Every year for the past 40 years, the Cancer Research Institute (CRI) has given an award to scientists in honor of the late William B. Coley, M.D., considered the Father of Cancer Immunotherapy. It’s become a tradition that the winners of the award give a lecture at CRI’s annual symposium, highlighting the research for which they are being honored. Today at the inaugural International Cancer Immunotherapy Conference we heard from this year’s two winners.
Alexander (Sasha) Rudensky, Ph.D., of Memorial Sloan Kettering Cancer Center, is the 2015 winner of the William B. Coley Award for Distinguished Research in Basic Immunology. In his Coley lecture, Rudensky discussed his lab’s work on the prosaically named but critically important immune cell type called regulatory T cells. Regulatory T cells, aka Tregs, are immune cells that act as lifelong guardians against autoimmunity and excess inflammation. Their main job is to shut down immune responses once a dangerous microbe or cancer cell has been eliminated. Were such immune responses to continue indefinitely, normal tissues would be damaged. Tregs also help to prevent the immune system from generating responses against parts of one’s own body—called autoimmunity. As our immune system develops, most self-reactive immune cells are eliminated through a natural culling process. But the process isn’t perfect, and that’s one of the major reasons why we need healthy, functioning Tregs—to hold the threat of autoimmunity in check and to maintain “tolerance” of our own tissues.
Rudensky’s lab was one of three that, in 2003, showed that a molecular switch called Foxp3 was the main driver of Treg development. Since then, Rudensky’s team has further elucidated how the transcription of Foxp3 is controlled and contributes to the functionality of Tregs. The critical importance of this switch is demonstrated by a naturally occurring genetic disease called IPEX, in which the Foxp3 gene is mutated. People with this condition develop severe, life-threatening autoimmunity. A similar condition, called scurfy, occurs in mice.
While Tregs are important to prevent autoimmunity and restrain excessive inflammation, they can also limit the effectiveness of immunotherapy for cancer. Rudensky’s talk was very timely, since there is much discussion at this conference about the need to eliminate Tregs at the site of a tumor in order to generate an effective anti-tumor immune response with immunotherapy.
The second Coley lecture was given by Glenn Dranoff, M.D., of Novartis and CRI’s Scientific Advisory Council, who is the 2015 recipient of the William B. Coley Award for Distinguished Research in Tumor Immunology. Over his long career, primarily at the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Dranoff has made many important contributions to the field. In his Coley lecture, he gave us a broad overview of his major research preoccupations, which shared an underlying theme. It all goes back to work that he did in the early 1990s on a therapeutic cancer vaccine, which came to be known as GVAX. Back then, Dranoff and his colleagues “stumbled” on the finding that an immune molecule called GM-CSF (granulocyte-macrophage colony stimulating factor) was distinct it its ability to strengthen anti-tumor immunity in mice. It was, Dranoff said, “the most potent molecule of 30+ tested.” The finding drew attention to the role of dendritic cells in tumor immunity because right around this same time Ralph Steinman was showing that GM-CSF was a key growth factor for dendritic cells. These twin observations helped to garner support for immunotherapies, such as GVAX, designed to stimulate antigen presentation by dendritic cells.
GVAX is made by genetically engineering a patient’s tumor cells to make GM-CSF. The cells are then irradiated and injected back into the patient. The idea is that the tumor cells will die, releasing tumor antigens, and the GM-CSF will attract dendritic cells that will take up the tumor antigens and present them to T cells to start an immune response.
In addition to performing the basic research showing the effectiveness of this vaccine in curing mice of cancer, Dranoff was also a key player in the clinical testing of GVAX in humans. A phase I trial was conducted in the late 1990s in patients with metastatic melanoma. Biopsies from patients indicated the vaccine was highly effective at triggering an immune response in the form of T and B cells moving into the tumors. Unfortunately, most patients did not experience lasting therapeutic benefit. That said, as Dranoff points out, a subset of the patients who received the vaccine are still alive and free of disease 20 years later. The vaccine demonstrated “very meaningful clinical benefit in absence of any toxicity. We shouldn’t lose sight of that,” he said.
Since then, much of Dranoff’s work has been focused on understanding what happens in the body when immunotherapies like GVAX work and do not work. Many of his insights are now informing the design of more effective immunotherapies for patients.
