Purpose: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. Results: 11 patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome and immunological response. Toxicity: There were no DLTs but 3/11 patients came off study early due to gemcitabine-attributed adverse events (AEs). Minimal AEs were attributed to p53MVA vaccination. Immunological and Clinical Response: Enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T cell compartments in 5/11 and 6/11 patients respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity post therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pre-treatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+T cell responses post therapy correlated with longer PFS. Therefore, if responses to p53MVA could be enhanced with alternative agents, superior clinical responses may be achievable.
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