Found: A Molecular Needle in the Cancer Haystack

Among the most powerful immunotherapies to hit the clinic in recent years are checkpoint blockade antibodies, also called checkpoint inhibitors. These drugs work by “taking the brakes off” the immune response, enabling a stronger attack against cancer. When checkpoint blockade therapy succeeds, it is believed that a patient’s T cells are revved up and empowered to destroy cancer cells bearing recognizable antigens—those tell-tale molecular fingerprints that distinguish cancer cells from normal cells. Only problem is, doctors have had no way to identify what those precise antigens are in any given patient. Until now.

New research by Cancer Research Institute (CRI) scientists published today in the journal Nature shows how it is possible to not only identify those elusive antigens, but also use them to make a powerful vaccine to knock out cancer. While the experiments were done in mice, the techniques have broad applicability and are beginning to be used in humans, as well.

“We are excited because these genomics approaches have significant clinical implications,” said lead author Matthew Gubin, PhD, a CRI-funded postdoctoral fellow working in the lab of Robert Schreiber, PhD, associate director of CRI’s Scientific Advisory Council and a professor of immunology at Washington University School of Medicine in St. Louis. “It takes just a few weeks to identify mutant tumor antigens, whereas previous approaches using cloning methods can often take many months.” This short turn-around time means it is entirely feasible to create a personalized cancer vaccine for a patient in just a matter of months.

Mutation Hunting

The new approach uses a form of molecular sleuthing called “exome sequencing” to identify the likely cancer targets seen by the immune system. Exome sequencing is a special form of DNA sequencing that allows researchers to quickly and comprehensively compare the genetic material between cancer cells and normal cells, and to identify DNA mutations—those molecular needles in the cancer haystack. Computer algorithms are then employed to predict which of the mutated protein antigens made from this DNA are most likely to bind to the antigen-recognition machinery on T cells.

To prove that the antigens identified in this way are the ones responsible for immune-mediated killing, Gubin and colleagues performed an elegant experiment. First, they showed that treating mice with a checkpoint inhibitor (anti-PD-1) caused tumors in the mice to completely regress. Then, they isolated T cells from these animals and used fluorescent probes to show that the only antigens recognized by the isolated T cells were the mutant antigens pinpointed by their sophisticated method.

Even more remarkable, by using “long peptides” of these antigens as a vaccine, the researchers could induce complete tumor regressions in mice that had not been treated with checkpoint blockade therapy. In other words, this vaccine made up of mutant antigens was equally effective as checkpoint blockade therapy at curing cancer in these mice.

Why, you might wonder, are these mutated antigens effective at treating cancer when they aren’t enough to prevent cancer in the first place? Gubin offers two possible explanations. First, when given as a vaccine, these antigens are accompanied by the powerful adjuvant called Poly-I:C, which goads the immune system into making an even stronger response against the antigens than would happen under normal circumstances. Second, the antigens in the vaccine are present at a higher concentration than they are at the site of the tumor, which also may result in a stronger immune response.

Asked what cancer types are likely to benefit from this approach, Gubin indicates that lung, kidney, and bladder cancer are good candidates; these cancers are known to be highly immunogenic and to have many genetic mutations, which make them more likely to be seen by the immune system. Melanoma patients, too, may benefit from the approach—particularly those who fail to respond to anti-CTLA-4 and anti-PD-1 therapy. The method might also assist researchers in identifying patients who are more likely to benefit from checkpoint blockade therapy. Ultimately, Gubin says, many if not most types of cancer may benefit from this approach, which could be combined with other therapies.

Now that’s something to be thankful for on this November 27.

This research was made possible by a CRI Irvington postdoctoral fellowship grant to Matthew Gubin, PhD, and a CRI Clinical and Laboratory Integration Program (CLIP) grant to Robert Schreiber, PhD 

Full citation: Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arther CD, Krebber W-J, Mulder GE, Toebes M, Vesely MD, Lam SSK, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee H-G, Melief CJM, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD. (2014) Checkpoint blockade cancer immunotherapy targets tumor-specific mutant antigens. Nature. 515, 577-581.