Advances in the Clinic
Kicking off the Day 2 plenary sessions was Jedd Wolchok, M.D., Ph.D., a medical oncologist at Memorial Sloan Kettering Cancer Center and director of CRI’s clinical program, who reported on results from ongoing clinical trials of combination checkpoint blockade therapy in patients with advanced melanoma. Wolchok has been one of the principal investigators of such combo trials, which have shown that the combination of two checkpoint inhibitors—ipilimumab (Yervoy®) and nivolumab (Opdivo®)—seems to be more effective than either drug alone (at least for some patients). At ASCO in June, Wolchok presented early results from a large phase III trial of 900 patients treated with either ipilimumab alone, nivolumab alone, or the combination. An interesting finding to emerge from that study is that patients who have higher levels of PD-L1 in their tumors seem to respond equally well to the combo or to nivolumab alone, whereas patients who have lower levels of PD-L1 in their tumors respond better to the combination than to nivolumab alone. What this suggests to Wolchok is that the combination might not be the best choice for every patient; some patients may do just as well with nivolumab administered as a single agent. And since nivolumab alone has much less toxicity than the combination, this is an important consideration. Though the biomarker is not perfect, Wolchok says it does provide doctors and patients with some ability to tailor treatments—a form of precision medicine.
Next up was Ron Levy, M.D., of Stanford University, who presented a fascinating talk on an immunotherapy he calls “in situ vaccination,” which he and others are using to treat patients with lymphoma. In this approach, a molecule called CpG is injected locally into lymphoma tumors along with a checkpoint blockade antibody. CpG is essentially pieces of DNA that mimic DNA from bacteria. The immune system senses the CpG as dangerous and is prodded into mounting an immune attack. By generating an immune response in the immediate context of the tumor, this approach can essentially “trick” the immune system into going after the tumor as well.
Levy presented the case of a 38-year-old man with follicular lymphoma who experienced complete regression of his cancer after local injection of CpG. Importantly, this approach treats not only the tumor at the site of injection; it also is effective at generating a systemic immune response that can kill cancer elsewhere in the body. As Levy said, “inject locally, treat globally.”
Using mouse models, Levy has tested this approach with a variety of different checkpoint antibodies given along with CpG. The one that seems to work best is an antibody directed to OX40, a stimulatory molecule on immune cells. Levy thinks the antibodies are acting to eliminate Tregs in the tumor site, which then permits an immune response to be initiated and spread throughout the body.
Besides vaccines and checkpoint inhibitors, the other approach to immunotherapy that has garnered significant interest is adoptive cell therapy, and in particular an approach called chimeric antigen receptor (CAR) T cell therapy. I have written about the basic mechanics of this approach elsewhere. Here, I’m going to focus on some new results presented today by Carl June, M.D., from the University of Pennsylvania, who is also a member of CRI’s Scientific Advisory Council. June has been using CAR therapy to treat different forms of leukemia. It seems to work best for acute lymphoblastic leukemia (ALL), where response rates reach above 90%, but also is effective against chronic lymphocytic leukemia (CLL), where response rates tend to hover around 60%.
Not all CARs are the same in terms of how they are built, and there seem to be important therapeutic consequences as a result. June has shown that in CLL patients treated with CAR T cells made with a certain internal bit of machinery called a 4-1BB domain can persist in patients for at least 4 years. This is much longer than CARs made with other internal domains, which seem to persist around 30 days. This difference in persistence doesn’t seem to matter much for the treatment of ALL, but for CLL it makes a big difference; it appears to take time for CARs to achieve their therapeutic benefit in CLL and so they need to stick around long enough to do the job. June has found that there is a direct correlation between persistence of the CAR cells and therapeutic response in patients with CLL.
Based on some new laboratory findings, June thinks that one reason that 4-1BB CAR T cells might stick around longer is that they rely on a different type of metabolism than other types of CARs (one that uses mitochondria rather than simple burning of glucose).
There were other highlights of the day, including a roundtable discussion of regulatory issues facing the development of CAR therapies, and several talks devoted to cross talk between immune cells and tumor cells in the tumor microenvironment, but I have to get dressed for a CRI banquet honoring excellence in scientific, philanthropic, and business efforts to advance cancer immunotherapy research, so I can’t report on them now!
Check back tomorrow for highlights from Day 3 of the inaugural International Cancer Immunotherapy Conference.