Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> Three patients were vaccinated with 1.0 × 10<sup>8</sup> plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6 × 10<sup>8</sup> 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 <i>in vitro</i>.</p><p><b>Results:</b> p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4<sup>+</sup> and CD8<sup>+</sup> T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8<sup>+</sup> T-cell compartment (<i>P</i> = 0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1<sup>+</sup> T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1<sup>+</sup> CD8<sup>+</sup> T cells showed an inverse correlation with the peak CD8<sup>+</sup> p53 response (<i>P</i> = 0.02) and antibody blockade of PD1 <i>in vitro</i> 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.</p><p><b>Conclusion:</b> p53MVA was well tolerated and induced robust CD8<sup>+</sup> T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit. <i>Clin Cancer Res; 20(17); 4459–70. ©2014 AACR</i>.</p></div>

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