p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T cell responses

Purpose: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers. Experimental Design: Three patients were vaccinated with 1.0 × 10 8 plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6 × 10 8 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro . Results: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4 + and CD8 + T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8 + T-cell compartment ( P = 0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1 + T cells detectable in patients9 peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1 + CD8 + T cells showed an inverse correlation with the peak CD8 + p53 response ( P = 0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent. Conclusion: p53MVA was well tolerated and induced robust CD8 + T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit. Clin Cancer Res; 20(17); 4459–70. ©2014 AACR .