Issue No. 2013
Date: January 3, 2013
Commonwealth Cancer Summit
The Commonwealth Foundation for Cancer Research, under the direction of Board Chairman William Goodwin, has been a leading supporter of translational, bench-to-bedside research at the Kimmel Cancer Center. After a review of research being conducted at cancer centers throughout the country, Goodwin and the Commonwealth Foundation identified the Kimmel Cancer Center and the Memorial Sloan Kettering Cancer Center as hotbeds of meaningful research that could be quickly applied to patient care. Investigators from both centers came together last summer for a cancer summit to discuss opportunities for collaboration.
Promising personalized cancer detection and treatment approaches inspired by Commonwealth funding include new tests for cancer and vaccines and other cancer-fighting immune strategies.
Clinical Biomarker Tests for Cancer
The Kimmel Cancer Center has become an incredible engine for biomarker discovery and for developing tests and platforms to evaluate and assess their benefit. Central to this is a new clinical sequencing laboratory focused on translating genetic and epigenetic research and findings into clinical tests that will guide cancer diagnosis, risk stratification, and therapy. Clinical experts, laboratory medicine experts, and genomics experts are working together to figure out how to move this science and technology forward.
Investigators believe that extremes in patient responses to the same therapy could be rooted in alterations in the cancer genome and epigenome. Using sequencing technology to compare the genetic and epigenetic characteristics of cancers that responded well to a treatment to those that did not, could reveal important new predictive biomarkers to differentiate patients who are likely to respond to a particular treatment from those patients who will not. The collaborative team of clinicians and investigators will apply the technology and method to two cancer types per year to develop an individualized treatment approach that can be studied and validated in large, multi-institutional studies.
The team has already begun studies of prostate cancer, ovarian cancer, and pancreas cancer to identify the changes that cause treatment resistance specific to each cancer as well as those that translate to better outcomes. The researchers believe that if they can decipher the molecular characteristics that make a seemingly aggressive and lethal cancer have a long-lasting response to treatment, they can potentially use drug interventions to convert less responsive tumors and make them more amenable to treatment. These biomarkers could then be used to guide personalized cancer medicine, getting the right treatments to the right patients.
Provoking an Immune Response to Cancer
Kimmel Cancer Center cancer immunology experts have had breakthrough discoveries related to an immune inhibitory checkpoint called PD-1. It is co-opted by tumors to shut down an immune response to cancer cells. Two clinical trials that used antibodies to block PD-1 and PD-L1, a related molecule that binds to PD-1, resulted in significant and long lasting responses against melanoma skin cancer, renal cell (kidney) cancer, and lung cancer. The findings in lung cancer were particularly significant it was not thought to be an immune responsive cancer. Experts say it demonstrates that, with the correct approach, essentially all cancers could be made vulnerable to immune attacks.
This research adds to the growing body of evidence that immune system is not passively tolerant to cancer but that cancer cells actively hijack immune pathways to acquire immune resistance. A tumor recognizing it is under attack by immune cells, up regulates PD-L1 to shut down the immune response. Conversely, in their studies tumors that did not engage PD-L1 did not respond to treatment. The finding opens the door to using PD-L1 as a predictive biomarker for identifying patients who will respond to anti-PD-1 therapies, but also as a target for combined treatments in patients whose tumors do not express PD-L1. Vaccines or other immune-targeted approaches could potentially be used to activate PD-L1 and prime them for subsequent anti-PD-1 treatment. The lung cancer studies, revealed potential synergy with epigenetic-targeted treatments and anti-PD-1 therapy.
The anti-PD-1 success has revealed a need for better ways to monitor these cancers. PD-1 targeted cancers are characterized by progression before regressing. Imaging scans, such as CT, for this type of therapy do not tell investigators what they need to know. Researchers are exploring the possibility of tests that measure tumor DNA in the blood to quantitatively analyze if the treatment is working.
These findings have inspired new collaborations funded by the Commonwealth Foundation and Stand Up to Cancer. Investigators believe that PD-1 is just the tip of the iceberg and that there are 10 to 15 immune additional checkpoints that are coordinately and differentially expressed in tumors. They are all potentially targetable with antibodies, molecular profiles of the tumors could be used to reveal these checkpoints and guide treatment.
Novel Methods of Cancer Detection
The research team that deciphered the genetic blueprints for cancer is using their findings to develop clinical tests performed on routinely collected biological fluids, including plasma, sputum, stool, and urine, to detect cancers in an early and curable stage and to monitor the effectiveness of targeted treatments in existing cancers. The tests in development are specific to cancer, have a low rate of false positives, are cost effective, and high throughput so they can rapidly process large quantities of DNA and information and be used routinely. The investigators envision such tests, which identify the unique genetic and epigenetic changes that define cancer, becoming part of a person’s regular physical.
