To improve prognosis in patients with advanced CRC and gain mechanistic insights, Doleschel et al. tested combinations of anti-PD-1 with multikinase inhibitor regorafenib (REG) in syngeneic CT26 and MC38 CRC models with different mutational and microsatellite profiles. Antitumor efficacy improved in both models with REG/anti-PD-1 treatment. In the CT26 model, combination treatment prevented tumor regrowth and liver metastases after treatment stopped. Anti-PD-1 significantly increased IFNγ levels and synergized with REG to induce sustained M1 macrophage polarization, while significantly decreasing immunosuppressive M2 infiltration and Tregs.
Contributed by Katherine Turner
Background: Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism.
Methods: Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses.
Results: In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression.
Conclusions: This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors.