Combination of Immunomodulatory Tumor-derived Vaccines Harboring OX40 Ligand and 4-1BB Ligand Boosts Antitumor Response and Confers Long-Term Protection in Rechallenged Mice.

Introduction

Therapeutic strategies based on immunotherapy aims strengthening the detection and elimination of tumor cells by reducing the threshold of immunological tolerance and shifting this balance in favor of immune surveillance. Strategies that target T cells have revolutionized the clinic, conferring higher survival rates and even the possibility of cure. Monoclonal antibodies that act blocking immunological checkpoints, such as anti-CTLA4 and anti-PD1, are successful examples of drugs that inhibit T cell immunosuppression mechanisms, potentiating antitumor response. Despite the success of these antibodies, due to the heterogeneity and complexity of cancer, there are still cases of patients who are not benefited by this kind of treatment, what justifies developing new therapeutic approaches. In this work, we compared combinations of immunomodulatory vaccines using an in vitro assay and also evaluating the therapeutic benefit in tumor-challenged mice.

Material and Method

Immunomodulatory vaccines consist of genetically modified tumor cells, that were transduced with recombinant viral vectors for expression of immunomodulators such as GM-CSF, 4-1BBL and OX40L. We developed an in vitro assay using a high content imaging platform, that makes possible to verify the co-stimulatory-mediated cytotoxic effect of T cells, on tumor cells. We also performed assays using immunocompetent mice that were challenged with syngeneic tumors. These animals were given vaccine combinations and monitored for tumor progression.

Results and discussion

We found that the combined use of the 4-1BBL and OX40L vaccines induced a reduction of tumor growth in challenged animals. In these animals, we observed an increased T-cell infiltrate and a decrease in regulatory T cells. Rechallenged animals that were previously vaccinated using combination of 4-1BBL and OX40L exhibited a long-term protection, preventing tumor growth.

Conclusion

The combination of tumor derived vaccines harboring 4-1BBL and OX40L enhanced antitumor response in challenged animals. This effect also was observed in rechallenged animals, suggesting the induction of an immune memory. These results may contribute to the development of new therapeutic strategies to treat human cancer.

Supported by FAPESP