Suzanne Topalian

Suzanne Topalian

Suzanne Topalian, M.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, is a pioneer in the search for biomarkers that predict responses to immunotherapy.

In April at the American Association for Cancer Research meeting in New Orleans, Topalian and her colleagues presented data linking a virus-associated cancer, called Merkel cell carcinoma - to response to one type of anti-PD-1 therapy.

In a new, preliminary study, Topalian takes a closer look at kidney cancer and immunotherapy. The kidneys are metabolic organs -- the filters of the body -- that control how nutrients are absorbed and waste is eliminated.

Up to 30 percent of patients with kidney cancer may respond to immunotherapy drugs that target the PD-1 and PD-L1 pathway, but scientists do not know why the majority of patients don't respond, says Topalian.

In the nine among 13 kidney cancers that did not respond to anti-PD-1 therapies, the expression of 110 genes involved in cell metabolism went into overdrive. One gene, called UGT1A6, had particularly high expression, found the researchers. It controls how some cells in the body get rid of toxins.

With these results, the researchers are asking: could tumors use this pathway to rid themselves of toxins, such as medicines and other chemical substances, thereby making the tumor cells more "fit" to keep up their hide-and-seek game with the immune system?

"This is a retrospective study in a limited number of patients, but we think it's a good start in exploring immunotherapy resistance," says Topalian.

In further research, Topalian and her colleagues will investigate the role of UGT1A6 and other metabolic genes in cancer cells and whether their results can be confirmed in larger groups of patients.

Read more: Topalian discusses advances in immunotherapy and the search for new biomarkers of response.

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Charles Drake

Charles Drake

So-called anti-PD-1 drugs, which block the interaction between proteins on cancer and immune cells, are currently approved by the Food and Drug Administration for certain patients with melanoma and non-small cell lung, kidney and bladder cancers. Now, a new study led by scientists at Oregon Health & Science University's Knight Cancer Institute and partially funded by the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, has given clinicians hope that some prostate cancer patients may respond to the anti-PD-1 drugs.

In a preliminary report on a clinical trial, 10 patients with advanced prostate cancer that had become resistant to a common hormone therapy called enzalutamide were treated with the PD-1 blocking drug pembrolizumab.  Of these patients, three experienced substantial reductions in their levels of prostate specific antigen (PSA), a marker of treatment response, from 46, 71 and 2503 ng/ml to less than 0.1 ng/ml. Two of the three patients also experienced tumor shrinkage of at least 50 percent of their total tumor volume – i.e. “partial responses.”

The three patients remain progression-free at 30, 55 and 16 weeks of follow up. The rest of the patients had stable disease or did not benefit from the treatment. One patient died of his prostate cancer. Adverse events included hypothyroidism in two patients and muscle inflammation in one subject.

Although it remains to be seen whether anti-PD-therapy has an effect on survival in prostate cancer, immunology expert Charles Drake, M.D., Ph.D., an associate director of the Bloomberg-Kimmel Institute, says that this type of treatment response is not the norm for prostate cancer patients whose disease has progressed after hormone therapy.

“Prior to these data, there was consensus that PD-1 blockade was ineffective for these patients, but this may change the way we think about immunotherapy and prostate cancer,” says Drake. Going forward, additional prostate cancer patients will be enrolled in the ongoing study, and several related studies are being planned.

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Stefanie Joho

Stefanie Joho

Stefanie Joho, 25, had been given a death sentence. Diagnosed with advanced colon cancer, she traveled to cancer centers around the U.S. in search of a therapy that could buy her time. She found it at the Johns Hopkins Kimmel Cancer Center -- the result of a combination of recent scientific advances in immunotherapy and a genetic discovery from 30 years earlier. Today, she received her last treatment, known as anti-PD-1 therapy, which breaks down barriers to the immune system's ability to recognize cancer cells. Johns Hopkins investigators at the Bloomberg-Kimmel Institute for Cancer Immunotherapy played a leading role in the clinical development of PD-1 blockade/anti-PD-1 therapy and the scientific studies to develop biomarkers for response to the therapy. Hopkins scientists also have led pioneering work in understanding the PD-1 pathway and how the therapy works. There is still plenty of ongoing research on these therapies, particularly on why they don't work for everyone, and much of the research is initiated and led by Johns Hopkins investigators. But Joho, who was days from dying from what would be considered an incurable colon cancer, is now in complete remission.

