Times Square in Manhattan today was home to a different sort of blockbuster show, as 1,400 of the world’s most talented immunologists converged on the Big Apple for the inaugural International Cancer Immunotherapy Conference. Co-hosted by the Cancer Research Institute (CRI) in partnership with three other nonprofit organizations, the conference is entitled, “Translating Science into Survival,” and is dedicated to the rapidly expanding field of cancer immunotherapy, also known as immuno-oncology.
Following introductory remarks by Jill O’Donnell-Tormey, Ph.D., CRI’s CEO and director of scientific affairs, the conference kicked off with a keynote address by one of the field’s pioneers. This opening salvo was followed by back-to-back plenary sessions devoted to two of the hottest areas in immunotherapy: checkpoint blockade biology and identifying genetic targets for immunotherapies.
T Cell Armies
Long before cancer immunotherapy was on the front page of every newspaper, a handful of daring and pioneering scientists toiled away in relative obscurity. One such stalwart soul was Steven Rosenberg, M.D., Ph.D., of the National Cancer Institute, who for the past 20 years has been honing an approach to immunotherapy called adoptive cell therapy (ACT). In this approach, immune cells called T cells are removed from a patient’s tumor, grown in the lab, and then given back to the patient in vastly increased numbers. Often, billions of cells are returned to the body. This army of T cells then goes to work finding and destroying cancer. When the approach works, it works very well. Among 93 patients with advanced melanoma treated this way, 20 (22%) had complete responses, and 19 have been in remission “well beyond 10 years,” Rosenberg said in his keynote lecture.
In recent years, Rosenberg has worked to improve the approach and expand its applicability to cancers besides melanoma. The biggest hurdle was figuring out just what T cells were seeing on tumor cells. In order for a T cell to kill a cancer cell, it must identify a marker, or antigen, it recognizes as foreign and dangerous. But for many years what those antigens were in any particular patient was largely a mystery. Now, thanks to advanced genomic methods, it is possible to identify the minute genetic differences that distinguish cancer cells from normal cells, and to perform adoptive cell therapy with just those T cells that uniquely recognize those specific antigens. The approach is allowing Rosenberg to expand ACT to cancer types besides melanoma, including common epithelial cancers like stomach, colorectal, esophageal, and pancreatic cancers.
Rosenberg presented the case of the first non-melanoma patient treated this way, a 45-year-old woman with advanced cholangiosarcoma, a cancer of the bile ducts, who also had lung metastases. After receiving the treatment, the patient’s cancer regressed completely, her PET scan registered no disease, and she is “now living normally.”
Releasing the Brakes
Much of the excitement about immunotherapy in recent years has come from clinical results achieved with immunotherapies known as checkpoint inhibitors. These are drugs—typically antibodies—that “release the brakes” on the immune system, allowing it to mount a stronger and more effective attack against cancer. The intellectual father of the approach, James Allison, Ph.D., a professor of immunology at MD Anderson Cancer Center and director of CRI’s Scientific Advisory Council, opened the first plenary session with a look back at what the development of the first checkpoint inhibitor, ipilimumab (Yervoy®), has meant to patients.
Since it was first tested in clinical trials in the early 2000s, ipilimumab has been given to more than 70,000 cancer patients. About 22% of those patients have experienced long-term, durable remissions lasting 5 years or more. The earliest patients to receive the drug are now 10 years out and still free of disease, leading Allison to conclude, “we can start to think of this treatment as being curative.”
“We can start to think of this treatment as being curative.” – James Allison, Ph.D.
For his groundbreaking work developing this approach to immunotherapy, which has come to be known as checkpoint blockade, Allison received this year’s Lasker-DeBakey Award, one of the world’s top scientific honors.
Since ipilimumab was developed, other checkpoint inhibitors have come into use, including those that target different braking molecules, or checkpoints, on immune cells. Of these, the most famous are drugs such as nivolumab (Opdivo®) and pembrolizumab (Keytruda®) that target the PD-1 checkpoint on immune cells. One of the co-discoverers of this pathway, Arlene Sharpe, M.D., Ph.D., of Harvard Medical School, gave an illuminating talk on recent work that her lab has done on a new role for the PD-1 pathway—that of regulating antibody production. (Sharpe was a co-recipient of last year’s William B. Coley Award and you can watch a video of her and her fellow awardees here.)
Continuing the theme of checkpoints was Alan Korman, Ph.D., of Bristol-Myers Squibb (BMS). Like Jim Allison, Korman has a long history working on checkpoint biology. In fact, Korman and Allison collaborated on the development of ipilimumab back in the late 1990s, when Korman worked at a company called Medarex (later acquired by BMS). A few years later, Korman and his colleagues were among the first to show that combining checkpoint antibodies like ipilimumab and nivolumab could lead to even more effective results in mice, providing a rationale for conducting clinical trials of the combo in humans. As of today, more than 900 patients have been treated with this combo, which is currently under review by the FDA for use in melanoma.
