T-cells attacking a tumor cell

A decade ago, Suzanne Topalian, M.D., led a team of researchers who made an astonishing contribution to how cancer is fought. Many cancers can “put the brakes” on the body’s immune cells — cells that would normally storm into a tumor and destroy it. Topalian, director of the Melanoma Program at the Johns Hopkins Kimmel Cancer Center and associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, and others developed a class of drugs called immune checkpoint blockers, which take the brakes off the immune system and give it a chance to fight back against cancer.

“Now, every oncologist is engaged in immunotherapy. These drugs are becoming a common denominator for cancer therapy,” Topalian says.

But as the drugs are approved for more types of cancer and used by more patients, oncologists still have questions they want to answer about cancer immunotherapy, says Topalian.

Which patients will respond best? Scientists are in the midst of a huge hunt for biomarkers — which can be anything from genetic mutations to proteins sampled from tissue or blood — that can help them determine which patients are most likely to benefit from immunotherapies, such as checkpoint blockers. There are some cancer treatments that target single genetic mutations, “but immunotherapy biomarkers are a bit more complex than that” and could involve a number of genes and proteins, Topalian says.

Johns Hopkins researchers have played leading roles in searching for these biomarkers, she says. For instance, in 2015, a team of Johns Hopkins oncologists found genetic biomarkers that identified a small group of colon cancer patients who responded well to a checkpoint blocker. “We need more sensitive and more specific markers like this to help us learn which patients are most likely to do well with these treatments,” says Topalian.

Can we combine immunotherapy with other treatments? “We know from lab studies that some of these checkpoint blocker therapies are potent, but they’re even more powerful when you combine them with other drugs,” Topalian notes.

Numerous clinical trials at Johns Hopkins and elsewhere are testing these combinations, whether adding a standard therapy, like radiation or chemotherapy, to a checkpoint blocker or combining an immunotherapy drug that lifts the brakes from the immune system with another drug that revs up the immune system. In some trials, Topalian says, both of the drugs could be still be experimental, “which is a new frontier for drug development.” The hope, she says, is that drug combinations that contain some kind of immunotherapy could extend the success of these drugs in difficult-to-treat cancers, like metastatic pancreatic, prostate, and head and neck cancers.

Can we improve how we deliver cancer immunotherapies? For the moment, checkpoint blockers are given to patients intravenously every two to three weeks during an hourlong treatment. But Topalian says scientists are studying whether this is really the best way to give these drugs, or if there might be a way to deliver them as a pill or in a form that requires less frequent clinic visits.

As more patients begin to benefit from these drugs, she notes, “We’re also doing active research to find out how long we can or should keep administering these drugs to patients, whether it’s months or years or indefinitely.”

What more can we tell patients about these treatments? “I think people are fairly well-informed about this, but it’s important to remember that this is a different kind of therapy because it doesn’t directly kill tumor cells,” Topalian explains. “This therapy treats the immune system, and then the immune system attacks cancer cells.”

Patients may worry about side effects from immunotherapy, especially whether the treatment will cause their immune systems to attack normal, healthy tissue. “Most of the side effects that we see are mild and managed fairly easily,” such as fatigue or rashes, says Topalian.

Topalian also wants patients to know that the work on immunotherapies — even ones that are already being used to treat cancer — never stops. “We study these drugs in patients and then in the lab and then back again to better understand how they are working,” she says. “For patients with cancer, I think there’s more reason than ever to be hopeful.”


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*The information in this blog post is based on the webinar, “Understanding Cancer-related Cognitive Impairment,” hosted by the Kimmel Cancer Center's Breast Cancer Program.

Q: What can I do to improve my cognition during and after cancer treatment?

A: Use areas of cognitive strength to compensate for any weaknesses, advises Tracy Vannorsdall, PhD, a neuropsychologist at Johns Hopkins in the Division of Medical Psychology. “You may have to do things a bit differently, and it takes work to create new habits,” she says. “Make things a habit whenever you can -- research shows habits are more deeply ingrained and resilient than telling yourself to remember things.”

For example, she says, leave your keys, cell phone and wallet by your front door. Have a routine every night to get ready for the next day so you don’t have to stop and think things through. Vannorsdall also recommends the following tips:

1. Pay attention and become an active listener. Remind yourself to pay attention; stop every few minutes when listening to someone talk or to a lecture and notice if your mind has wandered. If you meet someone new, say their name to yourself five times and use it when you say good-bye. When taking notes, take them in your own words and process them so you’re encoding them deeply. Make new information as rich as possible – think in multiple senses and think of where you were when you learned something new.

“Learning and memory is like a file drawer,” Vannorsdall says. “You really have to attend to what is going in and organize it so you can pull out the information you need later.”