**Note: Stefanie participated in a clinical trial funded by the Swim Across America. In September, she'll join other Baltimore swimmers in the Swim Across America event to benefit cancer research at the Johns Hopkins Kimmel Cancer Center. Learn more about the event and the research.

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Radiation oncologist Russell K. Hales, M.D. of the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus notes that clinical trials are treatments that are usually done at cancer centers with researchers, like Hopkins. “Clinical trials take an existing therapy, and add to it an investigational therapy, or give an investigational therapy altogether,” he says.

What are the advantages in each choice?
• The standard of care is the standard treatment that you should receive, anywhere across the world that you're treated.
• Clinical trials take discovery that's been found in the lab, or in smaller clinical trials, and apply it to a group of patients. Often, clinical trials can give a patient an opportunity to have a therapy that they otherwise wouldn’t be able to get, that may one day become the clinical standard of care.

Clinical trials also benefit the field at large, by helping the patient to-to be a participant in innovation, in lung cancer care. Hales notes that “We are at the heart of innovation in cancer treatment, because of patients that have gone before, and have been a part of clinical trials. This is the way that we transform cancer care. If you are choosing between the standard of care, versus the clinical trial, it really comes down to the individual clinical trial. I want to reassure you that no clinical trial is done without much data gathering beforehand, to show that there's promise in the therapy that's being tried. Clinical trials are always a good option, but they need to be taken on a case by case basis.”

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An antibody drug that targets part of the bone growth pathway can slow the growth of human osteosarcoma implanted in mice and prevent the tumor from spreading to other parts of the body, according to a study led by Johns Hopkins Kimmel Cancer Center scientists.

David Loeb

David Loeb

Osteosarcoma is one of the most common bone tumors affecting children and adolescents. It is usually treated with surgery and chemotherapy, but the disease spreads in between 25 and 40 percent of patients, and 75 percent of those patients will die of their disease.

These survival rates remain “mostly unchanged” since the 1980s, making it important to uncover new therapeutic options, says David M. Loeb, M.D., Ph.D., an associate professor of oncology and pediatrics and director of the Musculoskeletal Tumor Program at the Kimmel Cancer Center.

As Loeb and colleagues reported earlier this year in Oncotarget, the antibody targets a molecule called DKK-1, which may promote tumor growth in osteosarcoma. DKK-1 blocks part of the Wnt molecular signaling pathway that is key to normal bone development.

Loeb and colleagues implanted tumors grown from human osteosarcoma cells into mice and were able to detect human DKK-1 circulating in the blood shortly afterward. The higher the levels of DKK-1, the faster the tumors grew in the mice, the researchers found. When DKK-1 levels in the mice were high, during the first six weeks of tumor growth, tumors increased in volume at a rate of almost 1 percent every three days, while the rate later slowed to .35 percent when DKK-1 levels were low.

When the mice were treated with a DKK-1 antibody, their human DKK-1 levels became undetectable, and they experienced a substantial slowdown in tumor growth — a .47 percent volume increase every three days, compared to a .95 percent increase in untreated mice.

The researchers then studied the antibody’s effects on metastasis using a mouse model that Loeb and his colleagues developed to more closely mimic osteosarcoma treatment in young patients. They implanted the tumor in a leg bone in the mice, waited for the tumor to grow before doing surgery or amputation to remove the tumor, and then watched to see if the cancer would metastasize.

