DC Vaccination to Enhance Adoptive T Cell Transfer

细胞免疫系统在介导癌症患者的抗肿瘤应答方面具有很大的潜力。黑素瘤 由于T细胞识别几种黑色素瘤特异性抗原，因此对研究免疫疗法特别有吸引力 在过去的十年中被发现。在最近的临床试验中，接受离体- 扩增的肿瘤反应性T细胞已经显示出令人鼓舞的临床应答，特别是当与 过继细胞转移（ACT）前的淋巴细胞清除方案。然而，在许多患者中，输注的T细胞并没有 细胞转移后很长时间内都在增殖或存活，并且没有观察到肿瘤消退。这一观察表明， 增加体内T细胞的持久性将改善ACT后的临床反应。在我们的初步研究中， 已经评估了肿瘤抗原致敏的树突状细胞（DC）作为改善过继性T细胞免疫的免疫策略， 应答使用小鼠模型，我们发现DC免疫导致了过继性细胞的显著增殖， 转移的T细胞介导针对大皮下肿瘤的增强的免疫应答。虽然作用 DC介导内源性幼稚和静息T细胞的强烈刺激是有据可查的，它们的能力是， 增加过继转移的活化T细胞的功效构成了DC的新用途。我们假设， 这一原则在患者中也适用，抗原特异性过继转移的T细胞与 肿瘤抗原肽脉冲的DC将导致转移的T细胞在体内的持久性增强， 活化和功能，并改善向肿瘤部位的运输，最终导致改善的临床反应。 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、功能和表型中起作用。 细胞本提案的目标是了解发展中国家对ACT的影响，并利用这一点， 改善转移性癌症患者过继免疫治疗的信息。 该建议的具体目标是：（1）确定肽脉冲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DC免疫是否增强过继转移的抗原- 特异性T细胞浸润并在肿瘤部位起作用：和（3）确定患者临床反应并评估 反应是否与T细胞持续存在、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细胞之间相互作用的原理， 这可能允许为患者设计改进的免疫治疗策略。 我

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. i