Project 6

Combination of Antigen-Specific Cancer Immunotherapy and Anti-Angiogenesis to Treat Patients with Advanced Cervical Cancer

Description

Antigen-specific cancer immunotherapy and anti-angiogenesis have emerged as two attractive strategies for cancer treatment. We tested an innovative approach combining both mechanisms using calreticulin (CRT), which has been shown to enhance MHC class I presentation and exhibits an anti-angiogenic effect. In a preclinical model, we found that C57BL/6 mice vaccinated with CRT linked to HPV-16 E7 in a DNA vaccine exhibited a dramatic increase in E7-specific CD8+ T cell precursors and a significant anti-tumor effect against E7-expressing tumors compared to mice vaccinated with wild-type E7 DNA. Moreover, a potent antitumor effect was observed even in the absence of T cells, suggesting that anti-angiogenesis may have contributed to the anti-tumor effect. Examination of microvessel density in lung tumor nodules and an in vivo angiogenesis assay confirmed the anti-angiogenic effect generated by CRT/E7 and CRT. More recently, we found that CRT/E7 DNA generated significant potency against established E7-expressing murine tumors with down-regulation of MHC class I molecules. Our encouraging findings provide the basis for this proposal to examine the use of CRT/E7(detox) DNA to treat patients with advanced cervical cancers. E7(detox) is a minimally mutated form of E7 which disrupts its Rb-binding function but maintains antigenicity. We are concurrently seeking support from the Rapid Access to Intervention Development (RAID) program to generate clinical grade pNGVL4a-CRT/E7(detox) DNA for clinical trials. In the current proposal, we plan to: Aim 1 Evaluate the safety and toxicity associated with CRT/E7(detox) DNA vaccination in patients with advanced cervical cancers; Aim 2 Evaluate clinical responses associated with CRT/E7(detox) DNA vaccination; Aim 3 Identify and characterize E7-specific humoral and T cell-mediated immune responses in advanced cervical cancer patients before and after vaccination and correlate these immunologic parameters with clinical outcomes; Aim 4 Characterize infiltrating immune cells, cytokine profiles, and microvessel density and correlate these data with HPV status and pathology before and after vaccination; Aim 5 Characterize microvessel blood circulation in the tumors of cervical cancer patients using dynamic contrast enhanced magnetic resonance imaging (MRI) before and after DNA treatment.