Only one of 24 mice treated with the DKK-1 antibody developed metastatic disease, compared to six of 18 mice that did not receive the antibody. The one mouse that developed a metastasis appeared to have a local recurrence of its cancer, suggesting that the original surgery to remove the tumor was not completely successful.

“The major limitation to treating patients with osteosarcoma is prevention of metastasis, and I think our major finding is that in the mice who had a good surgery — meaning no local relapse — none of the [antibody]-treated animals developed metastasis,” says Loeb. “I would want to give this to patients early on in their treatment but continue throughout treatment and even up to a year after chemotherapy ended to maximize our chance of preventing metastasis.”

The antibody drug used in the study, called BHQ880 and manufactured by Novartis, also has been tested in clinical trials for the treatment of multiple myeloma. Novartis has discontinued the drug, but Loeb says that comparable antibody drugs could be developed.

It is also possible, Loeb says, that there may be other therapeutic targets to be discovered within the Wnt signaling pathway. “I think we’ve only scratched the surface in terms of understanding how Wnt signaling affects osteosarcoma,” he says.

Other scientists who contributed to the research include Johns Hopkins researchers Seth D. Goldstein, Wendy Bautista Guzman and Masanori Hayashi and Matteo Trucco of the University of Miami Sylvester Cancer Center.

Funding for the study was provided by the National Cancer Institute (1R01CA138212-01, 2P30CA006973), the Pablove Foundation and the Giant Food Children’s Cancer Research Fund.

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“Many lung cancers are not treated with one therapy alone,” says Russell K. Hales, M.D. “Sometimes it takes all three treatments—surgery, radiation, and chemotherapy-- to fully treat the lung cancer. And patients may be anxious after a surgery, about waiting in recovery for other treatments like chemotherapy and radiation.”

Hales, who is a radiation oncologist at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus, says, “Our goal is to start therapy as quickly as we can, but starting the therapy too quickly after surgery will just result in an unnecessary delay. If a patient starts therapy too quickly after surgery, they may not have fully recovered or healed. Then we may find a month into the next therapy that we need to put it on hold, so that they can recover. There's a balance that has to be maintained between recovering from surgery, and trying to start that therapy as quickly as possible,” he notes.

“At Hopkins, the window we usually use for that time of recovery is somewhere between three and seven weeks, after surgery. But that's going to be individualized, based on how well a patient recovers from surgery,” Hales says.

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The two main categories of lung cancer are small-cell lung cancer, and non-small-cell lung cancer, says Russell K. Hales, M.D. “Non-small cell lung cancer is further divided into adenocarcinoma, and squamous cell carcinoma.

“All lung cancer is aggressive, but all cancer in its early stages can be treated, and patients can have long term control of their disease,” says Hales, a radiation oncologist at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus. He notes that patients with small cell lung cancer are more likely to have disease that spreads outside of the lung, and although their tumors respond better to therapy, they're more likely to grow back.

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“It's not just smoking that leads to lung cancer,” says Russell K. Hales, M.D. “ We know that environmental exposures and underlying lung disease can increase the likelihood of lung cancer. Unfortunately, in patients with restrictive lung disease, we don't have any information to show that screening those patients will increase the likelihood of finding something.”

Hales, who is a radiation oncologist at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus, notes, “When people have other risk factors, like family members who have died from lung cancer, or those who have underlying lung problems, we still evaluate them in our pulmonary nodule clinic. On a clinical protocol, we can see if there's a benefit to being screened.” He recommends consulting with a pulmonologist at Hopkins to talk about next steps. Call 410-955-LUNG to set up a consultation.

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“Not everything that arises in the lung is cancer,” says Russell K. Hales, M.D., a radiation oncologist, at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus. “A nodule in the lung can be from infection, irritation, or inflammation. It can be from other diseases, unrelated to cancer at all.”

