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Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4
Lauren Dong1,2,3, Hyejin Choi1,2,3, Sadna Budhu1,2,3
1Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
Abstract:
MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.
Insights
MEK inhibitors (MEKi) show promise for MAPK/ERK cancers but cause T-cell suppression. Intermittent dosing combined with immunotherapy overcomes resistance, enhancing anti-tumor immunity and survival in mouse models.
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.
