Antigen is a term you might never have heard before, but chances are that if we ever cure cancer, it will be because we learned how to take advantage of these important molecules. There’s a reason that Day 1 of the Second International Cancer Immunotherapy Conference (#CICON16) kicked off featuring them.
So, what exactly are antigens? Well, they’re basically protein or carbohydrate fragments. All cells have them, and by displaying them on their surfaces or within their interior, cells broadcast bits of their identity to the immune system. This helps the immune system to determine if a cell is healthy or infected. It also makes it possible for the immune system to recognize abnormal cancer cells and eliminate them. Immunotherapy can help our immune system target specific cancer antigens and restore its ability to eliminate cancer.
In his opening keynote, Philip D. Greenberg, M.D., who is head of immunology at the Fred Hutchinson Cancer Research Center and the University of Washington and a member of CRI’s Scientific Advisory Council (SAC), discussed his chosen antigens, WT1, CyclinA1, and mesothelin. While expressed in normal cells, these proteins are often expressed abnormally at very high levels in cancer. Dr. Greenberg reengineers T cells to target these abnormal antigens, and then puts them back into patients in hope of generating an anti-cancer immune response. He has found that a particular subset of T cells, called central memory T cells, outcompete other T cells and retain their cancer-killing activity longer.
In addition to abnormally expressed antigens, tumors can express neoantigens, which are caused by DNA mutations and are unique to an individual patient’s tumor. In some cases, these neoantigens provide superior targets, but they must be chosen wisely. If the randomly mutated protein isn’t essential to cancer, then the cancer cells may discard it and evade an immune response against it.
Cornelis Melief, M.D., Ph.D., a professor at the Leiden University Medical Center in The Netherlands and a member of CRI’s SAC, discussed the development of personalized immunotherapies for patients. He described the properties of an ideal vaccine target and the need to get the vaccine to the right place, notably to dendritic cells (DCs), which can coordinate anti-tumor responses. Then he covered the use of complementary treatments, such as those that boost the immune system, deplete pro-tumor immune cells, and enable T cells to overcome the suppressive tumor environment.
Melief, along with Robert D. Schreiber, Ph.D., the director of the Center for Human Immunology and Immunotherapy Programs at Washington University School of Medicine and an associate director of CRI’s SAC, designed a strategy to identify the most promising neoantigens to target and then use them to develop patient-specific vaccines.
Schreiber, who spoke next, shared how this strategy shows promise in mouse studies he conducted with Matthew Gubin, Ph.D., a CRI-funded postdoctoral fellow sponsored by Dr. Schreiber. After sequencing tumors to identify mutations, they used an algorithm to identify two promising mutations--mLama4 and mAlg8--and then synthesized a protein-based vaccine against them. The vaccine alone was able to protect mice against progression of new tumors, to a similar extent as in mice treated with anti-PD-1 and anti-CTLA-4 checkpoint inhibitors. Neither approach was effective against large, established tumors; however, previously resistant tumors responded when mice received a combination of all three therapies.
Finally, Sara Mangsbo, Ph.D., a professor at Uppsala University in Sweden, spoke about a very interesting approach that utilizes the fact that most people have already been vaccinated against tetanus. By linking MTTE (a tetanus toxin) to fragments of cancer-specific antigen, Mangsbo elicited anti-tumor immune responses by getting the immune system—specifically DCs—to take up the cancer antigen when it engulfs the antibody-bound tetanus molecules. This approach is currently being tested in high-risk melanoma patients, and so far all treated patients have shown strong T cell responses against the tumor antigens.
Next up, our coverage will shift to the New Checkpoints!