Hales notes that a ground glass opacity is a radiologist's characterization of how something may look on the scan. “It’s almost as if you were to describe a car as a red car. Well, that tells us it's red, but it doesn't tell us what type of car it is,” he says. Many factors go into determining how likely the opacity is to be cancer, including the size of the lesion, or whether it's growing.

“At the Hopkins Kimmel Cancer Center, we evaluate carefully whether a ground glass opacity is cancerous or not,” Hales notes. “We have a solitary pulmonary nodule clinic to evaluate patients with ground glass opacities. If you're a patient who was recently told you have something like this, you can certainly call 410-955-LUNG, so that we can specifically evaluate the ground glass opacity that you may have.”

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Eric Raabe

Eric Raabe

A rare cell line developed by Johns Hopkins researchers is giving scientists their first chance in decades to test new therapies for a lethal pediatric brain cancer that has few treatments.

Kimmel Cancer Center scientist Eric H. Raabe, M.D., Ph.D., helped to develop the diffuse intrinsic pontine glioma (DIPG) cell line, grown from tumor tissue donated by parents whose children died from the cancer. In two studies, Raabe and his colleagues used this DIPG cell line and others to identify the drug panobinostat (Farydak), along with an experimental inhibitor drug called MRK003, as possible treatments for DIPG.

In their report published online last May in the journal Nature Medicine, the researchers tested the impact of 83 different potential drugs on 16 DIPG cell lines, including the one developed at Johns Hopkins. They found that panobinostat was the most effective compound against the cancer cells, significantly shrinking DIPG tumors in five mice. The tumors were 6.5-fold larger in untreated mice, compared with tumors in mice treated with a single dose of panobinostat.

Panobinostat has been approved for use in some adult cancers, and Raabe said that plans for a phase 1 clinical trial to test the drug’s safety in children are now underway, thanks to the promising results of the Nature Medicine study.

DIPG, which accounts for about 10 percent of all pediatric brain tumors, is usually diagnosed between the ages of 5 and 10. The cancer is invasive and infiltrates itself among healthy cells in the brainstem, making surgical removal impossible. Patients receive radiation to treat their symptoms, but most live only six months to two years after their diagnosis.

Because the cancer is located in the brainstem, the part of the brain that controls breathing and heart rate, the tumor is rarely biopsied, and for a long time scientists had no living cell lines with which to test treatments.

“But there was a big change that happened about five years ago, when families began to advocate and ask what they could do to help learn more about DIPG,” Raabe explained. Some families began giving permission for their children to undergo “rapid autopsies,” which removed some of the tumor tissue within six hours of the children’s deaths.

The generosity of these parents helped Raabe and others at Johns Hopkins grow one of the first and most robust DIPG cell lines, giving researchers an opportunity to explore the molecular makeup of DIPG and to grow DIPG-like tumors in mice.

“Before this, we were shooting in the dark, and we had no models with which to test drugs until the last three or four years. With these cell lines, we’re part of a group that decided to try something different,” Raabe said. “And we went in a few years from having no drugs with any activity against DIPG to having a drug like panobinostat that at least in tissue culture and mouse models appears to have activity against DIPG.”

In a second study published in the Journal of Neuropathology and Experimental Neurology, Raabe and colleagues tested compounds that block the NOTCH molecular pathway in DIPG cells, since these tumors have been shown to have high levels of NOTCH pathway proteins. They found that an inhibitor compound called MRK003 shrank the number of DIPG cells by 75 percent over seven days of treatment, stopping the cells’ proliferation and triggering cell death. By combining MRK003 with radiation treatment, the researchers were able to boost the percentage of cell death in one DIPG line to 16.6 percent, compared with just 6 percent in cells treated with radiation alone.

Raabe said that it will important to explore the possibilities of both panobinostat and NOTCH inhibitors, since each type of drug comes with its own advantages. For instance, MRK003 can be targeted to brain tissue, but it’s unclear yet whether panobinostat can reach brain tissue as well. And while researchers wait for safety trials of panobinostat in children, “the phase 1 clinical study for NOTCH inhibitors has already been done in children, so we have a dose that we know,” Raabe noted.