These changes are almost always present in early cancers, but the challenge is advancing the sensitivity of the tests to detect a minute amount of cancer DNA circulating within a sea of normal cells. Almost all of these changes are present before a cancer spreads, and they are not simply associated with cancer, as PSA (Prostate Specific Antigen) and other markers currently used for cancer detection, they are the cause and driver of cancer growth and progression. The greatest success has been achieved in tests for colon cancer and ovarian cancer. Other cancers, such as brain cancers, are proving more difficult. The research team is working with cancer clinicians to determine the best medium—i.e., plasma, stool, etc.—best suited to the detection of each specific cancer. Once the tests are perfected they can be used to monitor people at increased risk of developing cancer.
Personalized Cell Therapy
Bone marrow transplant and blood and bone marrow cancer experts have developed a personalized treatment approach that uses patients’ own immune cells to fight their cancer. It focuses on a type of tumor-specific T-cells. For cancers of the blood, these cells, known as marrow infiltrating lymphocytes or MILs, are found in the bone marrow where the cancer originates.
In their normal capacity, the cells are inactive and somewhat small in number so they have little effect against the cancer, but our experts are using a clinical concept known as adoptive T-cell therapy, in which they retrieve a patient’s own MILs from his or her bone marrow, grow the cells in a specialized laboratory to expand their numbers and then return them to the patient where they seek out and destroy cancer cells. The Kimmel Cancer is one of a few cancer centers in the U.S. that perform adoptive T-cell therapy, and, it is the only one using MILs. Currently, the therapy is being studied in multiple myeloma, an incurable cancer of the blood plasma cells, but research indicates that this personalized cell therapy would be beneficial in treating a variety of blood and bone marrow cancers and likely solid tumors as well. Cell therapy is also being explored in other medical disciplines, including cardiology.
In multiple myeloma, MILs cell therapy is used in conjunction with bone marrow transplant to prime antitumor immune response and improve the effectiveness of the transplant. Our experts believe this therapy will improve the duration of responses and may one day replace the need for any additional treatment.
Personalized Pancreas Cancer Vaccines
Cancer immunology experts continue to optimize the effects of the pioneering pancreas cancer vaccine they developed more than a decade ago. New work includes the use of peptides to individualize vaccines to the unique molecular characteristics of each patient’s cancer and, as a result, improve their response against pancreas cancer.
Peptides are the building blocks of proteins and are a “table of contents” of sorts displayed on the cell surface to reflect the internal molecular structure of the cell. Vaccines could use peptides to prime immune cells to recognize when something is not right within a cell, as in cancer. Researchers are studying whether identifying peptides that mark each patient’s specific tumor cells and incorporating them in the pancreas cancer vaccine could boost the immune response against cancer cells.
Other work includes use of multiple vaccinations to maintain long-term immune activity against tumor cells.
The team’s ultimate goal is to combine cancer vaccines that target the individual genetic alterations within the patient’s cancer cell with immune modulating agents that maximize the immune response against the cancer.
Optimist International Helping to Unlock the Mysteries of Pediatric Cancer
Optimist International has been a vital partner to Johns Hopkins Pediatric Oncology in its fight against childhood cancer. A $1 million legacy endowment has helped our clinician-scientists realize breakthrough discoveries. The success of this partnership is best reflected in the lives of the many children who have benefitted from innovative therapies developed by our Optimist Fellows. For the first time in the history of cancer medicine, the technology exists to quickly decipher the cellular causes of every cancer. Kimmel Cancer Center researchers have pioneered the science that has led us here and were the first to crack the genetic code of a pediatric cancer.What we have learned is now allowing our scientists to target the very biological mechanisms that cause a cancer to grow and spread. With these discoveries, they can begin to alter the course of pediatric cancers in ways that could only imagined a decade ago.
Optimist International has generously made an additional commitment to make sure we get there. The Optimist International Innovative Research Fund will allow us to significantly expand our clinical and research programs in childhood leukemia, pediatric brain tumors, sarcomas and other solid tumors, and bone marrow transplantation.
Brian Ladle, M.D., is the 2012 Optimist Fellow at Johns Hopkins. His research focuses on immunotherapy and novel new therapies that trigger the body's own immune system to recognize and attack cancer cells, just as they do bacteria, viruses, and other foreign invaders. Since cancer cells arise from normal cells, they most often go undetected by the immune system, but Johns Hopkins investigators have been on the cutting edge deciphering the mechanisms by which immune cells are activated, and plan to apply this new knowledge to innovative therapeutics. The immune system, much like cancer, is quite complex. Applying immunology to cancer patients is more difficult still as their immune systems have already been compromised by the drugs used to treat cancer. Dr. Ladle will be working with other senior investigators to uncover chinks in the immune system’s armor that will allow them to turn off the defense mechanism of tumors and ramp up the immune system’s attack against them.
