Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4...

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• MEK inhibitors (MEKi) face resistance in MAPK/ERK pathway-dependent cancers.
• CH5126766 (CKI27) inhibits MEK, increasing MHC expression but suppressing T-cell function.
• Balancing MEKi's immunomodulatory effects is crucial for combination immunotherapy.

Purpose of the Study:

• To optimize MEK inhibitor (CKI27) combination therapy for cancer treatment.
• To mitigate CKI27-induced T-cell suppression while enhancing anti-tumor immunity.
• To investigate the efficacy of intermittent CKI27 dosing with immunotherapy.

Main Methods:

• Utilized intermittent administration of CKI27 in Kras mutant lung and colon tumor mouse models.
• Combined CKI27 with GITR and OX-40 agonist antibodies for T-cell costimulation.
• Assessed tumor growth, survival, T-cell proliferation, activation, and regulatory T-cell populations.

Main Results:

• Intermittent CKI27 administration allowed partial T-cell recovery.
• Costimulation via GITR/OX-40 agonist antibodies alleviated CKI27-induced T-cell inhibition.
• The triple combination (intermittent CKI27, anti-GITR, anti-CTLA-4) reduced tumor growth and prolonged survival.
• This combination enhanced T-cell responses and destabilized intratumoral regulatory T-cells.

Conclusions:

• Intermittent MEK inhibition combined with immunotherapy can overcome resistance and reduce toxicity.
• This strategy generates robust, long-term anti-tumor immune responses.
• Optimized combination regimens are essential for effective cancer immunotherapy.