Abstract
BackgroundPatients 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.MethodsGrowth 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.ResultsIn 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.ConclusionsThis 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.
Highlights
Patients with advanced colorectal cancer (CRC) have a poor prognosis
Tumors were orthotopically implanted into the cecum wall as described previously [9], and mice were treated with either REG or anti-programmed cell death protein 1 (aPD1) alone or received REG + aPD1 until day 14 post-implantation
Macrophages and regulatory T cells are significantly reduced in CT26 tumors in response to treatment with REG and REG + aPD1 Our previous study demonstrated that REG significantly reduced intratumoral macrophages [9], and recent evidence indicates that PD1 blockade influences tumor-associated macrophages (TAMs) [34]
Summary
Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. 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. For advanced metastatic CRC, the 5-year survival rate after diagnosis is approximately 10% [3], emphasizing the need for novel therapeutic options to improve patient survival. The only approved firstand second-line treatment options for CRC were surgical interventions followed by chemotherapy regimens and combinations with antibodies against epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) if indicated [4]. REG and TAS-102 each increased overall survival when used as single-agent treatments for patients with CRC for whom previous chemotherapy regimens had failed [5]
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