Potentiation of combined p19Arf and interferon-beta cancer gene therapy through its association with doxorubicin chemotherapy

Abstract

Balancing safety and efficacy is a major consideration for cancer treatments, especially when combining cancer immunotherapy with other treatment modalities such as chemotherapy. Approaches that induce immunogenic cell death (ICD) are expected to eliminate cancer cells by direct cell killing as well as activation of an antitumor immune response. We have developed a gene therapy approach based on p19Arf and interferon-β gene transfer that, similar to conventional inducers of ICD, results in the release of DAMPS and immune activation. Here, aiming to potentiate this response, we explore whether association between our approach and treatment with doxorubicin (Dox), a known inducer of ICD, could further potentiate treatment efficacy without inducing cardiotoxicity, a critical side effect of Dox. Using central composite rotational design analysis, we show that cooperation between gene transfer and chemotherapy killed MCA205 and B16F10 cells and permitted the application of reduced viral and drug doses. The treatments also cooperated to induce elevated levels of ICD markers in MCA205, which correlated with improved efficacy of immunotherapy in vivo. Treatment of subcutaneous MCA205 tumors associating gene transfer and low dose (10 mg/kg) chemotherapy resulted in inhibition of tumor progression. Moreover, the reduced dose did not cause cardiotoxicity as compared to the therapeutic dose of Dox (20 mg/kg). The association of p19Arf/interferon-β gene transfer and Dox chemotherapy potentiated antitumor response and minimized cardiotoxicity.