Abstract 93: Anti-LAP-TGFb antibodies inhibit tumor growth in a CT26 syngeneic tumor model in combination with radiation therapy

Abstract

Anti-LAP-TGFβ antibodies inhibit tumor growth in a CT26 syngeneic tumor model in combination with radiation therapy. TGFβ is a major immunosuppressive cytokine that acts within the TME and is implicated in resistance to checkpoint inhibitors. TGFβ is synthesized as a pro-protein complex in which the mature cytokine is caged within LAP, the latency associated peptide of TGFβ1, and serves to hold TGFβ1 in a latent state. Anti-LAP-TGFβ antibodies have efficacy in mouse models of cancer (Gabriely et al., 2017) and offer a promising new treatment approach in oncology. Radiation is standard of care in many cancer indications and is a known potent inducer of TGFβ. TGFβ is also implicated in resistance to radiation treatment. Thus, combination treatment with anti-LAP antibodies and radiation may yield a novel approach for enhancing therapeutic responses in a population with significant unmet medical need. We have evaluated the anti-tumor effects of targeting TGFβ via an anti-LAP antibody in combination with radiation therapy in a murine syngeneic CT26 colorectal cancer model. We identified a unique class of anti-LAP antibodies, TLS-01, that specifically target LAP on the surface of cells, but do not bind to LAP-TGFβ in the extracellular matrix. We assessed the effects of combination of TLS-01 and radiation on both tumor efficacy and modulation of immune cell subsets within the TME. CT26 tumor bearing mice (tumor size ~300 mm3) were treated with either TLS-01, an isotype control antibody, 12 Gy or 20 Gy of targeted radiation, or a combination of TLS-01 with 12 Gy or 20 Gy of radiation. Seven days after treatment, 3 animals per group were analyzed for tumor infiltrating immune cell subsets and the remaining animals were followed for tumor growth and survival for up to 19 days. Radiation inhibited tumor growth in a dose dependent fashion. Combination treatment with TLS-01 and radiation inhibited tumor growth to a greater extent than was seen with TLS-01 or radiation treatment alone. Radiation treatment dramatically increased the number of CD8+ T cells in the TME and concomitantly increased both the number and immunosuppressive properties of inhibitory cell populations in the TME, including increases in CD73 expression on M-MDSCs and M2 macrophages. Treatment of irradiated mice with TLS-01 reduced Tregs, increased the CD8 / Treg ratio and reduced CD73 expression on immune suppressive cells. Combination of TLS-01 with radiation resulted in enhanced efficacy when compared to either agent alone. Our data provides mechanistic insights underpinning this enhanced efficacy. TLS-01 moderated immunosuppression in the TME by radiation via modulation of multiple immunosuppressive cell types. These data support the therapeutic utility of combination treatment of TLS-01 and radiation therapy in the treatment of solid tumors. Citation Format: Kenneth J. Simon, Stavros Kopsiaftis, Randall Burton, Patricia E. Rao, Jessie M. English, Barbara S. Fox. Anti-LAP-TGFb antibodies inhibit tumor growth in a CT26 syngeneic tumor model in combination with radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 93.