Abstract
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.
Highlights
Cancer is responsible for one quarter of deaths in the United States and current conventional treatments are proving inadequate at combating the majority of these malignant diseases [1]
GMDSC levels in the lymph node (Fig. 4E) were substantially, but not significantly, decreased in mice treated with adenovirus type 5 vectors (Ad5)-OVA plus 5-FU compared to the naıve group
Ko et al showed that the combination of an adenovirus encoding human Her2/neu, a low-dose chemotherapeutic gemcitabine and the Treg suppressive antibody, anti-GITR, was capable of causing tumor regressions in a murine colon cancer model where the cancer cell line used was transfected with syngeneic Her-2/neu [34]
Summary
Cancer is responsible for one quarter of deaths in the United States and current conventional treatments are proving inadequate at combating the majority of these malignant diseases [1]. Despite its limited therapeutic success, chemotherapy, for lack of better alternatives, is often the default treatment for many cancer patients. Sustained high doses of chemotherapeutic drugs can cause severe side-effects that include irreversible damage to vital organs and can be themselves carcinogenic [3,4]. Alternative or adjuvant therapies are required that are capable of replacing, or reducing the delivery dose of, chemotherapeutic drugs. Therapeutic cancer vaccinations using viral vectors encoding relevant tumor-associated antigens (TAA) have shown promising therapeutic benefit but are often less successful than expected in clinical settings, possibly due to excessive tumor burden and the presence of host-derived immunosuppressive mechanisms [5,6]. Recombinant adenovirus type 5 vectors (Ad5) are efficient at transducing genes to a range of cell types, including dendritic cells, and are good candidates for the delivery of TAAs [7,8,9]
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