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Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth. | LitMetric

AI Article Synopsis

  • Patients with advanced colorectal cancer (CRC) have a poor prognosis, prompting research into combining regorafenib, a multikinase inhibitor, with an anti-PD1 antibody to investigate potential synergies in treatment.
  • In preclinical models, this combination therapy showed significant anti-tumor activity compared to each treatment alone, with lasting benefits even after treatment stopped, especially in preventing tumor regrowth and liver metastasis.
  • The combination led to changes in the tumor microenvironment, including reduced immunosuppressive cells and increased inflammatory activity, suggesting strong potential for clinical application in treating CRC patients.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436536PMC
http://dx.doi.org/10.1186/s13046-021-02043-0DOI Listing

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