The annual meeting of the American Association for Cancer Research (AACR) kicked off on Saturday with back-to-back immunotherapy sessions. Starting the day was a grand overview called “Tumor Immunology and Immunotherapy for the Non-Immunologist.”
CRI Scientific Advisory Council (SAC) member Giorgio Trinchieri, M.D., of the National Cancer Institute, spoke about the role of the microbiome in cancer. The microbiome is our personal collection of bacteria, viruses, and fungi that live on and in us, and that shape the way our own cells behave. Noting that >16% of cancers worldwide are caused by infectious agents, including stomach and colorectal cancer, Trinchieri stressed the importance of understanding the role that the microbiome can play in causing cancer—by, for example, promoting inflammation. But he also discussed fascinating work showing that our particular constellation of germs can influence our response to cancer treatment, and that a fully functioning microbiota may in fact be necessary for an effective response to therapy. Killing off certain beneficial strains of bacteria with antibiotics, for instance, can reduce the effectiveness of some forms of chemotherapy and immunotherapy. Trinchieri likened cancer to an invasive species that takes over a field. One approach to killing the cancer “weed” is the slash-and-burn approach, where chemotherapy drugs are used to wipe out all the living plants in the field. A better approach, he suggests, is a kind of wise “park management,” where we learn to promote the species we want so that they can help keep the weeds in check.
Ton Schumacher, Ph.D., of the Netherlands Cancer Institute, and a member of the Cancer Research Institute’s SAC and a CRI-SU2C Cancer Immunology Dream Team member, presented his work on identifying the molecular targets that immune cells see when they successfully attack cancer. For decades, the focus of research in this area was on shared cancer antigens—proteins like MAGE and NY-ESO-1 that are commonly expressed by tumors, but not by normal adult tissues. But recent work has suggested that mutations unique to tumors—so-called neoantigens—might be more effective at eliciting an immune response. As Schumacher pointed out, neoantigens are as foreign to the immune system as viral antigens are, and therefore represent more obvious targets.
This realization helps to makes sense of recent findings that show that those patients whose tumors have a higher "mutational load"—that is, more mutations generating neoantigens—tend to have better responses to therapy. Schumacher’s lab has devised a truly clever way of identifying the mutant antigens within tumors that T cells can “see.” The approach involves using UV light to “cleave” (chop up) the different potential antigens into bits that can then sit in the groove of an MHC molecule, and then seeing which antigens light up an assay of T cells. An animated movie, shown during the presentation, helped to explain the technique. Other researchers, notably Robert Schreiber, Ph.D., of Washington University School of Medicine and an associate director of our SAC, have shown that neoantigens identified in this way can be used as an effective vaccine to treat cancer in mice, and the approach has already begun to be used in people too.
Jeffrey Weber, M.D., Ph.D., of Moffitt Cancer Center, also gave a talk on recent clinical work with checkpoint inhibitors, but I’m going to wait until later in the conference to discuss this topic, since new data are going to be released in the following days.
The afternoon was dominated by two major sessions devoted to the twin topics of “stepping on the accelerator” and “releasing the brakes” of the immune response. The first session was chaired by Suzanne Topalian, M.D., a medical oncologist at Johns Hopkins and a CRI-SU2C Dream Team grantee, while the second was chaired by Drew Pardoll, M.D., Ph.D., a former CRI investigator and now a member of our SAC as well. These sessions looked at current strategies to overcome immunosuppression by either engaging immune accelerators such as CD137, CD27, and OX40, or blocking immune brakes such as regulatory T cells, IDO, and myeloid derived suppressor cells.
A favorite moment during the afternoon sessions was when Nina Bhardwaj, M.D., Ph.D., of the Icahn School of Medicine at Mt. Sinai, a former CRI postdoctoral fellow and now a member of our clinical trials network, discussed recent work on cancer vaccines. Bhardwaj noted how current strategies to induce an immune response to cancer rely on an understanding of dendritic cells. Her former mentor, Ralph Steinman, M.D., whose earliest work with dendritic cell-based cancer therapies CRI funded in the 1980s, helped to establish the importance of these cells for the process of “antigen presentation.” Dendritic cells have Toll-like receptors that function as “taste buds” for the antigens found on pathogens—so-called “pathogen associated molecular patterns,” or PAMPs. Bhardwaj noted how William Coley, more than 100 years ago, had developed what was in essence the first cancer vaccine. Although he didn’t know it at the time, Coley was “basically injecting PAMPs into tumors,” said Bhardwaj. We now know that this was a sometimes effective way to stimulate the immune system to mount a valiant response against cancer. And many of today’s vaccine approaches—with oncolytic viruses, for example—can be thought of as continuing the important work started by Coley more than a century ago. If Coley were around today, he’d be gratified to know his approach to treating cancer is now being pursued by all the top minds in cancer biology and immunology.
Check back tomorrow for more updates on immunotherapy from AACR.