Altering T cells of the adaptive immune system to enable recognition of cancerous cells is a mainstream area of research these days. The approach of adding chimeric antigen receptors to T cells, tailored to a cancer, is well established for blood cancers, but still challenging for solid tumors, characterized a wide variety of cancerous cells and signatures. Researchers here show that genetic modification of T cells to produce IL-24 allows these immune cells to effectively destroy cancerous cells that lack recognizable surface features, so long as they are close to cancerous cells that can be recognized. Further, the process of cancer cell destruction via IL-24 leads to the ability of the immune system to later recognize those cells as cancerous, suppressing the possibility of recurrence of the cancer.
A protein called IL-24 attacks a variety of cancers in several different ways. Researchers now deliver the gene coding for IL-24, which is called MDA-7, to solid tumors using T cells. This isn't the first time T cells have been engineered for cancer immunotherapy. Chimeric antigen receptor T (CAR-T) cell therapy - which is designed to destroy cancer cells expressing specific surface molecules - has shown tremendous success for treating advanced cancers of the blood and lymphatic systems. But CAR-T has made limited progress on solid tumors, such as prostate cancer or melanoma, because the cells that make up those tumors aren't all the same, which blocks the engineered T cells from recognizing and attacking. Researchers armed T cells with MDA-7/IL-24 to target cancer more broadly.
At the sub-cellular 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. As a result of this process, the immune system generates memory T cells that can theoretically kill the tumor if it ever comes back. At the whole tumor level, IL-24 also blocks blood vessel formation, starving tumors of the nutrients so badly needed to sustain their unchecked growth.
In mice with prostate cancer, melanoma, or other cancer metastases, MDA-7/IL-24-expressing T cells slowed or stopped cancer progression better than unmodified T cells. The researchers also discovered that arming T cells with MDA-7/IL-24 allowed them to survive better and multiply in the tumor microenvironment - the space right around the cancerous mass. In the clinic, this approach would involve extracting the patient's own T cells from tumor samples, genetically engineering them to express MDA-7/IL-24, growing millions of copies of the cells in the lab and finally transplanting them back into the patient. CAR-T cells could also be engineered to express MDA-7/IL-24.