Project 3

The current standard-of-care for inoperable, locally advanced, stage IIB-IVA cervical cancer includes the chemotherapeutic drug, cisplatin, in conjunction with local radiation therapy. However, the five-year survival in most patients affected by stage IIB-IVA cervical cancer is ~30% (58%-63% for stage II patients, 32-35% for stage III patients, and 16% for stage IVA patients). Therefore, an innovative treatment strategy, such as immunotherapy, is needed improve patient outcomes. We have discovered that chemoradiation transiently converts the tumor microenvironment into a site permissive for the activation of an adaptive immune response, creating an opportunity for the direct injection of a peptide or protein vaccine into the tumor to elicit potent antigen-specific cell-mediated immune responses. We found that chemotherapy with cisplatin or radiation therapy combined with intratumoral antigenic peptide administration was sufficient to induce the accumulation of dendritic cells in tumor loci and elicit effective priming and expansion of antigen-specific CD8+ T cells, leading to synergistic therapeutic antitumor effects compared to either treatment alone. Furthermore, this combination treatment leads to the presentation of antigenic peptide by immunosuppressive stromal cells of the tumor, which are thus rendered susceptible to antigen-specific CD8+ T cell-mediated killing, potentially contributing to the control of tumor regardless of the type of HPV infection. Together, this results in potent antigen-specific CD8+ T cell immune responses and antitumor effects. Our overall goal is to treat stage IIB-IVA cervical cancer patients with intratumoral vaccination of the therapeutic TA-CIN protein vaccine in conjunction with standard chemoradiation therapy for the treatment of cervical cancer. We also propose preclinical studies to evaluate intratumoral TA-CIN vaccination with concomitant immune checkpoint blockade therapy to achieve enhanced immune and therapeutic responses in a novel spontaneous cervicovaginal carcinoma model.

Our overall hypothesis is that intratumoral TA-CIN vaccination combined with chemoradiotherapy will enhance HPV antigen-specific immune responses that will accumulate in the tumor microenvironment and promote the killing of immunosuppressive stromal cell and/or tumor cells, leading to better control of HPV-related tumors.

Aim 1: To evaluate the safety and toxicity of TA-CIN administered intratumorally in both HPV16 (+) and HPV16 (–) stage IIB-IVA cervical cancer patients.

Aim 2: To characterize the HPV16 E6/E7-specific T cell-mediated and L2-specific humoral immune responses as well as HPV16 viral load in stage IIB-IVA cervical cancer patients intratumorally vaccinated with TA-CIN.

Aim 3: To determine the phenotypes of immune cells infiltrating the lesion bed, expression of PD-1 and PD-L1 in the tumor microenvironment, and apoptotic lesion cell death in HPV16-associated stage IIB-IVA cervical cancer patients receiving intratumoral TA-CIN vaccination.

Aim 4: To characterize the HPV16 E6/E7 antigen-specific CD8+ T cell-mediated immune responses and therapeutic antitumor effects in a spontaneous HPV16 E6/E7-expressing cervicovaginal carcinoma model treated with intratumoral TA-CIN vaccination with or without checkpoint blockade treatment.

Investigators