title: p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T-cell responses.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Hardwick
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Mary
authors.initials: M
authors.lastname: Carroll
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California.
authors.forename: Teodora
authors.initials: T
authors.lastname: Kaltcheva
authors.affiliation: Bioinformatics Core Facility, City of Hope National Medical Center, Duarte, California.
authors.forename: Dajun
authors.initials: D
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Dean
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Lucille
authors.initials: L
authors.lastname: Leong
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, California.
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.affiliation: Department of Surgical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chao
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Marwan
authors.initials: M
authors.lastname: Fakih
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Division of Cancer Etiology and Outcomes Research, City of Hope National Medical Center, Duarte, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Espenschied
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Joshua D I
authors.initials: JD
authors.lastname: Ellenhorn
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California. ddiamond@coh.org.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chung
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53