Tumor Profiling Study Points to Combining Immunotherapy with Cancer-killing Viruses

Illustration of magnified cancer cells
Article Summary
  • Sylvester researchers profiled key molecular and cellular factors in neuroendocrine tumors, which are known to respond poorly to immunotherapy.
  • The findings show that many such tumors have an influx of immune cells, which correlates with high levels of a receptor for a therapeutic virus.
  • Treatment with the virus plus immunotherapy may offer an advantage over monotherapies, suggest the data. Sylvester researchers are now designing a clinical trial to test the combination.

Combining immunotherapy with a cancer-busting virus may provide a way forward to treat neuroendocrine tumors, a rare cancer that is growing in incidence.

Data from an ongoing study, led by Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, was presented at the American Association for Cancer Research Meeting.

Certain viruses can bust open cancer cells and kill them, and multiple clinical studies are testing their effects. Though such oncolytic viruses currently have a limited role in medicine, researchers are beginning to understand how to amplify their tumor-killing power, said study first author Samuel Kareff, M.D., Sylvester’s chief hematology and oncology clinical fellow.

One approach is to intelligently combine such viruses with anti-cancer drugs.

“It’s an exciting time for oncolytic virus research,” Dr. Kareff said.

Samuel Kareff, M.D., Sylvester chief hematology and oncology clinical fellow.
Dr. Samuel Kareff is investigating the efficacy of the SVV-01 virus in combination with immunotherapy.

Dr. Kareff and his colleagues investigated an oncolytic virus called SVV-01. This virus has been tested in a variety of tumor types in clinical trials. It seems to particularly elicit signs of a response in neuroendocrine tumors, which can arise anywhere in the body.

Dr. Kareff and his colleagues decided to investigate further. Why might neuroendocrine tumors be particularly susceptible to SVV-01 and how could the therapy be improved?

Cellular Profiling

Some oncolytic viruses, such as SVV-01, bind specific cellular targets in the body. SVV-01’s target is a molecule called TEM8, often found on the surface of cells associated with tumors.

Dr. Kareff and his colleagues assessed the levels of TEM8 and its parent gene, ANTXR1, in neuroendocrine tumors and examined other cellular factors that could affect response to treatment.

The researchers analyzed data from 1,724 neuroendocrine tumors in collaboration with Caris Life Sciences, a biotech company specializing in molecular profiling.

Consistent with previous, smaller studies, the researchers found that many neuroendocrine tumors had high levels of TEM8. The highest levels were found in tumors arising from the adrenal gland, followed by those from the colon and rectum, genitourinary organs and the small bowel.

High TEM8 levels also co-occurred with high levels of various immune cells, such as B cells and regulatory T cells—what researchers call an “immune infiltrate.”

Pathway to the Clinic

The findings suggest that tumors expressing TEM8 might be particularly susceptible to an approach combining oncolytic virus treatment with drugs directed at the immune infiltrate. In line with that notion, previous preclinical studies by the team showed that SVV-01 therapy enhanced the effect of drugs called immune checkpoint inhibitors.

Dr. Aman Chauhan
Dr. Aman Chauhan heads up Sylvester’s Neuroendocrine Tumor Program.

The researchers now want to test whether combining SVV-01 treatment with checkpoint inhibitors is also effective in patients.

Dr. Kareff and his colleagues are designing a clinical trial to test this two-pronged approach.

“We expect that we’ll have a better response for tumors that have high expression of TEM8,” said Dr. Kareff, since the molecule provides an entry point into the cell for the virus.

Researchers also plan to infuse SVV-01 directly into tumors, going beyond previous studies, which administered the virus into the bloodstream. The new study will be performed in collaboration with Seneca Therapeutics, which develops SVV-01 therapies.

The big goal, said Dr. Kareff, is to use SVV-01 to turn immune “cold” tumors that do not respond to immunotherapy into “hot” tumors that do respond.

Tackling an Increase in Neuroendocrine Tumors

Neuroendocrine tumors have historically been “poorly responsive” to immunotherapy, said senior author Aman Chauhan, M.D., a Sylvester medical oncologist and associate professor of medical oncology at the Miller School. The planned clinical trial has the potential to change that. It also adds to the growing list of trials Dr. Chauhan is implementing as the head of the Neuroendocrine Tumor Program, a position he was recruited for in February 2023.

“In the last year, we have developed one of the busiest and most robust neuroendocrine cancer programs,” said Dr. Chauhan. “We are not just caring for hundreds of new patients in our clinic, but we are also always looking ahead about how to think outside of the box and find ways to bring preclinical ideas from the bench to the bedside.”

The effort gains particular relevance in light of the alarming increase in the incidence of neuroendocrine tumors, which have risen more than six-fold over the last four decades in the United States. Singer Aretha Franklin, singer-songwriter Jimmy Buffet and Apple co-founder Steve Jobs all died from the disease.

Tags: Dr. Aman Chauhan, Dr. Samuel Kareff, Neuroendocrine Tumor Program, Sylvester Comprehensive Cancer Center