Advances in technologies that map a cell’s genome, or complete genetic makeup, are providing cancer researchers with important new tools to identify key genetic drivers in cancer growth. These tools may lead to precision treatments for an individual cancer patient’s disease, and might one day make possible preventive vaccines for people at high risk of developing some cancers.
Mutated or abnormally expressed genes can disrupt normal behavior and cause cells to grow out of control, migrate to other tissues, and survive treatment. But they can also make tumors look “foreign” to our immune system. And the more foreign tumors look, the better our immune systems can target and eliminate them.
While the immune system sometimes targets cancer naturally, scientists can improve this ability by identifying these cancer-specific markers and then telling the immune cells what to look for. Ton Schumacher, Ph.D., a member of CRI’s Scientific Advisory Council, and Elaine Mardis, Ph.D., each gave talks at the opening AACR plenary session about efforts to do just that. By comparing a patient’s cancer cells to their normal cells, scientists can determine what about those cancer cells looks most different to the patient’s immune system, and then pass on that knowledge to the immune system through therapeutic intervention.
Clinical trials have shown this approach can benefit some patients. The Cancer Research Institute recently announced that it is teaming up with the Parker Institute for Cancer Immunotherapy to explore neoantigen prediction and clinical testing of genomically-derived therapeutic targets.
The lab of Steven Rosenberg, M.D., Ph.D., also presented promising results using this approach. In a phase I study, genetically engineered T cells were used to evoke an immune response against one of these cancer-specific targets, an antigenic protein known as MAGE-A3. This protein is normally produced during fetal development, but not in adult tissues. However, due to genomic instability, cancer cells often resume production of MAGE-A3.
This was the first study to use customized “helper” CD4+ T cells that induce anti-tumor immunity indirectly, as opposed to the CD8+ “killer” T cells that directly attack cancer cells. In a Phase I trial to test the new therapy for safety and efficacy, the treatment was proven to be safe at multiple doses and stimulated a clinically beneficial immune response in several patients, including one cervical cancer patient whose response has lasted 15 months and one urothelial cancer patient whose response has lasted seven months.
While MAGE-A3 represents a normal protein that is only expressed in cancer, tumors also produce completely new molecules known as neo-antigens that arise through mutations that warp our normal proteins into new forms that the immune system sees as dangerous. These neo-antigens offer especially promising targets for precision immunotherapy. Since normal cells don’t express them, we can minimize the immune system’s collateral attacks on non-cancerous cells.
Stay tuned for our next post from #AACR16 today on the latest clinical data on checkpoint blockade therapy and improvements to anti-tumor immunotherapy.