New Drug Class Causes Cell Death in Blood Cancers

Stimulator of interferon gene agonists may offer hope in the treatment of in lymphoma, multiple myeloma, and certain forms of leukemia.

A protein found on the endoplasmic reticulum can be targeted for stimulating the immune system for a more direct target B cell malignancy cell death.

This protein, called Stimulator of interferon genes (STING), plays a key role in the production of type 1 interferons, which helps regulate the immune system.

The development of a new class of drugs called STING agonists induce powerful immune responses by boosting the production of interferons to enhance the response to therapy.

Additionally, STING agonists were found to induce apoptosis in normal and malignant B cells. This suggests they could potentially be used as a primary therapy in lymphoma, multiple myeloma, and certain forms of leukemia. So far the responses have been transient.

“In non-B cells, STING agonists stimulate the production of interferons, but since they induce apoptosis in B cells, these B cells do not live long enough to help boost the immune response,” said senior study author Chih-Chi Andrew Hu, PhD. “We wanted to determine why STING agonists behave differently in normal and malignant B cells and how to extend this cytotoxic activity in malignant B cell leukemia, lymphoma and multiple myeloma.”

The study, published in Cancer Research, primarily focused on the IRE-1/XBP-1 stress response pathway located in the endoplasmic reticulum.

In order for STING to function correctly in non-B cells, the pathway must be activated. If the cells are deficient in IRE-1 or XBP-1, they are unable to produce interferons in response to the STING agonists.

B-cell leukemia, lymphoma, and myeloma also require the IRE-1 or XBP-1 pathway to be activated for survival.

The results of the study showed that activation of the IRE-1/XBP-1 stress response pathway reduces the level of apoptosis, meaning that if the pathway activity is lowered it could help promote malignant B cell death.

Furthermore, the level of apoptosis in B cells increased after suppression of the IRE-1/XBP-1 pathway from STING agonists’ stimulation.

These results were further confirmed in animal models when STING agonist treatment caused the regression of multiple myeloma and chronic lymphocytic leukemia in mice.

“This specific cytotoxicity toward B cells strongly supports the use of STING agonists in the treatment of B cell hematologic malignancies,” said first study author Chih-Hang Anthony Tang, MD, PhD. “We also believe that cytotoxicity in normal B cells can be managed with the administration of intravenous immunoglobulin that can help maintain normal levels of antibodies while treatment is being administered. This is something we plan on studying further.”