DC Vaccination to Enhance Adoptive T Cell Transfer

描述(由申请人提供)：细胞免疫系统在调节癌症患者的抗肿瘤反应方面具有很大的潜力。黑色素瘤对免疫疗法的研究特别有吸引力，因为在过去的十年里，已经发现了几种被T细胞识别的黑色素瘤特异性抗原。在最近的临床试验中，接受体外扩增的肿瘤反应性T细胞的转移性黑色素瘤患者表现出令人鼓舞的临床反应，特别是在过继细胞转移(ACT)之前结合淋巴净化方案时。然而，在许多患者中，输注的T细胞在细胞移植后没有增殖或存活很长时间，也没有观察到肿瘤消退。这一观察表明，提高T细胞在体内的持久性将改善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致敏的树突状细胞(DC)作为一种免疫策略来改善过继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细胞显著增殖，这些T细胞介导了对大型皮下肿瘤的增强免疫反应。虽然DC在调节内源性初始和静息T细胞的强烈刺激中的作用得到了很好的证明，但它们提高过继转移的激活T细胞的有效性的能力构成了DC的一种新用途。我们假设这一原理在患者身上是正确的，并且将抗原特异的过继转移的T细胞与肿瘤抗原肽致敏的DC相结合，将导致转移的T细胞在体内的持久性增强，增强激活和功能，并改善向肿瘤部位的转运，最终导致临床反应的改善。在临床试验的背景下，我们建议在这一应用中调查特定的DC免疫在塑造过继转移的抗原特异性T细胞的持久性、功能和表型方面所起的作用。这项建议的目标是获得关于DC对ACT的影响的知识，并利用这些信息来改进转移性癌症患者的过继免疫治疗。该建议的具体目的是：(1)确定多肽冲击的DC免疫是否可以改变过继转移的抗原特异性T细胞在外周血中的持久性、细胞表面表型和功能；(2)评估多肽冲击的DC免疫是否能增强过继转移的抗原特异性T细胞在肿瘤部位的渗透和功能；以及(3)确定患者的临床反应并评估应答是否与T细胞的持久性、表型、功能和肿瘤的浸润程度相关。这些研究可能揭示体内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。

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.