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

Nicola R. Hardwick, Mary Carroll, Teodora Kaltcheva, Dajun Qian, Dean Lim, Lucille Leong, Peiguo Chu, Joseph Kim, Joseph Chao, Marwan Fakih, Yun Yen, Jonathan Espenschied, Joshua D.I. Ellenhorn, Don J. Diamond, Vincent Chung

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Abstract

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 patients' 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.

Original languageEnglish
Pages (from-to)4459-4470
Number of pages12
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume20
Issue number17
DOIs
Publication statusPublished - Sep 1 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hardwick, N. R., Carroll, M., Kaltcheva, T., Qian, D., Lim, D., Leong, L., Chu, P., Kim, J., Chao, J., Fakih, M., Yen, Y., Espenschied, J., Ellenhorn, J. D. I., Diamond, D. J., & Chung, V. (2014). p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T-cell responses. Clinical cancer research : an official journal of the American Association for Cancer Research, 20(17), 4459-4470. https://doi.org/10.1158/1078-0432.CCR-13-3361