assessed tumor antigen-pulsed dendritic cells (DCs) as an immunization strategy to improve adoptive T cell responses. Using a murine model, we found that DC immunization resulted in significant proliferation of adoptively transferred T cells which mediated enhanced immune responses against large subcutaneous tumors. While the role of DCs in mediating strong stimulation of endogenous naive and resting T cells is well documented, their ability to increase the efficacy of adoptively transferred activated T cells constitutes a novel use of DCs. We hypothesize that this principle will hold true in patients, and that the combination of antigen-specific, adoptively transferred T cells with tumor antigen peptide-pulsed DCs will result in enhanced persistence of the transferred T cells in vivo, increased activation and function, and improved trafficking to tumor sites, ultimately leading to improved clinical responses. Within the context of a clinical trial, we are proposing in this application to investigate the role that specific DC immunization plays in shaping the persistence, function, and phenotype of adoptively transferred antigen-specific T cells. The goals of this proposal are to acquire knowledge about the influence of DCs on ACT and to use this information to improve adoptive immunotherapy of patients with metastatic cancer. The specific aims of this proposal are: (1) Determine if peptide-pulsed DC immunization can alter the persistence, cell surface phenotype, and function of adoptively transferred, antigen-specific T cells in the peripheral blood; (2) Assess whether peptide-pulsed DC immunization enhances the ability of adoptively transferred, antigen- specific T cells to infiltrate and function at the tumor site: and (3) Determine patient clinical responses and assess whether response correlates with T-cell persistence, phenotype, function, and degree of tumor infiltration. These studies may uncover principles regarding the interaction between dendritic cells and adoptively transferred T cells in vivo which may allow the design of improved immunotherapy strategies for patients.