Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy Journal Article
| Authors: | Wang, Y.; Liu, S.; Yang, Z.; Algazi, A. P.; Lomeli, S. H.; Wang, Y.; Othus, M.; Hong, A.; Wang, X.; Randolph, C. E.; Jones, A. M.; Bosenberg, M. W.; Byrum, S. D.; Tackett, A. J.; Lopez, H.; Yates, C.; Solit, D. B.; Ribas, A.; Piva, M.; Moriceau, G.; Lo, R. S. |
| Article Title: | Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy |
| Abstract: | Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance. © 2021 The Authors |
| Keywords: | melanoma; colorectal carcinoma; brain metastasis; pancreatic ductal adenocarcinoma; anti-ctla-4; tumor immune microenvironment; anti-pd-1/l1; braf/nras/kras/nf1; mapk/braf/mek inhibitor resistance; sequential-combination therapy |
| Journal Title: | Cancer Cell |
| Volume: | 39 |
| Issue: | 10 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2021-10-11 |
| Start Page: | 1375 |
| End Page: | 1387.e6 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2021.07.023 |
| PUBMED: | 34416167 |
| PROVIDER: | scopus |
| PMCID: | PMC9126729 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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