Dendritics Cell Immunotherapy for Colorectal Cancer

描述(申请人提供)：尽管在各种恶性肿瘤中发现了肿瘤相关抗原，但绝大多数抗原充其量是弱免疫原性。树突状细胞(DC)是一种非常有效的抗原提呈细胞，能够使初始T细胞对抗原敏感，已被用来逆转这种对不同肿瘤的免疫无反应。树突状细胞携带肿瘤相关抗原，能够在体外和体内启动肿瘤特异性免疫反应，在各种动物模型中往往具有肿瘤保护作用。使用DC的临床试验表明，它们可以诱导T细胞和B细胞对肿瘤相关抗原的免疫反应。此外，在一些患者中观察到了临床反应，特别是免疫原性肿瘤，如淋巴瘤和黑色素瘤。最近，我们发现负载癌胚抗原(CEA)多肽的DC可以诱导T细胞对该抗原的免疫。对15名接受治疗的转移性结直肠癌患者接种疫苗后，产生了临床反应，其中包括2例完全反应。然而，如果这种免疫治疗方法要在临床上取得成功，就需要取得进展，使基于DC的疫苗更有效。目前的提案试图通过对结直肠癌患者的临床前和临床研究来解决DC免疫治疗中的几个基本问题。虽然我们之前的研究利用了通过密度梯度浓缩的血源性DC，但最近的研究表明，血树突状细胞至少由两个主要亚型组成，可能以不同的方式启动免疫。我们将通过直接从血液中纯化这两种不同的DC亚型，并检测它们处理和呈递抗原的相对能力，来探索它们在体外和体内诱导免疫的免疫原性。此外，我们将开发技术来在临床规模上纯化不同的DC亚型，并用这些亚型接种患者，以评估不同的亚型实际上是否在体内诱导了定性不同的免疫反应。我们还将继续开发并使用新的体外检测方法对这些患者进行免疫学监测，以评估这些疫苗策略的免疫效果。这些拟议的研究将为未来更有效的DC靶向癌症免疫疗法奠定基础。

DESCRIPTION (provided by applicant): Despite the identification of tumor-associated antigens in various malignancies, the vast majority of the antigens are at best weakly immunogenic. Dendritic cells (DC), which are extremely efficient antigen presenting cells uniquely capable of sensitizing naive T cells to antigen, have been used to reverse this immunologic unresponsiveness against different tumors. Armed with tumor-associated antigens, DC are capable of priming tumor specific immune responses in vitro and in vivo, often leading to tumor protection in various animal models. Clinical trials using DC have demonstrated that they can induce T cell and B cell immune responses against tumor associated antigens. Moreover, clinical responses have been observed in some patients, particularly with immunogenic tumors such as lymphoma and melanoma. Recently, we have demonstrated that DC loaded with a peptide derived from carcinoembryonic antigen (CEA) can induce T cell immunity to this antigen. Vaccination of fifteen patients with metastatic colorectal cancer who were treated resulted in clinical responses including two complete responses. Nevertheless, advances making DC-based vaccination more potent will be required if this immunotherapeutic approach is to succeed clinically. The current proposal seeks to address several fundamental issues in DC immunotherapy through preclinical and clinical studies in colorectal cancer patients. While our prior studies have utilized blood derived DC enriched through density gradients, recent studies have demonstrated that blood dendritic cells are comprised of at least 2 major subtypes that may prime immunity differently. We will explore the immunogenicity of the two distinct DC subtypes to induce immunity in vitro and in vivo by purifying them directly from the blood and examining their relative capacity to process and present antigen. Moreover, we will develop techniques to purify the different DC subtypes on a clinical scale and vaccinate patients with these subsets to assess whether the different subtypes in fact induce a qualitatively different immune response in vivo. We will also continue to develop and perform immunologic monitoring in these patients with novel in vitro assays to evaluate the immunologic efficacy of these vaccine strategies. The proposed studies will provide the foundation for a more potent DC targeted cancer immunotherapy for the future.