Targeted Cancer Therapies Can Impact Immune Cell Response

Combining drug trametinib with a superagonist can stimulate activity while preserving the cancer-blocking effects of the treatment.

A new signaling protein—or superagonist—combats targeted cancer therapies that suppress T cell immune responses by stimulating T cell activity, according to a recent study published in Cancer Research.

It has previously been found that dozens of targeted therapies suppress T cell activity that could potentially help fight tumors.

“We wanted to know what the consequences to the immune system were when tumor cells were exposed to targeted therapies,” said senior study author José R. Conejo-Garcia, MD, PhD. “The effect that these drugs have on the interplay between tumor cells and leukocytes, which are essential for controlling the growth of immunogenic tumors, must be understood if we are to maximize the benefits of combination or sequential administration of targeted therapies and immunotherapies.”

The study found that by combining the FDA-approved targeted therapy drug trametinib (Mekinist) (MEK 1/2) with a superagonist, it could stimulate activity while also preserving the cancer-blocking effects of the treatment.

While studying 41 different small molecule inhibitors and their effects on human T cells, researchers identified Mekinist as a powerful inhibitor of T cell activity. The cytokine interleukin-15 (IL-15) was then selected to be used in combination with Mekinist during the study.

ALT-803, an IL-15 superagonist currently in phase 1 and 2 clinical trials, was selected to discover if the drug was able to rescue T cells suppressed by Mekinist.

When the effects were tested in vivo, the results of the study found that Mekinist no longer affected T cell proliferation.

“MEK inhibitors like trametinib are being tested in a variety of tumors, and we've demonstrated an effective means of controlling the effect that these drugs have on T cells that could further help in the fight against cancer,” said first study author Michael Allegrezza. “We plan to continue to study the effects of targeted therapies on the tumor microenvironment and see if other immune cells are impacted in the manner we observed in effector T cells.”