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

Abstract

BACKGROUND:

The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: 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
• Journal: Journal of translational medicine (J Transl Med) Vol. 14 Pg. 58 (Feb 24 2016) ISSN: 1479-5876 [Electronic] England
• PMID: 26911136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Calreticulin
• Interferon-gamma

Topics

• Administration, Metronomic
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology, therapeutic use)
• Calreticulin (metabolism)
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Enzyme-Linked Immunospot Assay
• Female
• Interferon-gamma (biosynthesis)
• Melanoma, Experimental (drug therapy, immunology, pathology)
• Mice, Inbred C57BL
• Survival Analysis
• T-Lymphocytes, Regulatory (drug effects)