Raabe added that none of this research—and the studies yet to come—would have been possible without the parents of DIPG patients making a difficult decision to donate tumor tissue. “The cell lines from these autopsies, and the amount of information that we have learned about DIPG in the last five or so years is remarkable, and it’s all due to the generosity of the families during very difficult times, and their consideration for the next generation of patients with DIPG.”

Other researchers on the Nature Medicine study include Catherine S. Grasso, Michael J. Quist, Nicholas Wang, Paul T. Spellman, Lara E. Davis, Elaine C. Huang, Charles Keller, Jinu Abraham, and Matthew N. Svalina of Oregon Health & Science University; Yujie Tang, Lining Liu, Pamelyn J. Woo, Anitha Ponnuswami, Spenser Chen, Tessa B. Johung, Michelle Monje, and Wenchao Sun of Stanford University; Nathalene Truffaux, Marie-Anne Debily, Ludivine Le Dret, and Jacques Grill of CNRS; Noah E Berlow and Ranadip Pal of Texas Tech University; Mari Kogiso, Yuchen Du, Lin Qi, Yulun Huang, Hua Mao, and Xiao-Nan Li of Baylor College of Medicine; Marianne Hütt-Cabezas of Johns Hopkins University; Katherine E. Warren, Paul S. Meltzer, and Martha Quezado of National Cancer Institute; Dannis G. van Vuurden and Esther Hulleman of VU University Medical Center, Amsterdam; Maryam Fouladi of Cincinnati Children’s Hospital Medical Center; Cynthia Hawkins of University of Toronto; Javad Nazarian at Children’s National Health Systems; and Marta M. Alonso of University Hospital of Navarra.

Scientists who contributed to the Journal of Neuropathology study include Kimmel Cancer Center scientists Isabella C. Taylor, Marianne Hütt-Cabezas, William D. Brandt, and Charles G. Eberhart; Madhuri Kambhampati and Javad Nazarian of George Washington University School of Medicine and Health Sciences; Howard T. Chang of Michigan State University; and Katherine E. Warren of the National Cancer Institute.

The research was supported by the Matthew Larson Foundation; the National Cancer Institute (P30 CA006973); Lyla Nsouli Foundation, the Children’s Oncology Group (COG) Central Nervous System Committee, the DIPG Collaborative (The Cure Starts Now Foundation, Reflections of Grace Foundation, Smiles for Sophie Foundation, Cancer-Free Kids Foundation, Carly’s Crusade Foundation, Jeffrey Thomas Hayden Foundation, Soar with Grace Foundation), the Accelerate Brain Cancer Cures Foundation (ABC2), CureSearch for Childhood Cancer, the Team Julian Foundation and the COG Chair’s Grant (5UOCA098543), the National Institutes of Health (K08NS070926), Alex’s Lemonade Stand Foundation, the McKenna Claire Foundation, the Connor Johnson Memorial Fund, the Dylan Jewett Memorial Fund, the Elizabeth Stein Memorial Fund, the Dylan Frick Memorial Fund, the Abigail Jensen Memorial Fund, the Zoey Ganesh Memorial Fund, the Wayland Villars DIPG Foundation, the Jennifer Kranz Memorial Fund, Unravel Pediatric Cancer, the Virginia & D.K. Ludwig Fund for Cancer Research, the Price Family Charitable Fund, the Godfrey Family Fund in Memory of Fiona Penelope, the Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, Etoile de Martin, Fondation Lemos and Le Défi de Fortunée, the Scott Carter Foundation, the Semmy Foundation, the Department of Defense, National Science Foundation (CCF0953366), Marie Curie grant (IRG270459), the Spanish Ministry of Health grant (PI13/0125), and the St. Baldrick’s Foundation and Iron Matt Foundation.

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