Sylvester Researchers Receive $2M to Conduct Clinical Trial on Unique Immunotherapy
Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, led by Glen Barber, Ph.D., are leveraging a $2 million, NCI-sponsored Small Business Technology Transfer (STTR) grant to potentially advance cancer care. The STTR will fund a first-in-humans, phase 1 clinical study to determine if a novel immunotherapy, targeting the STING pathway, is safe and can proceed to more advanced trials.
“We’ve developed a simple and inexpensive way to potentially stimulate the STING pathway and generate a robust anti-tumor immune response,” said Dr. Barber, who is Eugenia J. Dodson Chair in Cancer Research at Sylvester and professor and chair of the Miller School’s Department of Cell Biology. “We believe this approach has tremendous potential for the future treatment of many different cancers.”
STING: The First Line of Immune Defense
The Barber lab discovered STING in 2008 and has been writing the book on it ever since. As part of the cell’s innate immune response, STING detects DNA in the cytoplasm of cells, which often indicates a bacterial or viral infection, and alerts the immune system to the intruder.
“STING is critically important to detect microbial infections,” said Dr. Barber. “It does this by recognizing microbial DNA in the cytoplasm, which is generally a DNA-free zone.”
STING also plays a major anti-cancer role. For example, DNA damage in tumor cells can lead to extra chromosomal DNA (ecDNA) escaping from the nucleus, which can also activate STING and alert the immune system. This includes phagocyte recruitment to remove infected or damaged cells.
Here’s where cancer leverages cellular evolution to protect itself from immunity. Phagocytes routinely eat millions of dead cells every day, with cellular enzymes (DNases) degrading 3 billion nucleotide base pairs to avoid activating inflammatory signaling.
While this protects the body from an overly harsh immune response, it can also give cancer cells a survival advantage since the phagocyte can’t really distinguish between a dying normal cell and a dying tumor cell. “We believe this is one of the major mechanisms tumor cells adopt to escape generating an immune response,” said Dr. Barber.
Quite often, there not enough ecDNA outside the tumor cell nucleus to trigger STING and alert the immune system. Also, in many cases, tumor cells have found ways to suppress STING signaling to avoid activating immunity.
Seeing that microbe-infected cells stimulate phagocytes, while cancer cells do not, Dr. Barber had an interesting idea:
What if we could prime the immune response using synthetic cytosolic DNA?
“We designed some DNA molecules and electroporated them into the tumor cells,” said Dr. Barber. “The cellular DNases couldn’t digest all the synthetic DNA, which accumulated in the cytoplasm. Then we prevented the tumor cells from proliferating using radiation and fed them to phagocytes. The non-degraded synthetic DNA in the cancer cells activated STING in the phagocytes and generated a massive cytotoxic T cell response to the tumor antigens. It made cold tumors hot.”
Often, lab researchers hand off their work to translational and clinical scientists.
However, Dr. Barber and colleagues created a small biotech, called STINGINN, to advance this work.
Armed with the STTR grant, the Miller School will soon begin a phase 1 clinical trial to test whether this approach is safe in a variety of leukemia patients. Any clinical response will be a bonus.
Juan Carlos Ramos, M.D., and Justin Watts, M.D., in the Division of Hematology, will spearhead the clinical trial, which will be implemented with the transplant team, led by Aisha Khan of the Interdisciplinary Stem Cell Institute.
“This is very much a team effort,” said Dr. Barber. “We have been working on this strategy, based on the research of Dr. Jeonghyun Ahn in our lab, for quite a while. It was quite an achievement to obtain FDA approval and find the resources to fund this trial.”
If successful, this STING immunotherapy could benefit many cancer patients.
Current immunotherapies are extremely expensive ($500K for CAR-T) and not always effective. However, the synthetic, STING-activating DNA is quite inexpensive and could be broadly effective against multiple cancer types. In addition, these STING agonists could make other immunotherapies, particularly checkpoint inhibitors, more effective.
“People don’t fully understand why checkpoint inhibitors don’t always work, but if there are no T cells around the tumor in the first place, we’re not going to see any effect,” said Dr. Barber. “Our strategy may generate a lot of T cells, and if we get through phase 1, this will open the floodgates to target a wide variety of tumors with checkpoints and other types of immunomodulatory therapy.”
Tags: Aisha Khan, Department of Cell Biology, Division of Hematology, DNA, Dr. Glen Barber, Dr. Glen N. Barber, Dr. Jeonghyun Ahn, Dr. Juan Carlos Ramos, Dr. Justin Watts, Juan Carlos Ramos, Miller School of Medicine, National Cancer Institute, NCI, Phase 1 clinical trials, STING pathway, STTR grant, Sylvester Comprehensive Cancer Center