Strategies for the development of recombinant vaccines for the immunotherapy of breast cancer

Abstract

The development of recombinant vaccines for specific immunotherapy of carcinoma represents a novel approach for the treatment of breast cancer and other tumor types. This article reviews the various parameters that should be considered in the development of recombinant vaccines. Several breast cancer associated antigens are also discussed which may provide potential target molecules. The human carcinoembryonic antigen (CEA), which is expressed on approximately 50% of breast cancers, represents one such target for immunotherapy. To enhance the immunogenicity of this antigen, a recombinant CEA-vaccinia vaccine, designated rV-CEA, was produced. To study the effects of this vaccine in an animal model, a murine colon carcinoma cell line was transduced with CEA and transplanted into immunocompetent mice for protection and therapy studies. Pre-clinical toxicity studies were also conducted in non-human primates. The results of these studies showed the rV-CEA vaccine to be immunogenic and safe in both rodents and primates, and to elicit good anti-tumor responses in the rodent model. In a Phase I clinical trial in metastatic breast, lung, and colorectal cancer patients involving three immunizations of rV-CEA, at three dose levels, enhancement of T-cell and antibody responses to vaccinia virus proteins were observed with no toxicity. Specific T-cell responses were studied via stimulation of peripheral blood lymphocytes with specific peptide epitopes from the CEA molecule. These studies demonstrated clear cut differences in establishment of T-cell lines pre- versus post-immunization. The T-cell lines were shown to be CD8+ and/or CD4+/CD8+, to lyse EBV transformed B-cells transduced with the CEA gene, and to lyse CEA positive carcinoma cells in a HLA restricted manner. Thus, in a Phase I clinical trial the rV-CEA vaccine has been shown to stimulate a CTL response specific for CEA defined epitopes in cancer patients.

Inhibition of tumor growth by recombinant vaccinia virus expressing GA733/CO17-1A/EpCAM/KSA/KS1-4 antigen in mice

“…42,44,46,57 -59 In some of those studies, costimulatory molecules or cytokines were used to enhance vaccine effects. 44,45,59,64 These studies have suggested a role for antibodies, 36 -41,43,47,48,51 -53,60,63,64 CTL, 36 -48 and delayed-type hypersensitive T cells, 36,37,46,53 although the role of these factors was not directly demonstrated by in vivo cell depletion or adoptive cell transfer. The mouse models targeting human carcinoembryonic Ag (CEA ) and MUC-1 with VV vaccines, 36,39 -41,43,45 -48,52,63 similar to the human GA733 model used in the present study, include Ags that are expressed by tumors and by normal tissues.…”

External Beam Radiation of Tumors Alters Phenotype of Tumor Cells to Render Them Susceptible to Vaccine-Mediated T-Cell Killing

“…CEA expression is prevalent among diverse human carcinomas, namely, colorectal, gastric, pancreatic, breast, and nonsmall cell lung malignancies (10). Transgenic mice expressing the human CEA gene as "self" in tissues similar to expression in humans were used as a more relevant preclinical model to investigate various experimental immunotherapies (11).…”

Preexisting Immunity to Poliovirus Does Not Impair the Efficacy of Recombinant Poliovirus Vaccine Vectors

“…Despite these considerations, our results can be relevant for vaccination in humans. For instance, recent research with vaccinia virus recombinants in people demonstrated that in humans, as in mice, preexisting immunity to vaccinia virus limits the effectiveness of recombinant vaccinia virus vectors (7,24). Therefore, at least in the case of vaccinia virus, results in mice predict the outcome in humans.…”