Abstract LB-229: Agonistic antibodies to costimulatory molecules, OX40 and GITR, significantly enhance the antitumor efficacy of Listeria monocytogenes (Lm-LLO)-based immunotherapy

Abstract

Abstract Combinational anti-cancer immune therapies that target multiple tumor-mediated suppressive mechanisms or enhance effector immunity are emerging as promising strategies for cancer treatment. Recently, we demonstrated that the combination of Listeria monocytogenes (Lm-LLO)-based immunotherapy (ADXS11-001) and anti-PD-1 antibody results in improved anti-tumor therapeutic and immune efficacy. Interestingly, regardless of the presence of an antigen or treatment with anti-PD-1 antibody, treatment with the Lm-LLO alone significantly inhibited the suppressive arm of the immune system, including regulatory T cells and myeloid-derived suppressor cells. We therefore hypothesized that combination of ADXS11-001 with agonistic antibodies against co-stimulatory molecules will lead to further improvement of immune and therapeutic efficacy as a result of the combined down-regulation of the suppressive arm and the enhancement of the effector arm. Here we demonstrate that combining Lm-LLO-based immunotherapy with anti-OX40 or anti-GITR antibodies lead to significant inhibition of tumor growth and prolonged survival of animals. The complete regression of established TC-1 tumors occurs in 40% and 60% of animals treated with ADXS11-001 in combination with anti-OX40 and anti-GITR antibodies, respectively. We show that this therapeutic potency enhancement is due to a significant increase in antigen-specific immune responses along with ADXS11-001-mediated inhibition of suppressor cells. Thus, we believe that simultaneous stimulation of T cells while inhibiting the suppressor cells, specifically using Lm-LLO-based immunotherapy combination with agonistic anti-co-stimulatory molecule antibody is a feasible and translatable approach that can lead to overall enhancement of the efficacy of an anti-tumor immunotherapy. Citation Format: Mikayel Mkrtichyan, Rajeev Shrimali, Shamim Ahmad, Rasha Abu Eid, Zuzana Berrong, Anu Wallecha, Robert Petit, Samir N. Khleif. Agonistic antibodies to costimulatory molecules, OX40 and GITR, significantly enhance the antitumor efficacy of Listeria monocytogenes (Lm-LLO)-based immunotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2015-LB-229