The antitumor and immunoadjuvant effects of IFN-alpha in combination with recombinant poxvirus vaccines.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hance
Kenneth W
KW
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Rogers
Connie J
CJ
Zaharoff
David A
DA
Canter
Daniel
D
Schlom
Jeffrey
J
Greiner
John W
JW
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000235:genetics / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004274:DNA, Recombinant / Q000032:analysis; D005260:Female; D005587:Fowlpox virus / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D016898:Interferon-alpha / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D014616:Vaccinia virus / Q000235:genetics*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D004274:DNA, Recombinant; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha