IL-15 Agonist + MEK Inhibitor Combination Cancer Therapy

MEK inhibitors, such as trametinib, target the MAPK signaling pathway. As this pathway is also essential for T cell function, at the active dose, trametinib leads to a loss of T cell activation. Designing combination therapies that can overcome the T-cell suppressive effects is critical to the advancement of sustainable immunotherapy.

Our recent findings suggest that trametinib and other MEK inhibitors paradoxically synergize with immunomodulatory therapies such as IL-15 agonists to increase tumor antigen expression (1-2).

Our research demonstrates that combining trametinib with cytokine IL-15 agonists alters the tumor microenvironment and prevents aggressive tumor recurrence.

– The mechanism of action for trametinib that leads to tumor suppression, in some tumors, is independent of direct cancer cell interaction. Surprisingly, the microenvironment plays a key role in trametinib anti-tumor activity.

– Although trametinib directly suppresses T cell activation, it also decreases monocytic MDSCs, enhancing protective immunity, explaining why full anti-tumor efficacy paradoxically requires CD8 T cells in their KRas-driven tumor model.

– Current treatments being clinically investigated which combine PI3K and MEK inhibitors should be challenged. This combination could potentially restrict T cells, leading to poor clinical outcome and tumor recurrence.

– Using high throughput techniques, we mechanistically approached the optimization of a dual therapy strategy that utilizes trametinib’s interaction with T cells and MDSCs. This resulted in a rationale for combining trametinib with cytokine-based immune therapies, specifically IL-15 agonists.

We have received a notice of allowance in the United States; worldwide rights are available.

We are seeking a licensing partner to advance this new combination therapy.

1. Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213-9.
   
   
2. Kono M, Dunn IS, Durda PJ, Butera D, Rose LB, Haggerty TJ, et al. Role of the mitogen-activated protein kinase signaling pathway in the regulation of human melanocytic antigen expression. Mol Cancer Res. 2006;4:779-92.