The combination of a low-dose chemotherapeutic agent, 5-fluorouracil, and an adenoviral tumor vaccine has a synergistic benefit on survival in a tumor model system

• Published in: PloS one 2013-06, Vol.8 (6), p.e67904
• Main Authors: Geary, Sean M, Lemke, Caitlin D, Lubaroff, David M, Salem, Aliasger K
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adenoviridae - immunology; Adenoviruses; Animals; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - immunology; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - immunology; Biology; Cancer; Cancer therapies; Cancer vaccines; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Chemotherapy; Clinical trials; Combinatorial analysis; Dendritic cells; Dosage; Drug dosages; Drug Synergism; Fluorouracil - administration & dosage; Fluorouracil - immunology; Granulocytes; Immune response; Immune system; Immunotherapy; Lymph nodes; Lymph Nodes - drug effects; Lymph Nodes - immunology; Lymphatic system; Lymphocytes; Lymphocytes T; Male; Medicine; Mice; Mice, Inbred C57BL; Ovalbumin; Ovalbumin - administration & dosage; Ovalbumin - immunology; Pharmaceutical sciences; Pharmacy; Rodents; Side effects; Spleen - drug effects; Spleen - immunology; Studies; Survival; Survival Rate; Tumors; Vaccines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0067904

Standard cancer therapies, particularly those involving chemotherapy, are in need of modifications that both reduce short-term and long-term side effects as well as improve the overall survival of cancer patients. Here we show that combining low-dose chemotherapy with a therapeutic vaccination using an adenovirus encoding a model tumor-associated antigen, ovalbumin (Ad5-OVA), had a synergistic impact on survival in tumor-challenged mice. Mice that received the combinatorial treatment of Ad5-OVA plus low-dose 5-fluorouracil (5-FU) had a 95% survival rate compared to 7% and 30% survival rates for Ad5-OVA alone and 5-FU alone respectively. The presence of 5-FU enhanced the levels of OVA-specific CD8(+) T lymphocytes in the spleens and draining lymph nodes of Ad5-OVA-treated mice, a phenomenon that was dependent on the mice having been tumor-challenged. Thus 5-FU may have enhanced survival of Ad5-OVA-treated mice by enhancing the tumor-specific immune response combined with eliminating tumor bulk. We also investigated the possibility that the observed therapeutic benefit may have been derived from the capacity of 5-FU to deplete MDSC populations. The findings presented here promote the concept of combining adenoviral cancer vaccines with low-dose chemotherapy.