A phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-α-2b in patients with CEA-expressing carcinomas

Prime-boost vaccination with recombinant (r) vaccinia(V)-CEA(6D)-TRICOM (triad of co-stimulatory molecules B7.1, ICAM-1 and LFA-3) and rFowlpox(F)-CEA(6D)-TRICOM infect antigen-presenting cells and direct expression of co-stimulatory molecules. We hypothesized that co-administration of vaccine with...

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Published in:Cancer Immunology, Immunotherapy Immunotherapy, 2016-11, Vol.65 (11), p.1353-1364
Main Authors: Duggan, Megan C., Jochems, Caroline, Donahue, Renee N., Richards, Jacob, Karpa, Volodymyr, Foust, Elizabeth, Paul, Bonnie, Brooks, Taylor, Tridandapani, Susheela, Olencki, Thomas, Pan, Xueliang, Lesinski, Gregory B., Schlom, Jeffrey, Carson III, William E.
Format: Article
Language:English
Subjects:
Alanine
Alanine transaminase
Antigen-presenting cells
Aspartate transaminase
B7-H1 Antigen - genetics
Cancer Research
Cancer Vaccines - immunology
Carcinoembryonic antigen
Carcinoembryonic Antigen - genetics
Carcinoembryonic Antigen - immunology
Carcinoma
CD27 antigen
CD58 antigen
CD58 Antigens - genetics
Colorectal cancer
Colorectal Neoplasms - immunology
Colorectal Neoplasms - mortality
Colorectal Neoplasms - therapy
Female
Granulocyte-macrophage colony-stimulating factor
Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage
Humans
Hyperglycemia
Hyperglycemia - etiology
Immunology
Intercellular adhesion molecule 1
Intercellular Adhesion Molecule-1 - genetics
Interferon
Interferon-alpha - administration & dosage
Lymphocytes T
Male
Medicine
Medicine & Public Health
Middle Aged
Oncology
Original Article
Patients
Suppressor cells
Survival Analysis
T-Lymphocytes - immunology
Transaminase
Treatment Outcome
Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism
Vaccination
Vaccines
Vaccines, Synthetic
Vaccinia
Vaccinia virus - genetics
α-Interferon
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Summary:Prime-boost vaccination with recombinant (r) vaccinia(V)-CEA(6D)-TRICOM (triad of co-stimulatory molecules B7.1, ICAM-1 and LFA-3) and rFowlpox(F)-CEA(6D)-TRICOM infect antigen-presenting cells and direct expression of co-stimulatory molecules. We hypothesized that co-administration of vaccine with GM-CSF and interferon alpha (IFN-α) would have efficacy in CEA-expressing cancers. Patients with CEA-expressing cancers received the rV-CEA(6D)-TRICOM vaccine subcutaneously (s.c.) on day 1 followed by GM-CSF s.c. to the injection site on days 1–4. In Cycle 1, patients received thrice weekly s.c. injections of IFN-α-2b the week after rV-CEA(6D)-TRICOM. In Cycles 2–4, patients received thrice weekly s.c. injections of IFN-α-2b the same week that rF-CEA(6D)-TRICOM was given. The first cohort received no IFN followed by dose escalation of IFN-α in subsequent cohorts. Thirty-three patients were accrued (mean 59.8 years). Grade 3 toxicities included fatigue and hyperglycemia. Grade 4–5 adverse events (unrelated to treatment) were confusion (1), elevated aspartate transaminase (AST)/alanine transaminase (ALT) (1), and sudden death (1). No patients had a partial response, and eight patients exhibited stable disease of ≥3 months. Median progression-free survival and overall survival (OS) were 1.8 and 6.3 months, respectively. Significantly higher serum CD27 levels were observed after vaccine therapy ( p  = 0.006 post 1–2 cycles, p  = 0.003 post 3 cycles, p  = 0.03 post 4–7 cycles) and 42 % of patients assayed developed CEA-specific T cell responses. Pre-treatment levels of myeloid-derived suppressor cells correlated with overall survival ( p  = 0.04). Administration of IFN-α led to significantly increased OS ( p  = 0.02) compared to vaccine alone. While the vaccine regimen produced no clinical responses, IFN-α administration was associated with improved survival.
ISSN:0340-7004
1432-0851
DOI:10.1007/s00262-016-1893-7