Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Area of Science:

• Oncology
• Immunotherapy
• Cancer Genomics

Background:

• Innate and acquired resistance limit the efficacy of targeted cancer therapies.
• Previous immune checkpoint therapy enhances clinical benefit from MAPK inhibitors (MAPKi).

Purpose of the Study:

• To compare sequential and combinatorial regimens of anti-PD-1/L1 and MAPKi in preclinical cancer models.
• To investigate the immunomodulatory effects of sequential therapy on macrophage and T-cell populations.
• To evaluate the efficacy of sequential therapy in suppressing melanoma brain metastasis (MBM).

Main Methods:

• Utilized subcutaneous murine models of melanoma (Braf, Nras, Nf1 mutations) and colorectal/pancreatic carcinoma (Kras G12C mutation).
• Administered sequential (anti-PD-1/L1 lead-in followed by MAPKi) and combinatorial regimens.
• Assessed tumor response, survival, macrophage polarization, and T-cell dynamics (interferon-γ, CD8+, CD4+ T cells).

Main Results:

• Anti-PD-1/L1 lead-in followed by MAPKi optimized response durability and promoted pro-inflammatory macrophage polarization.
• This sequence enhanced clonal expansion of interferon-γ-expressing, CD8+ cytotoxic T cells.
• Sequencing suppressed MBM, improved mouse survival, and promoted robust T-cell expansion in both intracranial and extracranial sites.

Conclusions:

• Sequential anti-PD-1/L1 therapy before MAPKi combination is a potent strategy to overcome therapeutic resistance.
• This approach effectively suppresses melanoma brain metastasis and enhances anti-tumor T-cell responses.
• Clinical trials of brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment are warranted.