Preventing Breast Cancer
The John Fetting Fund for Breast Cancer Prevention
“Our goal should be to do more than cure breast cancer. We must prevent it,” John Fetting told a group of women who came to the Kimmel Cancer Center to learn about the John Fetting Fund for Breast Cancer Prevention. Fetting, a breast cancer clinician for more than three decades believes that recent research breakthroughs about the biology of breast cancer can now be applied to prevent it from occurring at all.
“Over the course of my career, I’ve seen substantial progress made against breast cancer, and I’m very gratified by that,” says Fetting. “Screening mammography has led to earlier diagnosis, and treatments have become more effective, so more patients are surviving and living full lives. Still, I think we can do better. With the same kind of concerted effort that has been mounted to cure breast cancer, we can prevent it from ever occurring.”
One in nine women will be diagnosed with breast cancer in her lifetime. As a breast cancer survivor, Leslie Ries has a firsthand appreciation of the statistics. “Advances in treatment options are not enough. We have to try to protect ourselves, our children, and others from getting this disease,” says Ries who helped to establish the Fetting Fund with her husband Tom to allow laboratory discoveries to be translated into prevention strategies. To date, with the help of Lorraine and Mark Schapiro and many others, nearly $1 million has been raised toward the cause.
Fetting says that discoveries made at the Kimmel Cancer Center that reveal the genetic (mutations to DNA) and epigenetic (nonmutational alterations to DNA) changes that cause breast cancer can be used to better distinguish those women at risk for breast cancer so that clinicians can intervene early before the cancer can cause her harm. At the same time, this information can also reveal women who will not get breast cancer, so clinicians can steer screening and detection resources away from them and to the women who truly will benefit. One in nine women will be diagnosed with breast cancer, says Fetting. “That means one will get breast cancer, but eight will not. We need to advance our science so that we can identify “the one” and intervene to prevent her breast cancer. We also need to use this science to identify and reassure the eight who will not,” he says. “A normal cell does not become a breast cancer overnight,” says Fetting. “It happens over many years. In the future, we could use fine need aspiration to sample breast tissue to look for this genetic and epigenetic signature of breast cancer and figure out who has these changes and who does not.”
Kimmel Cancer Center breast cancer experts are examining several ways to interfere with the biological changes that set breast cancer in motion. Breast cancer experts are investigating the protective effects of certain natural chemicals found in fruits and vegetables and figuring out how best to deliver them to individuals. They also are studying ways to halt the molecular and cellular changes that trigger breast cancer with drugs that reactivate key tumor suppressor genes that had been turned off through epigenetic alterations.
Leading cancer experts agree that prevention is one of the best ways to manage cancer risk, however, it is an area of cancer research that is currently underfunded. “The Fetting Fund will support this type of work so that we can begin to replace fear with hope,” says Ries, “because we all deserve a future without breast cancer.”
For more information on the Fetting Fund for Breast Cancer Prevention or to make a contribution, contact Dina Klicos at 410-516-4203 or firstname.lastname@example.org
Swim Across America Making Waves to Fight Cancer
Over the last three years, the Swim Across America (SAA) Baltimore event has raised more than $1 million for the Kimmel Cancer Center creating the Swim Across America Laboratory at Johns Hopkins directed by gastrointestinal cancer physician-scientist Luis Diaz, M.D. The money is helping Diaz and his team develop gene-based tests that can detect cancer, monitor its progression, and pinpoint the best treatments. “We have made a lot of progress with the Swim Across America donations. We are applying it to research against cancers that are hard to treat and where there are currently no standard therapies that are curative,” says Diaz. “This support makes it possible for us to take the best ideas and bring them to patients.”
Swim Across America funds also support a number of patient-directed initiatives including new clinical trials for targeting pancreatic cancer and advanced colon cancer; a survivorship clinic for colon cancer patients who have finished treatment; and a special three-day couples retreat for colon cancer patients with advanced disease and their caregivers.
Hundreds of swimmers took to the water at Meadowbrook Aquatic Center in Baltimore and the Waltjen-Shedlick Farm near Gibson Island on September 23 for the 2012 event. As in the previous two years, a number of current and former Olympic swimmers joined the pool and open water events including Brad Snyder and Ian Silverman (both gold medalists at the 2012 London Paralympics), Craig Beardsley, Brenda Bartlett, Wendy Weil and Tara Kirk Sell. During their time in Baltimore they also stopped by the Kimmel Cancer Center to visit children with cancer and their families.
