IFN-alpha is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines.
The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-alpha with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. The phenotypic and functional effects of IFN-alpha were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-alpha administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-alpha and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. We identified a dose and schedule of IFN-alpha that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8+) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-alpha distal to the site of vaccination. The combination of IFN-alpha and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA+ adenocarcinomas. In mice with pancreatic tumors, IFN-alpha slowed tumor growth, induced CTL activity, and increased CD8+ tumor-infiltrating lymphocytes. These data suggest that IFN-alpha can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas. In another study, (51)Cr-prelabeled colon cancer cells (simulating circulating tumor cells (CTCs)) were added to human peripheral blood and exposed to staurosporine (ST) to increase carcinoembryonic antigen (CEA) expression. CTCs were captured with immunomagnetic beads coated with Ber-EP4 monoclonal antibody, recognizing the common epithelial antigen present in the majority of cancer cells of epithelial origin, with capture efficiency of more than 80%. Moreover, ST treatment increased CEA expression without compromising Ber-EP4 capture efficiency. In a pilot clinical study on 37 patients, CTCs were captured using Ber-EP4 beads, and recognized by RT-PCR set for CEA or cytokeratin-19 (CK) mRNA detection. The results showed that: (a) the percentage of CEA-positive CTCs (CTC(CEA), 54.1%) was lower than that of CK-positive CTCs (CTC(CK), 70.3%);(b) in vitro ST treatment converted a significant number of CTC(CEA)-negative into CTC(CEA)-positive cases. Therefore, immunomagnetic capture combined with exposure to ST provides a feasible and sensitive technique for the detection of functionally-active CTCs responsive to ST-mediated CEA up-regulation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Vandeveer, Amanda J; Fallon, Jonathan K; Tighe, Robert et al. (2016) Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor. Cancer Immunol Res 4:452-62
Fallon, Jonathan; Tighe, Robert; Kradjian, Giorgio et al. (2014) The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget 5:1869-84
Tucker, Jo A; Jochems, Caroline; Boyerinas, Benjamin et al. (2014) Identification and characterization of a cytotoxic T-lymphocyte agonist epitope of brachyury, a transcription factor involved in epithelial to mesenchymal transition and metastasis. Cancer Immunol Immunother 63:1307-17
Schlom, Jeffrey; Hodge, James W; Palena, Claudia et al. (2014) Therapeutic cancer vaccines. Adv Cancer Res 121:67-124
Takai, Shinji; Schlom, Jeffrey; Tucker, Joanne et al. (2013) Inhibition of TGF-?1 signaling promotes central memory T cell differentiation. J Immunol 191:2299-307
Takai, Shinji; Sabzevari, Helen; Farsaci, Benedetto et al. (2012) Distinct effects of saracatinib on memory CD8+ T cell differentiation. J Immunol 188:4323-33
Bonmassar, Laura; Fossile, Emanuela; Scoppola, Alessandro et al. (2010) Detection of circulating tumor cells is improved by drug-induced antigen up-regulation: preclinical and clinical studies. Anticancer Res 30:4721-30
Hance, Kenneth W; Rogers, Connie J; Zaharoff, David A et al. (2009) The antitumor and immunoadjuvant effects of IFN-alpha in combination with recombinant poxvirus vaccines. Clin Cancer Res 15:2387-96
Wansley, Elizabeth K; Chakraborty, Mala; Hance, Kenneth W et al. (2008) Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses. Clin Cancer Res 14:4316-25
Zeytin, Hasan; Reali, Eva; Zaharoff, David A et al. (2008) Targeted delivery of murine IFN-gamma using a recombinant fowlpox virus: NK cell recruitment to regional lymph nodes and priming of tumor-specific host immunity. J Interferon Cytokine Res 28:73-87