Abstract
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.
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Abbreviations
- AST/ALT:
-
Aspartate transaminase-to-alanine transaminase ratio
- CEA:
-
Carcinoembryonic antigen
- CEFT:
-
Mixture of cytomegalovirus, Epstein–Barr virus, influenza, and tetanus toxin
- DIC:
-
Disseminated intravascular coagulation
- DLT:
-
Dose-limiting toxicities
- ECOG:
-
Eastern Cooperative Oncology Group
- G-MDSC:
-
Granulocytic myeloid-derived suppressor cell
- M-MDSC:
-
Monocytic myeloid-derived suppressor cell
- MDSC:
-
Myeloid-derived suppressor cell
- MTD:
-
Maximum tolerated dose
- PFS:
-
Progression-free survival
- PR:
-
Partial response
- SD:
-
Stable disease
- TAA:
-
Tumor-associated antigen
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This work was supported by NIH Grants: P01 CA095426 (W. Carson), P30 CA016058 (W. Carson), and T32 GM068412 (M. Duggan).
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Duggan, M.C., Jochems, C., Donahue, R.N. et al. 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. Cancer Immunol Immunother 65, 1353–1364 (2016). https://doi.org/10.1007/s00262-016-1893-7
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DOI: https://doi.org/10.1007/s00262-016-1893-7