Dispatches from CRI’s 21st Annual Symposium
October 10, 2013 |
CRI wrapped up its 21st annual Cancer Immunotherapy symposium
last week on Wednesday. The theme of the symposium was “Dynamics of Host-Tumor Interaction.” The key word is ‘dynamic.’ Sitting in a dimly lit (and somewhat chilly) conference room at the Grand Hyatt Hotel in NYC, I couldn’t help but feel like I was in a cinema at times—as speaker after speaker showed electrifying movies of immune cells in action. In one movie, a single natural killer (NK) cell makes mincemeat of a band of roving cancer cells. In another, T cells crawl along collagen fibers to reach their destination deep within a lymph node. The movies are the result of a new—and apparently quite popular—technology called intravital microscopy, which is allowing researchers an unprecedented look at the real-time interactions between cancer cells and the surrounding host tissue. More on that in a moment.
The symposium kicked off with a keynote speech by this year’s Coley Award winner, Michael Karin, of UCSD. Karin—who holds the honor of being the most-cited author in all of molecular biology—spoke about his lab’s work on inflammation and cancer. For many years, inflammation was seen as an ally in the fight against cancer—going back at least to the work of William Coley in the 19th century who noted that patients with certain skin infections also sometimes experienced tumor regressions. And in the 1970s, Lloyd Old and colleagues at Sloan-Kettering discovered that the inflammatory cytokine called tumor necrosis factor (TNF) could strangle a mouse tumor, reducing it to a blackened pulp in a matter of hours.
But inflammation is now known to have a downside, too. Certain cancers are clearly associated with chronic inflammation, colon cancer being a good example. Karin’s lab has found that both colitis-associated and sporadic colon cancer cells show the same “signature” of inflammation at the level of gene expression. A molecule called NF-κB is activated in both types of colon cancer and leads to heightened levels of pro-inflammatory cytokines. Karin’s work suggests that antibodies blocking certain of these inflammatory cytokines, when combined with chemotherapy, might improve outcomes for patients with colon cancer.
The symposium itself was divided into five main sessions over three days. The first session, on “Tumor Microenvironment,” featured six talks by researchers exploring what one of them called “the traffic pattern of immune cells.” What emerged from these talks was a picture of a heterogeneous tumor microenvironment, unevenly infiltrated by immune cells. The precise locations and overall distribution of immune cells were identified by fluorescent staining methods combined in many cases with intravital microscopy. The six talks in this session raised important questions for immunotherapy. How can we use knowledge of the cues and substrates that immune cells rely on to increase effectiveness against tumors? And how can we take advantage of our understanding of inflammation to reduce the formation of a pro-cancer environment? In that vein, Shannon Turley, of the Dana-Farber Cancer Institute, presented interesting evidence suggesting that the collagen-dissolving drug pirfenidone promotes control of tumor growth in experimental animals by reducing the “wall” of collagen that surrounds a solid tumor, allowing T cells to enter.
The second session, appropriately—since it followed lunch—was all about how tumor cells and immune cells metabolize glucose. Despite having a little glucose overload of my own, I was able to glean from these talks that different types of immune cells prefer different pathways of metabolism, and that cancer cells may specifically alter the metabolism of immune cells in ways that hamstring their function. This raises the possibility of using enzymes involved in the metabolism of glucose to interrupt this process.
The festivities continued later that evening at Cipriani, where CRI celebrated its annual awards dinner. The night was extra special as CRI was celebrating its 60th anniversary. Honorees included Sean Parker, founder of Napster and Facebook, and Dr. Bahija Jallal, of MedImmune, both of whom have made major contributions to cancer research. Molecular biologist Michael Karin received this year’s William B. Coley award, and CRI’s own Jill O’Donnell-Tormey was awarded the Frederick W. Alt award, which is presented each year to a past CRI postdoctoral fellow who has made an outstanding contribution to the field of immunology. The highlight of the night was a video created by CRI featuring the remarkable story of 7-year-old Emily Whitehead, who was cured of her leukemia by an experimental immunotherapy pioneered by Dr. Carl June at Penn, now a member of CRI’s Scientific Advisory Council. A wonderful end to a great day.