Korman is an expert on the nuts and bolts of checkpoint inhibitors, which are formed by engineering antibodies with precise molecular attributes. A little background on antibodies: these are Y-shaped molecules that bind to precise targets called antigens, which they match like puzzle pieces. The parts of the antibody that bind to antigens are the two tips at the top of the Y. The base of the Y can do different things depending on whether it binds to other things or not. Some antibodies, for example, bind to receptors on immune cells called macrophages that gobble up whatever is bound to the antibody—say, a microbe or cancer cell.
One way that checkpoint inhibitors are believed to work is by blocking molecules on T cells that act as brakes. In the case of ipilimumab, the brake molecule is called CTLA-4; in the case of nivolumab and pembrolizumab, it’s PD-1. In this scenario, the antibody is just covering up the brake molecule so it can’t be engaged by other cells, and the T cell speeds along to attack the cancer. But Korman and other researchers have shown that in some situations, checkpoint antibodies can actually recruit macrophages to bind the antibody and engulf the attached cell. This is a bit perplexing, since in this case the attached cell is a T cell and you want those to stick around to fight cancer. It turns out that other immune cells, called regulatory T cells, also have these braking molecules, are also bound by checkpoint inhibitor antibodies, and their depletion by macrophages is actually helpful in promoting an immune response against cancer. The bottom line, though, is that the rear end of the antibody matters, and engineering it to perform different functions is likely to be a focus of research in the coming years.
Antigens, which Antigens?
The focus of the second plenary session shifted to the genetic targets of immunotherapies. For decades, a major focus of research in cancer immunology has been on searching for unique markers on (or in) cancer cells—“tumor antigens,” in the lingo of scientists. The first tumor-specific antigens were identified in the early 1990s. These were proteins such as MAGE and NY-ESO-1 that were commonly found in cancer cells but not normal adult body cells (with a few minor exceptions). Once these antigens were identified, the race was on to use them to make therapeutic cancer vaccines. Unfortunately, despite some individual successes, several large clinical trials failed to show that vaccines made with shared tumor antigens improved survival for patients with cancer.
In recent years, the focus of attention has shifted from shared tumor antigens to unique antigens that are specific to an individual patient’s tumor. These are so-called “neo-antigens.” While it has been known for a long time that cancers had these unique genetic fingerprints, they were not considered good candidates for vaccines because they are so idiosyncratic—they’re different for every tumor, and every patient; trying to identify them to make a vaccine would mean genetically sequencing each patient’s entire genome to identify these few bits of relevant genetic information—truly like finding a needle in a haystack. The technology just didn’t exist to make this feasible.
Until now. Robert Schreiber, Ph.D., a professor at Washington University School of Medicine in St. Louis and an associate director of CRI’s Scientific Advisory Council, discussed the approach that he and his colleagues have used to identify the unique genetic mutations—the neo-antigens—that are seen by the immune system. Called exome sequencing, the approach involves comparing the genetic material between a person’s normal cells and their cancer cells, and pulling out the bits of protein that are likely to be processed and posted to the cell surface for detection by immune cells. Schreiber has shown that he can make a vaccine with these few molecular fragments that is effective at curing mice of their cancers. He views this as a truly “personalized immunotherapy.” Clinical trials of the approach are currently under way at Wash U and elsewhere.
Several other talks also focused on identifying cancer antigens and using them in vaccines. Hans-Georg Rammensee, Ph.D., of University of Tuebingen, gave a talk that focused on identifying appropriate cancer antigens in cancers that are less prone to having widespread genetic abnormalities. While all cancers are characterized by having genetic mistakes or mutations—which is what makes them cancerous in the first place—not all have quite as many mutations as melanoma or non-small cell lung cancer—two cancers that are chock full of genetic damage caused by UV radiation and cigarette smoking, respectively. It’s relatively easy to find neo-antigens in these types of cancers. But what about cancers such as ovarian, liver, and kidney cancers? Rammensee and his team found that neo-antigens that could be recognized by the immune system were exceedingly rare or non-existent in these tumor types. They therefore focused their attention elsewhere—on non-mutated antigens that were abundant in cancer cells but restricted in their tissue expression. These sorts of antigens, they found, were much more common. As to how to explain the restriction of these non-mutated antigens to tumors, Rammensee suggests that they may represent genes whose RNA is spliced together in a unique way to make unique proteins that differ from patient to patient. He argues that these sorts of antigens, too, might be useful targets for personalized immunotherapy.
Day 1 ended with a poster session, featuring many CRI-funded postdoctoral fellows. One lucky CRI post-doc, Ed Roberts, Ph.D., of UCSF, was chosen to give a talk describing his poster. In a vibrant, multi-colored presentation, Roberts showed how he could use fluorescent dyes to track individual immune cells from tumors to lymph nodes and back again. He even showed a movie featuring a “scrum” of immune cells cavorting in a lymph node. An action-packed end to an action-packed day.
Check back tomorrow for highlights from Day 2 of the International Cancer Immunotherapy Conference.