Perspectives from those who live it everyday.

Immunotherapy has become one of the hottest areas of cancer research, and the number of cancers successfully treated by immunotherapy is growing. Nearing the end of 2016, there are now four FDA-approved immunotherapy drugs that target immune system checkpoints to treat six types of cancer.

We asked Drew Pardoll, M.D., Ph.D., director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, to review this year’s research findings that have made a significant impact on this field.

Pardoll’s picks for the top five research findings are:

1. Virus-associated skin cancer responds to immunotherapy.
   Results of a study published in April and presented at the American Association for Cancer Research annual meeting gave oncologists the first hints that “a new category of cancer may be highly responsive to immunotherapy,” says Pardoll. The study, led by the Fred Hutchinson Cancer Research Center and Johns Hopkins’ Bloomberg~Kimmel Institute, showed that half of 25 patients with Merkel cell carcinoma, a rare, virus-linked skin cancer, had major tumor shrinkage and outperformed conventional chemotherapy. Pardoll says that worldwide, more than 20 percent of cancers are associated with viruses, and scientists are studying such cancers for their response to immunotherapy.
2. Immunotherapy replaces chemo as first-line weapon against lung cancer.
   The FDA approved two immunotherapy drugs as a second course of treatment for patients with lung cancer who do not respond to chemotherapy. Then, a study published in November, led by researchers at the Johns Hopkins Bloomberg~Kimmel Institute and other scientists, showed that lung cancer patients taking the immunotherapy drug pembrolizumab as first-line therapy fared much better than those who took chemo. Pardoll says that the study was a “dramatic demonstration” that so-called PD-L1 proteins are a biomarker for response to the therapy. Results from this study led the FDA to approve pembrolizumab as the first treatment for patients with lung cancer whose tumors express PD-L1 proteins.
3. Safety Trials of Immunotherapy for Early Lung Cancer Pass “Go.”
   At an international cancer meeting in October, researchers from the Johns Hopkins Bloomberg~Kimmel Institute presented early data in a small number of patients with lung cancer that giving the immunotherapy drug nivolumab before their surgery to remove the cancer is safe and feasible. At the time of surgery, 40 percent of patients had over 90 percent regression of their tumor associated with influx of killer T cells. “Immunotherapy could potentially work inside the early-stage tumor as a vaccine that activates T cells, which can circulate through the body and attack residual deposits of cancer, ultimately causing relapse after surgery,” says Pardoll.
4. When Immunotherapy Doesn’t Work, Researchers Ask Why.
   Despite response rates of between 20 to 50 percent in certain groups of patients, scientists still don’t know why the majority of people with cancer don’t respond to immunotherapy drugs. Some of the first clues to immunotherapy resistance are beginning to unravel. This month, a team of researchers led by UCLA, including those at the Bloomberg~Kimmel Institute, published results in Cancer Discovery that point to mutations in genes called JAK1 and JAK2 in a small number of patients. The genes produce receptors that glom onto an immune system-signaling product called interferon gamma, which is made by T cells when they spot a cancer cell. When mutations disrupt the production of JAK1 or JAK2, the signaling system fails to rouse the immune system’s attack on cancer cells. Additional research is being done to see if more patients who are resistant to immunotherapy have these and other mutations that influence the immune system.
5. Oncologists need more education on how to spot immunotherapy side effects early.
   No drug is immune from side effects, and immunotherapy is no different. Oncologists are sharing their knowledge of immunotherapy’s side effects and how to combat them at medical meetings and educational seminars. A recent story in The New York Times highlights some of the drugs’ known side effects, including rare cases of diabetes, inflammatory arthritis and even death. Kimmel Cancer Center oncologist Julie Brahmer, M.D. speaks at medical meetings about recognizing immunotherapy-related side effects. In a panel discussion during The Washington Post’s Chasing Cancer summit, Pardoll said that oncologists “need to go back to school” to learn about a different set of toxicities than what they are used to managing with chemotherapy. “We know that when clinicians spot and treat toxicities early, most of the effects can be mitigated before they get serious,” says Pardoll. He adds that oncologists also need to educate patients receiving immunotherapy about symptoms that should prompt an immediate call to the doctor.

Looking forward, Pardoll says that emerging basic science research and clinical trials are demonstrating how to block multiple immune checkpoints simultaneously. Immunologists also are studying ways to develop therapies that target the metabolism of the immune system, thereby strengthening tumor-killing activity. The final frontier, he says, may be in gaining more understanding about how the microbiome or microorganisms, such as bacteria, influence tumors. Overall, he says, 2016 has been a “good year” for immunotherapy.

Watch a video introduction to immunotherapy.

In a head-to-head comparison between the immunotherapy drug pembrolizumab and standard chemotherapy as a first-line therapy for advanced nonsmall cell lung cancer, patients taking pembrolizumab had a 50 percent greater drop in the risk of death or disease progression and a four-month greater increase in progression-free survival compared with those who took chemotherapy.

Julie Brahmer

A report on these findings of an international clinical trial of 305 patients with stage 4 nonsmall cell lung cancer appeared Oct. 9 in The New England Journal of Medicine and is noted in today's Washington Post. What made the trial significant and novel, say the researchers, is that it included only people whose tumor cells were abundantly studded with so-called PD-L1 proteins.

“This is a group of patients we think should get anti-PD-1 therapy first before chemotherapy,” says Julie Brahmer, M.D., director of the Thoracic Oncology Program at the Johns Hopkins Kimmel Cancer Center co-director of the Upper Aerodigestive Program of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. Pembrolizumab and another immunotherapy drug, nivolumab, are approved by the Food and Drug Administration to treat patients with advanced nonsmall cell lung cancer, but only after their cancers have progressed after treatment with chemotherapy.