Day 2 of the symposium began with a session focused on innate immunity. There were two main themes of these talks: 1) the role of bacteria and other “microbiota” in inflammation and cancer, particularly at mucosal sites in the body (read: the gut); and 2) the role of natural killer cells in tumor killing and surveillance. The focus on microbiota comes out of the upsurge of interest in the microbiome in all manner of physiological processes, from obesity to immunity. Because mucosal sites like the colon are a common place for malignancies to develop, it is only natural to wonder what role bacteria and inflammation may play in this process. Researcher Wendy Garrett, of Harvard, presented work showing that certain bacteria are associated with human colorectal carcinoma, and may contribute to cancer formation by recruiting immune cells that trigger chronic inflammation. On the other hand, Romina Goldszmid, of the NCI, presented research showing that the effectiveness of chemotherapy may in some cases depend on patients having bacteria that stimulate inflammatory cytokines. (Bacteria are recognized by Toll-like receptors on macrophages, known to be important triggers of inflammation.) Overall, the talks of the symposium reveal that we still have a lot to learn about inflammation and how to balance what seems to be a double-edged sword.
Natural killer (NK) cells are some of my favorite immune cells. Discovered in the 1970s on the basis of their ability to kill tumor cells without being warned of their presence by antigen-presenting cells, NK cells kill enemies that lack identifying MHC molecules on their surface. This is what’s known as the “missing self” model of NK activity. Multiple speakers, including Joseph Sun, of MSKCC, and Jack Bui, of UCSD, presented research showing how NK cells could be made more or less reactive to cancer cells, and also discussed previously unrecognized cytokines that recruit NK cells to the site of a tumor and thereby provoke a further anti-tumor immune response. This was also the session that featured the awesome NK slasher flick, which as far as I know was not directed by Quentin Tarantino.
Perhaps the most long-awaited session of the conference was the one on “Therapeutics.” After all, that’s why we are all in this business. And sure enough, there were reasons to feel optimistic. Mario Sznol, of Yale, presented the latest results of a phase I study combining ipilimumab plus nivolumab for melanoma—the same study that Jedd Wolchok, head of the CVC Trials Network, presented at this year’s ASCO meeting (to much acclaim and fanfare). Sznol got visibly excited as he recounted the many dramatic responses he witnessed in patients, including that of a 75-year-old woman who was “on the way to hospice” but who went on to have a near complete response. Others researchers in this session presented work on regulatory T cells (Tregs) and ways to dampen their action to increase anti-tumor responses—an approach that seems likely to greatly improve immunotherapy in the coming years, especially adoptive T cell therapies, where Treg-induced tolerance is a challenge.
Lymphocytes (green) and blood vessels (red) in the tail fin of the zebrafish. Credit: Corrie Painter, Ph.D.
Most inspiring, I thought, was the session devoted to the stellar research being conducted by the newest members of the immunotherapy community—the CRI Irvington postdoctoral fellows. Five fellows out of the 100 or so who attended the meeting were invited to present their research in detail. Topics covered included tumor-induced NK anergy (sluggishness), immunotherapy involving the checkpoint protein PD-1, using monoclonal antibodies to increase the effectiveness of chemotherapy for pancreatic cancer, and more. My favorite talk was given researcher and cancer survivor Corrie Painter, who discussed her efforts to use zebrafish as a model system for exploring adaptive immunity in melanoma. Turns out zebrafish have an immune system much like humans (they are vertebrates, after all), form melanomas that look and behave much like human melanomas, and—best of all—they are transparent! So you can look right into their tissues and watch their immune cells battle cancer. Painter ultimately plans to make intravital movies of the action, to which I can only say: grab the popcorn.
You can read more about the event, view photos, or download the symposium abstract book here.