Dendritic cell immunotherapy for ovarian cancer

描述（由申请人提供）：大多数卵巢癌患者在诊断时已是晚期疾病，卵巢癌在妇科恶性肿瘤中死亡率最高。基于诱导肿瘤特异性细胞毒性T淋巴细胞（CTL）反应的免疫治疗可能代表这些患者的可行治疗。近年来，癌症免疫治疗的前景急剧上升，部分基于协同努力，以确定肿瘤特异性抗原，可作为CTL靶点，部分基于树突状细胞（DC）作为肿瘤特异性T细胞反应的强大诱导剂的应用。DCV Technologies将利用一系列新的卵巢肿瘤抗原的鉴定，特别是角质层胰凝乳蛋白酶（SCCE），用于开发卵巢癌的治疗性DC疫苗。SCCE在卵巢癌中高度表达，但在正常卵巢或其他正常成人组织中不表达。用SCCE肽脉冲的DC可以刺激CD 4+辅助性T细胞应答和HLAA2.1限制性CD 8 + CTL，其杀死A2.1匹配的卵巢肿瘤细胞。第一个特定目标将进一步鉴定具有刺激SCCE特异性CD 4 + T细胞应答能力的25-30个残基的肽。在第二个特定目标中，我们将确定负载有延伸肽的DC是否也能够交叉引发SCCE特异性CD 8 + CTL应答。这种策略的基本原理是，抗原特异性CD 4 + T细胞为诱导有效的CD 8 + T细胞应答提供了必要的帮助，无论是在支持方面。DC成熟，并且还用于支持抗原特异性CD 8 + T细胞在体内的持久性。因此，能够诱导CD 8 + CTL应答和CD 4+辅助T细胞应答的负载肽的DC免疫疗法比单独用负载CD 8 + CTL肽表位的DC治疗提供了更大的诱导持久免疫应答和临床益处的潜力。该项目旨在支持卵巢癌患者治疗性DC疫苗接种的临床试验方案的开发。

DESCRIPTION (provided by applicant): The majority of ovarian cancer patients have advanced disease at the time of diagnosis, and ovarian cancer has the highest mortality rate among gynecological malignancies. Immunotherapy based on induction of tumor-specific cytotoxic T lymphocyte (CTL) responses may represent a viable treatment for these patients. The prospects for immunological treatment of cancer have risen sharply in recent years, based in part on concerted efforts to identify tumor-specific antigens that may serve as CTL targets, and in part on the application of dendritic cells (DC) as powerful inducers of tumor-specific T cell responses. DCV Technologies will exploit the identification of a series of novel ovarian tumor antigens, in particular stratum corneum chymotryptic enzyme (SCCE), for the development of therapeutic DC vaccines for ovarian cancer. SCCE is highly expressed in ovarian cancer, but not in normal ovaries or other normal adult tissues. DC pulsed with SCCE peptides can stimulate CD4+ helper T cell responses and HLA A2.1-restricted CD8+ CTL that kill A2.1-matched ovarian tumor cells. The 1st Specific Aim will identify further 25-30 residue peptides with the ability to stimulate SCCE-specific CD4+ T cell responses. In the 2nd Specific Aim, we will determine whether DC loaded with extended peptides are also capable of cross-priming SCCE-specific CD8+ CTL responses. The rationale for this strategy is that antigen-specific CD4+ T cells provide essential help for the induction of effective CD8+ T cell responses, both in terms of supporting. DC maturation and also for supporting the persistence of antigen-specific CD8+ T cells in vivo. Peptide-loaded DC immunotherapy that is capable of inducing both CD8+ CTL responses and CD4+ helper T cell responses thus offers greater potential for inducing durable immune responses and clinical benefit than treatment with DC loaded withCD8+ CTL peptide epitopes alone. This project is designed to support the development of clinical trial protocols for therapeutic DC vaccination in patients with ovarian cancer.