Active specific immunotherapy with vaccinia colon oncolysate enhances the immunomodulatory and antitumor effects of interleukin-2 and interferon α in a murine hepatic metastasis model

Abstract

The role of cytokines as primary or adjuvant antineoplastic agents has been well established. Interleukin-2 (IL-2) and the interferons have, particularly, proven to be effective antitumor agents when given alone, and seem to act synergistically on the eradication of metastases from immunogenic tumors. Active specific immunotherapy, in the form of viral oncolysates, has also shown effectiveness in cancer therapy. Bearing this in mind, we decided to combine these agents in an adjuvant triple regimen and compare their effectiveness to other treatments in terms of tumor burden and survival in a murine colon cancer hepatic metastases model. BALB/c mice were injected with CC-36, a weakly immunogenic murine colon adenocarcinoma, intrasplenically, to produce artificial liver metastases. The animals were divided into one control group and seven treatment groups receiving either vaccinia colon oncolysate (VCO), IL-2, interferon-alpha (IFN alpha) alone, or combinations of these agents. Half the animals were followed for survival and the other half were sacrificed at the end of the experiment for quantification of tumor burden. The blood of the sacrificed animals was utilized in a series of immunological tests in order to demonstrate the cytolytic potential of the peripheral blood lymphocytes (PBL) in each treatment group, as well as to characterize phenotypically the cells acting as effectors. The triple-adjuvant regimen group was by far the most effective treatment group, demonstrating 100% survival and a significant reduction in tumor burden when compared to other groups. Furthermore, the PBL from the animals in this group showed 69.4% lysis of the CC-36 target cells in vitro. These effector lymphocytes were characterized as ASMG1-/Lyt2.2+ cytolytic lymphocytes. We conclude that these lymphocytes were stimulated by the administration of VCO and further augmented by the immunomodulation of the cytokines given in the triple regimen, and that such a regimen might prove beneficial in the treatment of established hepatic metastases from weakly immunogenic tumors.

Adjuvants for Enhancing the Immunogenicity of Whole Tumor Cell Vaccines

“…Viral oncolysates have been utilized to increase whole tumor cell vaccine immunogenicity, which can be mediated through DC activation by "danger signals" released by virally infected tumor cells, or via increased uptake of tumor lysate by DCs due to viral ligands expressed on the surface of virally infected tumor cells, which may engage additional receptors on DCs [66][67][68][69][70] [74]. A phase II clinical trial of NDV-modified autologous tumor cells in 63 patients with advanced breast and ovarian cancers disease also showed a benefit in survival (P = 0.026) and disease-free survival (P = 0.089) [75].…”

A Novel Dendritic Cell-Based Cancer Vaccine Produces Promising Results in a Syngenic CC-36 Murine Colon Adenocarcinoma Model

“…The murine colon cancer cell line CC-36 [14], human fibroblast cell line MRC5, monkey kidney cell line VERO (ATCC, Bethesda, MD), and the NK sensitive cell line YAC-1 were used in the described experiments.…”

Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

“…This led to the development of a variety of viral oncolysates for use in clinical trials for many different cancers, including ovarian cancer [170][171][172]. Clinical experimentation with viral oncolysate vaccines has shown that antitumour immune responses may be elicited in select patients.…”