Dendritics Cell Immunotherapy for Colorectal Cancer

描述（由申请方提供）：尽管在各种恶性肿瘤中鉴定了肿瘤相关抗原，但绝大多数抗原充其量是弱免疫原性的。树突状细胞（DC）是非常有效的抗原呈递细胞，其独特地能够使初始T细胞对抗原敏感，已被用于逆转针对不同肿瘤的这种免疫无应答性。DC携带肿瘤相关抗原，能够在体外和体内引发肿瘤特异性免疫应答，通常在各种动物模型中产生肿瘤保护作用。使用DC的临床试验已经证明，它们可以诱导针对肿瘤相关抗原的T细胞和B细胞免疫应答。此外，在一些患者中观察到临床应答，特别是免疫原性肿瘤如淋巴瘤和黑色素瘤。最近，我们已经证明，DC负载的肽来源于癌胚抗原（CEA）可以诱导T细胞免疫这种抗原。15名接受治疗的转移性结直肠癌患者接种疫苗导致临床应答，包括两名完全应答。然而，如果这种免疫方法要在临床上取得成功，则需要使基于DC的疫苗接种更有效的进展。目前的提案旨在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。虽然我们先前的研究利用了通过密度梯度富集的血液来源的DC，但最近的研究表明，血液树突状细胞由至少2种主要亚型组成，其可以不同地引发免疫。我们将探索两种不同DC亚型的免疫原性，通过直接从血液中纯化它们并检查它们加工和呈递抗原的相对能力，在体外和体内诱导免疫。此外，我们将开发技术，以纯化不同的DC亚型在临床规模和接种这些子集的患者，以评估是否不同的亚型实际上在体内诱导不同的免疫反应。我们还将继续开发并通过新型体外试验对这些患者进行免疫监测，以评估这些疫苗策略的免疫功效。拟议的研究将为未来更有效的DC靶向癌症免疫疗法提供基础。

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.