A novel multi-drug metronomic chemotherapy significantly delays tumor growth in mice

Maria Tagliamonte, Annacarmen Petrizzo, Maria Napolitano, Antonio Luciano, Domenica Rea, Antonio Barbieri, Claudio Arra, Piera Maiolino, Marialina Tornesello, Gennaro Ciliberto, Franco M. Buonaguro, Luigi Buonaguro

The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response. In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious. Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA. The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.