Through T cell engineering, researchers at the Massey Cancer Center at the Commonwealth of Virginia University are showing that it is possible to stop tumor growth for a variety of cancers and crush the spread of cancer to d ‘other fabrics. This research will be published in tomorrow’s print edition of Research against cancer.
The article draws on decades of research by lead study co-author Paul B. Fisher, M.Ph., Ph.D., a member of the Massey Cancer Biology research program, who discovered a protein called IL-24 which attacks a variety of cancers in several ways.
In this latest study, Fisher teamed up with his colleague Xiang-Yang (Shawn) Wang, Ph.D., who co-leads the Developmental Therapeutics research program at Massey, to provide the gene encoding IL-24, called MDA -7, to solid tumors using T cells.
“I think the beauty of what we’ve been involved in is that it broadens the scope of immunotherapy,” said Fisher, professor and director of the department of human and molecular genetics at the VCU School of Medicine, Director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman endowed the Research Chair in Oncology. “Our approach is less dependent on cancer cells expressing something specific to target.”
After all, this is not the first time that T cells have been designed for cancer immunotherapy. FDA-approved chimeric T antigen receptor (CAR-T) cell therapy – which is designed to destroy cancer cells expressing specific surface molecules – has seen tremendous success in treating advanced cancers of the blood systems and lymphatic.
But CAR-T has made limited progress on solid tumors, such as prostate cancer or melanoma, because the cells that make up these tumors are not all the same, preventing the modified T cells from recognizing and d ‘attack.
Wang and Fisher have armed T cells with MDA-7 / IL-24 to target cancer more broadly.
“Engineering T cells to produce MDA-7 / IL-24 kills cancer cells regardless of their expression of target molecules. This will help prevent cancer cells from escaping an immune attack, ”said Wang, who is also professor of human genetic research at VCU, associate director of immunology at VIMM and holder of the Harry and Judy Wason Distinguished Professor title. at Massey.
At the subcellular level, MDA-7 / IL-24 binds to receptors on the surface of cells and instructs them to make and release more copies of the MDA-7 / IL-24 protein. If the cell is normal, the protein is simply secreted and no damage occurs. But if the cell is cancerous, MDA-7 / IL-24 causes oxidative stress damage and ultimately cell death, not only within the primary tumor but also among its distant metastases – the cause of death in 90% of patients. patients.
As a result of this process, the immune system generates memory T cells that can theoretically kill the tumor if it recurs. In the entire tumor, IL-24 also blocks the formation of blood vessels, depriving tumors of nutrients so necessary to maintain their uncontrolled growth.
In mice with prostate cancer, melanoma, or other cancer metastases, T cells expressing MDA-7 / IL-24 slowed or stopped cancer progression better than unmodified T cells.
The researchers also found that arming T cells with MDA-7 / IL-24 allowed them to survive better and multiply in the tumor microenvironment – the space just around the cancerous mass.
“The tumor site is often very hostile to immune cells,” Wang said. “We have found that MDA-7 / IL-24 can help T cells to proliferate and outnumber cancer cells.
Clinically, this approach would involve extracting the patient’s own T cells from tumor samples, genetically engineered to express MDA-7 / IL-24, growing millions of copies of the cells in the lab, and finally transplant them to the patient. With the manufacturing standards imposed by the federal government, the procedure is generally safe and minimally invasive. CAR-T cells could also be engineered to express MDA-7 / IL-24.
To be more effective, MDA-7 / IL-24 T cells would likely be used in conjunction with other therapies.
While it’s never easy to bring technology from the bench to the bedside, Fisher is optimistic that much of the groundwork has already been laid.
Clinical trials using different methods of delivering IL-24 are already underway for several cancers. A phase 1 trial using an adenovirus – similar to the common cold – to deliver MDA-7 / IL24 to the tumor has shown about 44% efficacy against several forms of cancer and was generally found to be non-toxic.
“I think we’ve got a head start and a rolling ramp that could be really accelerated,” Fisher said.
Together, Wang and Fisher recently won a grant from the National Cancer Institute to optimize their technology for treating solid tumors and cancer metastases, in preparation for future human trials.