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Effective Combination of Chemotherapy and Dendritic Cell Administration for the Treatment of Advanced-Stage Experimental Breast Cancer

H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612

Purpose: The goal of this study was to investigate the utility of a new approach to the treatment of advanced stage breast cancer, a combination of chemotherapy and dendritic cell (DC) administration.

Experimental Design: Mice bearing mammary adenocarcinoma expressing a model tumor antigen, influenza virus HA (DA3-HA), and parental tumor (DA3) were treated with different doses of paclitaxel with or without DCs. Paclitaxel was injected three times weekly, DCs were injected either i.v. or into tumor site (t.s.) 36 h after each injection of paclitaxel. Apoptosis was measured using Annexin V binding or terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays. CD8-mediated response of T cells to HA-derived peptide epitope was measured in an enzyme-linked immunospot (ELISPOT) assay. CD4-mediated response of T cells to HA-derived peptide was measured in proliferation assay. Nonspecific T-cell proliferation was measured in response to ConA and immobilized anti-CD3 and anti-CD28 antibodies.

Results: We have selected the dose of paclitaxel that induced a substantial level of apoptosis and moderate inhibition of T-cell function. Combined treatment resulted in the induction of HA-specific CD8-mediated response in all nine of the tested mice, and CD4-mediated responses in four of six treated mice. These effects were observed only if DCs were injected into tumor site, but not when injected i.v. No specific responses were found in mice treated with either chemotherapy or DCs alone. Injection of dexamethasone together with paclitaxel did not affect the induction of immune responses. Significant antitumor effect of combined treatment was observed in DA3-HA tumor-bearing mice as well as in mice bearing parental DA3 tumor.

Conclusion: The combination of DC administration with repeated cycles of chemotherapy and dexamethasone (conditions similar to real clinical practice) resulted in the induction of antitumor response despite the immunosuppression induced by such treatment.

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