Dendritic Cell Immunotherapy for Cervical Cancer

描述（由申请人提供）：人乳头瘤病毒（HPV）16型和18型与宫颈癌的诱导和进展有关。该实验室的研究表明，负载HPV E7的树突状细胞（DC）是CD8+ CTL的有效诱导剂，具有裂解宫颈癌患者自体肿瘤细胞的能力，并且DC还能够诱导抗原特异性CD4+辅助T细胞应答。这些观察结果为用HPV E7负载的DC进行免疫治疗以治疗宫颈癌提供了理论基础。中心假设是，负载HPV抗原的自体DC疫苗接种将在携带HPV 16或HPV 18基因型的IB或IIA期宫颈癌患者中诱导抗原特异性和肿瘤特异性免疫应答。这一假设将在DC疫苗接种的I期、递增剂量临床试验中得到解决，共招募12名患者，涵盖3个剂量水平的DC疫苗接种。我们将使用来自外周血单核细胞的完全成熟的自体DC，并通过脂质转染负载HPV E7抗原和钥孔血蓝蛋白作为免疫追踪抗原。特异性目的1将测试负载E7的DC疫苗接种是否能够在体内诱导E7特异性T细胞应答，如通过延迟型T细胞应答测定的。 用E7抗原进行超敏反应皮肤试验。特异性目标2将测试负载E7的DC疫苗接种是否能够诱导抗原特异性T细胞应答，如通过体外分析测量的。实验室研究将包括CD4+ T细胞和CD8+ T细胞对HPV E7的增殖反应，以及通过ELISPOT评估抗原特异性CD4+和CD8+ T细胞的细胞因子表达。我们还将对识别已知HLA* 0201限制性HPV 16 E7肽表位的HLA* 0201抗原限制性外周血CD8+ T细胞的频率进行HLA二聚体分析。这项研究将确定E7抗原负载的自体DC疫苗接种是否为HPV16或HPV18相关宫颈癌患者提供潜在的治疗益处。

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) types 16 and 18 are implicated in the induction and progression of cervical cancer. Studies from this laboratory have shown that HPV E7-loaded dendritic cells (DC) are effective inducers of CD8+ CTL with the ability to lyse autologous tumor cells from cervical cancer patients, and that DC are also able to induce antigen-specific CD4+ helper T cell responses. These observations provide a rationale for immunotherapy with HPV E7-loaded DC for the treatment of cervical cancer. The central hypothesis is that HPV antigen-loaded autologous DC vaccination will induce antigen-specific and tumor-specific immune responses in patients with stage IB or IIA cervical cancer carrying the HPV16 or HPV18 genotypes. This hypothesis will be addressed in a Phase I, escalating dose clinical trial of DC vaccination, enrolling a total of 12 patients and covering 3 dose levels of DC vaccination. We will use fully mature autologous DC derived from peripheral blood monocytes, and loaded by lipofection with HPV E7 antigen and keyhole limpet hemocyanin as an immunological tracking antigen. Specific Aim 1 will test whether E7 loaded DC vaccination is capable of inducing E7-specific T cell responses in vivo, as measured by delayed-type Hypersensitivity skin tests with E7 antigen. Specific Aim 2 will test whether E7-loaded DC vaccination is capable of inducing antigen-specific T cell responses as measured by in vitro analysis. Laboratory studies will include CD4+ T cell and CD8+ T cell proliferative responses to HPV E7, and assessment of cytokine expression by antigen-specific CD4+ and CD8+ T cells by ELISPOT. We will also conduct HLA dimer analysis of the frequencies of HLA* 0201 antigen-restricted peripheral blood CD8+ T cells recognizing known HLA* 0201-restricted HPV16 E7 peptide epitopes. This study will determine whether E7 antigen-loaded autologous DC vaccination offers the potential of therapeutic benefit for patients with HPV16 or HPV18-associated cervical cancer.