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Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy
- Source :
- Cancer cell, vol 39, iss 10, Cancer Cell
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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) Tcells 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 Tcell 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.
- Subjects :
- MAPK/ERK pathway
Neuroblastoma RAS viral oncogene homolog
Cancer Research
Colorectal cancer
Oncology and Carcinogenesis
pancreatic ductal adenocarcinoma
Article
Mice
Rare Diseases
colorectal carcinoma
Neoplasms
MAPK/BRAF/MEK inhibitor resistance
melanoma
Animals
Humans
Medicine
Cytotoxic T cell
brain metastasis
Oncology & Carcinogenesis
Immune Checkpoint Inhibitors
Cancer
Mitogen-Activated Protein Kinase Kinases
tumor immune microenvironment
BRAF/NRAS/KRAS/NF1
business.industry
Melanoma
Neurosciences
medicine.disease
Immune checkpoint
sequential-combination therapy
Good Health and Well Being
Oncology
5.1 Pharmaceuticals
anti-CTLA-4
Cancer research
Immunotherapy
anti-PD-1/L1
Development of treatments and therapeutic interventions
Digestive Diseases
business
CD8
Brain metastasis
Subjects
Details
- ISSN :
- 15356108
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Cancer Cell
- Accession number :
- edsair.doi.dedup.....f486a9fbc2a74ee46654f535545c259b