Dendritic Cell Immunotherapy for Cervical Cancer

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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.