Pembrolizumab, which is sold under the trade name Keytruda, blocks a molecular “handshake” between immune system T cells and cancer cells carrying PD-L1 proteins on their surface. With no handshake, T cells target the cancer cells for destruction.

Brahmer, who led the trial with a group of international scientists, says that another study showed little difference in progression-free survival of patients with nonsmall cell lung cancer who took a different PD-1 inhibitor compared with chemotherapy. “That study included nonsmall lung cancer patients with any level of PD-L1 protein on their tumors, but this study included only those with high levels of PD-L1 proteins on their tumor cells, whose tumors are more likely to respond,” says Brahmer. Some 23 to 28 percent of patients with advanced nonsmall cell lung cancer have high levels of PD-L1 proteins on their tumor cells. Nonsmall cell lung cancer accounts for more than 80 percent of an estimated 220,000 lung cancers diagnosed annually in the U.S.

For the study, funded by Merck, which makes pembrolizumab, tumor biopsy samples from 1,729 patients from 142 hospitals worldwide were evaluated by the researchers to determine which of them had more than 50 percent of tumor cells marked with PD-L1 proteins. From that group, 305 patients were randomly chosen to receive 35 intravenous doses of pembrolizumab over more than two years versus the standard treatment of four to six cycles over six months of one of five types of chemotherapy.

Among the two groups, 154 patients who received pembrolizumab had a median progression-free survival rate of 10.3 months, compared with six months for 151 patients on chemotherapy. Median follow-up was 11.2 months. The researchers estimated that patients who took pembrolizumab were 50 percent less likely to die from their cancer or have disease progression over the duration of the trial, which began in 2014. “Extending the time we can keep these patients’ cancer under control is an important step in creating more long-term survival,” says Brahmer.

The trial was stopped early because researchers’ interim analysis revealed the pembrolizumab’s benefit on progression-free survival. As a result, 66 patients who had received chemotherapy were switched to pembrolizumab, and more than half of them were still taking the drug at the end of the trial.

During the study, 108 patients died. One of the patients died after taking pembrolizumab potentially associated with that treatment, and three deaths were potentially caused by chemotherapy. The most common side effects in patients taking pembrolizumab were diarrhea, fatigue and fever. In patients taking chemotherapy, common side effects were anemia, nausea and fatigue.

“This study shows that immunotherapy can benefit some patients early on in their treatment, and our hope is that when we determine the best combinations of immunotherapy and targeted anticancer drugs, these patients may never need chemotherapy,” says Brahmer.

In her practice, Brahmer says treatment options for patients whose cancer progresses after taking pembrolizumab include clinical trials using combinations of immunotherapy drugs as well as chemotherapy.

Pembrolizumab’s cost can reach more than $100,000 annually for each patient, and Brahmer says her goal is to determine which groups of patients are more likely to benefit from it by itself. Plans are underway, she says, to study more closely the drug’s effectiveness in lung cancer patients whose cancers have lower levels of PD-L1 proteins.

Funding and materials for the study described in this press release were provided by Merck. Dr. Brahmer is also a paid consultant to Merck. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

Researchers who contributed to the study include Martin Reck from the German Center for Lung Research; Delvys Rodriguez-Abreu from the Hospital Universitario Insular de Gran Canaria; Andrew Robinson from the Cancer Centre of Southeastern Ontario; Rina Hui from Westmead Hospital and the University of Sydney; Tibor Csoszi from the Jasz-Nagykun-Szolnok County Hospital; Andrea Fulop from Orszagos Koraanyi TBC es Pulmonologiai Intezet; Maya Gottfried from the Meir Medical Center; Nir Peled from the Davidoff Cancer Center; Ali Tafreshi from the Southern Medical Day Care Centre; Sinead Cuffe from the St. James’ Hospital and Cancer Trials Ireland; Mary O’Brien from the Royal Marsden Hospital; Suman Rao from MedStar Franklin Square Hospital; Katsuyuki Hotta from Okayama University Hospital; and Melanie Leiby, Gregory Lubiniecki, Yue Shentu and Reshma Rangwala from Merck.

The University of Chicago and Johns Hopkins' Bloomberg~Kimmel Institute for Cancer Immunotherapy  have published a pair of studies looking at biomarkers involved in the immune system's response to tumors in the Nov. 7 issue of the Proceedings of the National Academy of Sciences.

The University of Chicago studies are explained here.

Janis Taube

For the Johns Hopkins research, scientists studied 3500 tumor samples among nine cancer types recorded in The Cancer Genome Atlas to analyze five biomarkers of immune activity within tumors. They include: whether the microenvironment within a tumor is inflamed, the number of mutations present in tumor cells, and expression levels of immune-system related proteins called PD-1, PD-L1, and PD-L2, which can be coordinately expressed in the environment surrounding a tumor to ward off an immune system attack.

"Scientists have been looking at these markers independently, but we wanted to know how

they relate to each other and which was most influential in patients' survival," says Janis Taube, M.D., associate professor of dermatology and pathology at the Johns Hopkins University School of Medicine and member of the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Taube and her team found that all five factors were important in predicting survival of patients with metastatic melanoma.  Four of the factors — PD-1, PD-L1, PD-L2 and inflammation — have very tight links, they say, and their research suggests that when expression levels of these factors are high, they are more important in predicting patients’ survival than the amount of mutations present in the tumor.  However, when these factors are low, mutational load plays an important role in predicting survival.

"This is an important step in understanding how to develop multifactorial-biomarkers for predicting patient outcomes," says Taube.