Nav: Home

New class of drugs specifically induces cell death in B cell blood cancers

March 10, 2016

PHILADELPHIA--(March 10, 2016)--In almost every mammalian cell, you will find the endoplasmic reticulum, a network of continuous membranes responsible for controlling metabolism as well as the folding, assembly and secretion of proteins. Since the endoplasmic reticulum is critical in manufacturing important proteins that facilitate communication between cells, researchers are exploring new ways to find important targets within these membranes that could help stimulate immune responses against cancer cells.

Now, new research from The Wistar Institute shows how one protein found on the endoplasmic reticulum can serve as a target for stimulating the immune system and a more direct target for cellular death in B cell malignancies. The findings of the study were published in the journal Cancer Research.

A protein called Stimulator of interferon genes (STING) is found on the endoplasmic reticulum and plays a critical role in producing type I interferons that help regulate the immune system. A new class of drugs called STING agonists were developed to induce powerful immune responses by boosting the production of interferons as an adjuvant therapy, meaning they were applied to enhance response to therapy. Improved immune responses were observed when STING agonists were used in cancer immunotherapy or as vaccine adjuvants.

As an adjuvant therapy, STING agonists play an accessory role in eliciting a response. However, additional studies confirmed that these drugs also induce apoptosis in normal and malignant B cells, suggesting that they could be used as a primary therapy in certain types of leukemia, lymphoma and multiple myeloma. The responses that have been observed thus far are transient, meaning that longer responses could lead to better direct treatment in B cell malignancies like chronic lymphocytic leukemia and multiple myeloma.

"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 Chih-Chi Andrew Hu, Ph.D., associate professor in the Translational Tumor Immunology program at The Wistar Institute and senior author of the study. "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."

Hu and his colleagues focused their attention on the IRE-1/XBP-1 stress response pathway found in the endoplasmic reticulum. This pathway must be activated for STING to function properly in non-B cells. If cells are deficient in either IRE-1 or XBP-1, the cells cannot produce interferons as a response to STING agonists. Additionally, B-cell leukemia, lymphoma, and myeloma require the IRE-1/XBP-1 pathway to be activated for survival. Results showed the activation of this pathway reduces the level of apoptosis, suggesting that lowering activity of this pathway is important in promoting death of malignant B cells. Interestingly, stimulation by STING agonists also suppresses the IRE-1/XBP-1 pathway, which increases the level of apoptosis in malignant B cells. The team further confirmed these results in animal models, as treatment with STING agonists led to regression of chronic lymphocytic leukemia and multiple myeloma in mice.

"This specific cytotoxicity toward B cells strongly supports the use of STING agonists in the treatment of B cell hematologic malignancies," said Chih-Hang Anthony Tang, M.D., Ph.D., a postdoctoral fellow in the laboratory of Dr. Hu and first author of the study. "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."

The Wistar Institute's business development team is looking for a co-development partner for the advancement of novel STING agonists in treating B-cell hematologic malignancies.
-end-
This work was supported by the National Institutes of Health grant R01CA163910. Co-authors of this study from The Wistar Institute include Joseph Zundell, Cindy Lin, and Yulia Nefedova. Other co-authors include Sujeewa Ranatunga and Juan Del Valle from the University of South Florida in Tampa.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

The Wistar Institute

Related Immune System Articles:

Using the immune system as a defence against cancer
Research published today in the British Journal of Cancer has found that a naturally occurring molecule and a component of the immune system that can successfully target and kill cancer cells, can also encourage immunity against cancer resurgence.
First impressions go a long way in the immune system
An algorithm that predicts the immune response to a pathogen could lead to early diagnosis for such diseases as tuberculosis
Filming how our immune system kill bacteria
To kill bacteria in the blood, our immune system relies on nanomachines that can open deadly holes in their targets.
Putting the break on our immune system's response
Researchers have discovered how a tiny molecule known as miR-132 acts as a 'handbrake' on our immune system -- helping us fight infection.
Decoding the human immune system
For the first time ever, researchers are comprehensively sequencing the human immune system, which is billions of times larger than the human genome.
More Immune System News and Immune System Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...