title: Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer.
abstract: A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.
authors.affiliation: Etubics Corporation, 410 West Harrison Street, Suite 100, Seattle, WA, 98119, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Balint
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gabitzsch
authors.forename: Adrian
authors.initials: A
authors.lastname: Rice
authors.forename: Yvette
authors.initials: Y
authors.lastname: Latchman
authors.forename: Younong
authors.initials: Y
authors.lastname: Xu
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Messerschmidt
authors.forename: Arvind
authors.initials: A
authors.lastname: Chaudhry
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jones
mesh_terms: D000256:Adenoviridae; D017498:Adenovirus E1 Proteins / Q000235:genetics; D017502:Adenovirus E2 Proteins / Q000235:genetics; D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology; D017384:Sequence Deletion / Q000235:genetics; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C000602305:Ad5(E1-,E2b-)-CEA(6D) vaccine; D017498:Adenovirus E1 Proteins; D017502:Adenovirus E2 Proteins; C405522:CAP1-6D; D019496:Cancer Vaccines; D009842:Oligopeptides; D007371:Interferon-gamma