2. Give your memory a rest. Use memory aids – take notes, use index cards to write things down, create detailed calendars, use smartphone applications/apps, take photos or leave yourself voice messages. Become an active reader using the PQ4R method: preview the material, ask yourself questions, read it, reflect on it, recite answers to your questions, review what you’ve just done. Review your day before falling asleep at night. Memories become stronger and more permanent when you pull them up and review.

3. Set yourself up for success. “Multitasking is difficult,” Vannorsdall says. “Limit yourself to one activity at a time. Make a list of what you want to do or break down the steps in a large task, pick one task, and work on and complete it before moving on.” Minimize distractions -- get materials together, work in a quiet area or use a white noise machine, turn off alarms for email or social media; and give yourself plenty of time. Take breaks as needed so you stay fresh.

4. Stay mentally active. There is no one magic activity but diversity and novelty are important. Do new things to keep your brain healthy. “Like with physical exercise, where your body acclimates and needs to be pushed harder, our brains adjust, too,” Vannorsdall says. Socialize, play card games, take a class, do puzzles, or go for walks in new neighborhoods.

5. Eat a healthy diet and exercise. Walking and low-impact exercise like yoga, Qigong, and Tai Chi have been shown to improve thinking speed, memory, executive functioning, and improvement in quality of life in as little as one month, Vannorsdall says. Exercise can also decrease fatigue and improve stress.

6. Get good sleep. “Fatigue is a major issue in those being treated for cancer,” Vannorsdall says. “It’s closely tied to one’s degree of distress.” There is good evidence that memories are consolidated during sleep, and adults need six hours of natural sleep to make stable memories. Sleep medications can interfere with natural sleep patterns, she says. Keep a regular schedule for meals, medications, and exercise. Avoid naps, caffeine after lunch and alcohol within six hours of bedtime. Don’t smoke before bed or be too hungry or too full. Avoid strenuous exercise before bed. Establish rituals to help you relax each night, and don’t go to bed unless you are sleepy. Keep your bedroom quiet, dark and cool.

7. Learn how to manage stress. Cancer treatment can be stressful, between a person’s reaction to the diagnosis, managing treatment challenges and its impact on work and family life, Vannorsdall says. Deep breathing exercises or progressive muscle relaxation can help.

8. Pursue treatment. Some patients benefit from psychotherapy or supportive counseling, medications, or formal cognitive rehabilitation programs, where you attend a session once or twice a week and learn tools to use at home. Start a diary or log to track your cognitive problems – When do they occur? In what settings? This can give you a sense of when you do well or when you need additional help, Vannorsdall says.


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More than 20 years ago, when Johns Hopkins scientists Bert Vogelstein, Ken Kinzler and their colleagues linked certain cancers to mutations in genes that repair DNA, they may not have imagined that their findings would spark an idea that has become a crystal ball for predicting whether immunotherapy is more likely to work in a person with cancer.

The idea, featured in the American Society of Clinical Oncology's Clinical Advances 2017, began four years ago at a meeting between Vogelstein and scientists at the Bloomberg~Kimmel Institute for Cancer Immunotherapy to figure out why a single patient with colon cancer had responded to an immunotherapy drug and 15 others with colon cancer had not. What was different in that single patient? The scientists had a hunch that tumor cells in the lone responder had more mutations than those of the other patients. More mutations trigger the production of more abnormal proteins, which appear foreign to the immune system. These mutation-ridden tumor cells are more visible to the immune system than tumors with fewer mutations, and immunotherapy may be much more likely to work in these patients.

The hunch paid off, and when the scientists sequenced the patient's tumor, they found mutations in a set of genes, called "mismatch repair," which work to mend DNA mistakes. Bloomberg~Kimmel Institute scientists organized a clinical trial of patients with and without mismatch repair mutations and presented and published initial results in 2015. The trial was expanded and more results were presented in 2016 showing high response rates to the immunotherapy drug pembrolizumab among patients with many types of cancer who carry mismatch repair mutations. Bloomberg~Kimmel Institute experts estimate that 20,000 new patients who carry mismatch repair mutations are diagnosed each year in the U.S.

One of those patients is Stefanie Joho. Given a death sentence and no hope, Stefanie came to Johns Hopkins looking for a therapy that could buy her time. She enrolled in the Bloomberg~Kimmel Institute clinical trial and is now in complete remission. Listen to Stefanie's experience with immunotherapy:


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On a block of vacant row homes near the Johns Hopkins Medicine campus in East Baltimore, the Ulman Cancer Fund is building an 8,000 square-foot residence for young adults being treated for cancer. It will serve as a "home away from home" for people 15 to 39 who come from a distance to be treated at either the Kimmel Cancer Center or University of Maryland Greenebaum Cancer Center. Kenneth Cooke, M.D., director of bone marrow transplant at the Kimmel Cancer Center says, "it will be a place where our patients can rest and re-energize; where they can educate, motivate and support one another; where they can laugh and cry without batting the eye of a passerby; where they can shout out in anger or in joy; where they can celebrate or be comforted."

