Abstract B39: Potentiation of doxorubicin low-dose efficacy through its association with p19Arf/Interferon-beta immunotherapy: Combining two immunogenic cell death inducers for the treatment of cancer
Authors: Medrano Ruan F. V. , Mendonca Samir A. , Ribeiro Aline H. , Catani João PP , Feitosa Valker A. , Rodrigues Elaine G. , Strauss Bryan E. 
Published: May 2019

Association of immunotherapies with chemotherapy can significantly improve cancer treatment, either by enhancing cell death or by superior immune stimulation. However, as reported in some studies, combinatorial strategies are hampered by a strong increase of severe treatment-related toxicity. Previously, we have developed specialized adenoviral vectors for the delivery of p19Arf (tumor suppressor protein) and Interferon-beta (IFN-beta immunomodulatory cytokine) to p53wt tumor cells, a unique combination capable of promoting immunogenic cell death and immune activation. Here, we explore potential benefits of the association of p19/IFN-beta immunotherapy with doxorubicin chemotherapy, also an inducer of immunogenic cell death. First, we observed that single-agent treatment of s.c. MCA205 sarcomas was successful only in immunocompetent, but not immunodeficient, mice, indicating that each treatment depends, at least in some part, on the immune system. Next, using factorial experimental design and propidium iodide staining, we revealed that the combined therapies augment cell death at lower doses of virus and doxorubicin than those needed for the individual treatments. This observation was confirmed by MTT assay, caspase 3 activity, calreticulin exposure, and also in the B16F10 cell line. In order to investigate the in vivo effects of p19Arf/IFN-beta and doxorubicin association, tumor-bearing mice were treated with the single or combined agents. Molecular imaging indicated a prolonged caspase 3 activation in situ only in the p19Arf/IFN-beta+dox group, even though doxorubicin alone (20 mg/kg) achieved the greatest extension of survival, with no evident benefit from its association with p19/IFN-beta immunotherapy. Furthermore, we asked if by using the combined treatment we could reduce the dose of doxorubicin and still maintain tumor control, an application that would be truly interesting since doxorubicin has been shown to severely affect heart function. Indeed, the subtherapeutic dose of doxorubicin (10 mg/kg) extended survival only in association with p19/IFN-beta and, most importantly, echocardiogram analysis revealed the elimination of the cardiotoxicity seen with the 20-mg/kg dose. The results obtained so far indicate that pretreatment with p19Arf and IFN-beta immunotherapy restores therapeutic efficacy of subtherapeutic dose of doxorubicin, preserving cardiac function. More studies are on the way to reveal the immunologic impact of this association.

Citation Format: Ruan F. V. Medrano, Sr., Samir A. Mendonca, Sr., Aline H. Ribeiro, Sr., João PP Catani, Sr., Valker A. Feitosa, Sr., Elaine G. Rodrigues, Sr., Bryan E. Strauss, Sr.. Potentiation of doxorubicin low-dose efficacy through its association with p19Arf/Interferon-beta immunotherapy: Combining two immunogenic cell death inducers for the treatment of cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B39.