Targeted Therapies Suppress T-cell Response But Superagonist Can Overcome the Suppression

Dozens of targeted therapies, which are preferred as treatment over chemotherapy and surgery, suppress the activity of T cells that could help to fight tumors.
Dozens of targeted therapies, which are preferred as treatment over chemotherapy and surgery, suppress the activity of T cells that could help to fight tumors.

Dozens of targeted therapies, which are preferred as treatment over chemotherapy and surgery, suppress the activity of T cells that could help to fight tumors.1 Targeted therapies are preferred because they attack and kill cancer cells that have specific tumor-promoting mutations and simultaneously spare cells that are healthy and normal because those cells do not express the mutations.

A study found that pairing trametinib, an U.S. Food and Drug Administration-approved targeted therapy, with a signaling protein superagonist, known as ALT-803, stimulated T-cell activity and also preserved the cancer-blocking effects of the trametinib.

"We wanted to know what the consequences to the immune system were when tumor cells were exposed to targeted therapies," said senior author José R. Conejo-Garcia, MD, PhD, professor and program leader in the Tumor Microenvironment and Metastasis program at The Wistar Institute in Philadelphia, PA.

"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 research team examined how 41 different small molecule inhibitors affected healthy human T cells. The T cells were more potently inhibited than were cancer cells by every targeted therapy tested, with trametinib being a particularly powerful inhibitor of T cell activity.

The researchers investigated cytokines, which are cell signaling proteins. The goal was to promote signaling on immune cells but not tumor cells so that the T cells could be rescued from the negative effects of trametinib treatment. Interleukin-15 (IL-15) was found to promote stronger signaling activity for effector T cells while not expanding the population of regulatory T cells that could suppress the activity of effector T cells.

In vivo tests of ALT-803, an IL-15 superagonist that is in phase 1 and 2 trials, found that trametinib no longer affected T-cell proliferation when ALT-803 was added.

"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 author Michael Allegrezza, a predoctoral trainee in the Conejo-Garcia lab.

"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."

Reference

1. Allegrezza MJ, Rutkowski MR, Stephen TL, et al. IL-15 agonists overcome the immunosuppressive effects of MEK inhibitors. [Published online March 15, 2016] Cancer Research. doi:10.1158/0008-5472.CAN-15-2808.

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