Kimmel Cancer Center patient Karen Sollenberger spoke at the groundbreaking event for the Ulman Fund's new residence and was featured in an interview with WBAL-TV. The Baltimore Sun also reported on the new residence, featuring comments from Dr. Cooke.

Listen to Dr. Cooke speak about issues facing young adults with cancer:


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AACR Cancer Screening Guidelines WebinarWhat cancer screenings do I need and when? If this answer isn't clear to you, listen to Kimmel Cancer Center director William Nelson moderate a webinar on "Making Sense of Cancer Screening Guidelines," hosted by the American Association for Cancer Research and Cancer Today magazine. Nelson and his co-panelists will summarize the guidelines and provide their perspectives so that you can make informed choices with your doctor. Register today at

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The Johns Hopkins Greenberg Bladder Cancer Institute recently announced a joint effort with the Bladder Cancer Advocacy Network (BCAN) to fund up to two awards totaling $100,000 for young scientists. As part of the announcement, the Institute's director, David McConkey, Ph.D., gave us his thoughts on recent bladder cancer advances and ongoing research.

Recent advances, says McConkey, include the FDA approval of the immunotherapy drug atezolizumab for bladder cancer patients whose disease worsens after receiving chemotherapy. Scientists have recently charted the genomic characteristics of some rare bladder tumors, in addition to muscle-invasive and nonmuscle-invasive bladder cancers. Such characterization helps create a genomic blueprint of these cancers to help pathologists more easily identify them. The blueprints, says McConkey, also give scientists clues to the behavior of certain tumors, sorting out which ones may be more aggressive and need different therapies.

McConkey says that bladder cancer scientists also are working to identify genetic characteristics of patients who may be cured by chemotherapy alone, potentially avoiding surgery to remove the bladder. He expects that other immunotherapy drugs that work through the same mechanisms as atezolizumab may soon be approved by the FDA to treat bladder cancer, and scientists are looking for genetic or molecular characteristics of patients more likely to respond to them.



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Victor Velculescu

Victor Velculescu, M.D., Ph.D.

Nearly 19,000 de-identified genomic records from cancer patients treated by an international group of hospitals, including the Johns Hopkins Kimmel Cancer Center, have been collected in a database coordinated by the American Association for Cancer Research (AACR) and are now available to scientists across the globe.

The data was gathered from the genomic sequencing of thousands of patients’ tumor samples, including 59 cancer types. The clinical-grade genomics data included in the database focuses on a targeted set of genes typically used to diagnose the cancers or provide additional information to help doctors prescribe treatments, an indication of the high quality of the data.

In addition to the openly-available genomics data, scientists can apply to AACR to receive more in-depth clinical information about patients’ tumors, such as survival data and treatment regimens.

“We want other scientists to use this information to pursue their own scientific studies about cancer,” says Victor Velculescu, M.D., Ph.D., co-director of the cancer biology program at the Johns Hopkins Kimmel Cancer Center and member of AACR’s steering committee on its Project GENIE (Genomics, Evidence, Neoplasia, Information, Exchange).

Velculescu says scientists could use to the data to find subgroups of patients with particular mutations to determine their response to certain anti-cancer drugs. The vast amount of data in AACR Project GENIE and large numbers of patients enables this type of needle-in-the-haystack research, he says.

Each institution contributing to AACR Project GENIE will continue to add data, and the effort aims to add more hospitals to its network.

Johns Hopkins Kimmel Cancer Center collaborators on AACR Project GENIE include Alexander Baras, M.D., Ph.D., Christopher Gocke, M.D., and Ben Park, M.D., Ph.D.

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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.

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A ceremony was held yesterday at the White House to sign the 21st Century Cures Act, which authorizes $4.8 billion in National Institutes of Health funding for a broad range of biomedical initiatives, including cancer and precision medicine. Immunotherapy patient Stefani Joho [watch a video of Stefani's story] and Dr. Elizabeth Jaffee, deputy director of the Johns Hopkins Kimmel Cancer Center, co-chair of the Blue Ribbon Panel of advisers for Vice President Joe Biden’s Cancer Moonshot Initiative and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, attended the signing ceremony. The “Cures” Act provides funding for the Moonshot initiative, which is now named for Joe Biden’s late son, Beau, who died of cancer. “This is a national effort with broad bipartisan support during a time when new technologies are revolutionizing medical science,” says Jaffee.


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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.

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