This coming weekend is the annual American Association of Cancer Research (AACR) meeting, and I wanted to offer a preview of what to expect. Once again, immunotherapy promises to be a major focus of the meeting, with dozens of presentations and poster sessions devoted to the rapid progress being made in the field. I have my eyes on five major topics:
PD-1/PD-L1 in Triple Negative Breast Cancer
Triple negative breast cancer (TNBC) is one of the most challenging forms of breast cancer to treat. Unlike women with HER2-positive and/or hormone-positive breast cancers, those with TNBC have few treatment options. Neither targeted therapies like Herceptin nor hormone antagonists like Tamoxifen work for their tumors. And immunotherapy vaccines designed to prevent recurrence after surgery are currently available only for patients with HER2-positive tumors.
That’s why recent results showing that TNBC may respond to PD-1/PD-L1 checkpoint inhibitors represent real progress for these patients. Checkpoint inhibitors are drugs that “release the brakes” on immune cells, enabling a stronger attack against cancer. Leisha A. Emens, M.D., of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and colleagues will present results from a phase I trial of the PD-L1 checkpoint inhibitor MPDL3280A, made by Genentech/Roche, in patients with TNBC.
Ipi + Nivo Combo for Melanoma
Two years ago, Cancer Research Institute (CRI) clinical director Jedd Wolchok, M.D., Ph.D., and colleagues stunned audiences at the American Society of Clinical Oncology (ASCO) with results from a phase I trial of a combination of two checkpoint inhibitors (ipilimumab and nivolumab) for patients with advanced melanoma. The combination was far more effective, in more patients, than ipi alone, raising hopes about the power of combinations to greatly improve treatment odds for patients. As of July 2014, nearly 90% of patients treated at the best-responding dose of the combination were still alive two years out. This is compared to about 15% of patients treated with standard chemotherapy who are typically still alive at 2 years.
On Monday, F. Stephen Hodi, M.D., director of Immuno-Oncology at Dana-Farber Cancer Institute and a member of our clinical trials network, will present the results from a phase II trial directly comparing the ipi + nivo combination to ipi alone. Ipi is currently standard-of-care treatment for advanced melanoma. The results of this trial could pave the way for establishing the combination as standard of care for this condition.
Checkpoint Blockade for More Cancers
Checkpoint blockade therapy, developed by James P. Allison, Ph.D., director of CRI's Scientific Advisory Council, has helped to usher in a new era of immunotherapy and generate renewed excitement in the field. The first drug targeting an immune checkpoint, ipilimumab (anti-CTLA-4), was approved by the FDA in 2011 for the treatment of advanced melanoma.
A second immune checkpoint, PD-1, has emerged as an important new target for checkpoint inhibitors. Last year, the PD-1-targeting drugs pembrolizumab, made by Merck, and nivolumab, made by BMS, received FDA approval for the treatment of advanced melanoma that had failed prior therapy. Earlier this year, nivolumab received FDA approval for the treatment of non-small cell lung cancer (NSCLC), making it the first checkpoint inhibitor approved for that indication. The list of cancers that are being treated in clinical trials with anti-PD-1 drugs is long and growing.
One of the latest targets is mesothelioma, a cancer caused principally by asbestos exposure that commonly affects the lining of the lungs and chest wall. Evan W. Alley, M.D., Ph.D., from the Abramson Cancer Center at the University of Pennsylvania and colleagues will present results from a phase I study of pembrolizumab in mesothelioma. Other investigators will also provide up-to-date information on the trial of pembro in NSCLC.
CAR T Cells for Solid Tumors
Some of the most exciting results in immunotherapy in recent years have been obtained with chimeric antigen receptor (CAR) T cells in leukemia. In some studies, greater than 90% of patients have had complete responses to this form of therapy—which involves equipping a patient’s own T cells with an antibody-like receptor that can latch on to a cancer target and destroy it. In the case of acute lymphoblastic leukemia, the target is a cell-surface molecule called CD19, found on all B cells.
Researchers are keen to expand the reach of CAR T cell therapy to other cancer types, beyond B cell leukemias. One potential new target is a molecule called mesothelin, found at low levels on tissues of mesothelial origin, including the pancreas, the outer part of the ovary, and the pleura of the lungs, but overexpressed on cancers of these tissues. Because this protein is strongly associated with cancer—nearly 100% of pancreatic cancers and mesotheliomas, and 70% of ovarian cancers express this protein—yet is not widely expressed elsewhere in the body, it may be possible to target cells bearing this marker without undo toxicity.
A team of investigators at the Perelman School of Medicine at the University of Pennsylvania, including CRI Scientific Advisory Council member and Coley Award-winner Carl H. June, M.D., and Gregory L. Beatty, M.D., Ph.D., will present results of a phase I study of CAR T cells in mesothelin-expressing solid tumors, including pancreatic cancer, epithelial ovarian cancer, and mesothelioma. The principal study aims are to determine safety and feasibility of this technique.
Using Chemotherapy and Immune Stimulation to Create a Cancer Vaccine
Pancreatic cancer remains one of the hardest cancers to treat, and has one of the lowest 5-year survival rates. So far, this cancer type has failed to respond to immunotherapy with checkpoint inhibitors. One possible reason for this failure is that the immune system in pancreatic cancer patients has not mounted an initial attack on the cancer. “Releasing the brakes” on the immune response therefore has no effect because there is nothing to release.
CRI Scientific Advisory Council member Robert H. Vonderheide, M.D., D.Phil., and his colleagues at the Perelman School of Medicine at the University of Pennsylvania, will present results from experiments in laboratory mice showing how treatment with chemotherapy plus an antibody directed at an immune molecule called CD40 may serve as a kind of vaccine that can trigger immune recognition of the cancer. CD40 is found on antigen-presenting cells and is an important lever for activating the immune system. The chemo + CD40 combination has already been tested in clinical trials with pancreatic cancer patients, where it has shown efficacy; this new research helps to dissect the mechanism by which chemotherapy and the immune system cooperate, and also suggests that combining such a ‘vaccine’ with checkpoint inhibitors might have a big therapeutic payload in pancreatic cancer.
Check back here on the CRI blog for updates from the AACR meeting, to be held April 18-22, 2015 in Philadelphia.