The Antitumor and Immunoadjuvant Effects of IFN-α in Combination with Recombinant Poxvirus Vaccines

Abstract

Purpose: IFN-a 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-a with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. Experimental Design: The phenotypic and functional effects of IFN-a were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-a administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-a and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. Results:We identified a dose and schedule of IFN-a 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-a distal to the site of vaccination. The combination of IFN-a and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA + adenocarcinomas. In mice with pancreatic tumors, IFN-a slowed tumor growth, induced CTL activity, and increased CD8 + tumor-infiltrating lymphocytes. Conclusions: These data suggest that IFN-a 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.

Photodynamic therapy of tumors can lead to development of systemic antigen-specific immune response

“…We believe that more investigators should consider whether antigen-specific immune response is involved in patients receiving PDT for cancer. Consequently, the results presented in this study have led us to explore the effects of PDT employing tumors expressing clinically relevant tumor antigens like P815 mastocytoma expressing murine homologue of cancer testis antigen P1A [63] or pancreatic adenocarcinoma Panc02 expressing human carcinoembryonic antigen [64]. The preliminary results obtained in these models are highly encouraging and in agreement with the presented data (unpublished results).…”

Interferons and Their Stimulated Genes in the Tumor Microenvironment

“…186 potentially thus facilitating antigen-specific T cell immunity as suggested by studies combining IFN-α with a CEA poxvirus vaccine. 187 In addition to MHC and tumor-associated antigens as ISGs that can influence T cell function, other ISGs such as SECTM1 can serve as a co-stimulatory ligand for T cells after TCR activation. 188 …”

Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

“…IFN-α and IFN-β also possess direct antitumor and immunomodulatory properties [30,31]. In this line, a combined therapy of recombinant IFN-α with poxvirus vaccines targeting pancreatic adenocarcinomas slowed tumor growth, induced cytotoxic lymphocyte activity, and increased CD8+ tumor-infiltrating lymphocytes [32]. Also noticeable was the induction of tumor regression/stabilization in 50% of treated mice after in vivo lentiviral administration of hIFN-β [33].…”