This year’s event also included a special tribute to Alec Cosgarea. Seventeen-year-old Alec was a world-class swimmer and Swim Across America veteran who organized “angel swimmers” matching accomplished swimmers like himself with novice participants as companions for the open water swim. Tragically, Alec was killed just months before the event in an automobile accident, but his spirit was an unmistakable and powerful part of the day’s event. Many thousands of dollars were raised in his memory, and SAA Baltimore established the Alec Cosgarea Award for the top fund raiser under 18 years old. “Alec was all about caring for other people,” said Eric Posegay, high performance coach at Meadowbrook. Alec’s father Andy Cosgarea, a Johns Hopkins orthopedic surgeon, took his son’s place in the water, and his younger brother Will organized this year’s “angel swimmers.”
Alec’s legacy contributed to the palpable sense of community that defined the day as people from all around Baltimore and surrounding areas joined together for a common cause. As 11-year-old friends Harry and Brook, students at the Highlands School in Bel Air demonstrated, it is a cause that touches virtually everyone, young and old. Harry and Brook were joined by many other Baltimore area students who took to the water for SAA. Harry swam in memory of his grandmother and Brook for her Godmother. Diaz also was among the swimmers. “I am so proud of Baltimore. The support of our community is not only motivating to the clinicians and researchers but to patients as well,” says Diaz. “It means a lot to them to know their community is behind them.
An Example of Where SAA Money Goes
Unmasking Cancer’s Hidden Defenses
It is perhaps the most challenging and frustrating aspect of cancer therapy, for doctors and patients alike. A treatment works; the cancer shrinks, and then suddenly the treatment is no longer effective, and the cancer returns with a vengeance. New findings from Swim Across America and Ludwig Center researchers have begun to unravel what happens within the cancer cell to cause its resistance to treatment. In fact, their research finds, the origins of the cancer treatment resistance were hidden in the cancer cell all along.
Personalized therapies involve drugs that target specific gene alterations within a patient’s cancer. Clinicians decide which drugs will work against the cancer based on the alterations they find inside the cells’ DNA.
Cancer is generally characterized by a combination of tumor cell-suppressing genes being turned off and growth-promoting oncogenes getting turned on. Each person’s cancer has a unique combination of these molecular mistakes contained within the sequestered DNA of the cancer cell. This genetic fingerprint helps determine which drugs are likely to work against the cancer and which ones will not.
When a treatment does not work, resistance mutations are often the cause. A cancer cell is, after all, a normal cell that has errantly acquired genetic traits that allow it to grow immortally and uncontrollably. Resistance mutations occur among these alterations and they add up over time as cancer cells divide and grow. “Tumors always contain thousands of resistance cells,” says Luis Diaz, director of the Kimmel Cancer Center Swim Across America Laboratory. The more advanced a cancer is, the more resistance alterations it acquires, giving the cells that contain them a greater chance to survive treatment.
Diaz worked with leading cancer genetics researchers Bert Vogelstein and Kenneth Kinzler, codirectors of the Ludwig Center for Cancer Genetics and Therapeutics, to better decipher and understand the molecular origins of targeted therapy resistance.
The team analyzed blood samples from 28 patients with advanced colorectal cancer who were being treated with a drug that targets an important tumor cell growth pathway known as EGFR. Patients most likely to respond to the targeted agent have normal copies of the cell-growth-promoting oncogene known as KRAS. Among the study group, only four patients tested positive for mutations of the KRAS gene. Researchers would not expect them to respond to the treatment, but the remaining 24 should have benefited. So why have so many of these patients relapsed? The answer, Diaz, Vogelstein, and Kinzler found, was there all along. The resistance mutations were already there. They were simply undetectable until the tumor grew.
As cancer cells multiply, they shed DNA into the blood and reveal the genetic mutations contained in the cell. The more cancer cells there are, the more DNA that is shed. Diaz, Vogelstein, and Kinzler have lead the world in developing blood and other tests that pluck this obscured DNA from within a sea of normal cells. They used this technology to periodically look for cancer DNA in simple blood samples obtained from the patients. Five to seven months into treatment, their test revealed that nine of the patients who began treatment with normal KRAS genes, now had KRAS mutations. This molecular evidence foretold that the cancers would continue to grown even before the advancing disease could be detected in imaging scans, but when did these mutations occur?
The team called upon the mathematical expertise of Harvard University colleague Martin Nowak who developed a mathematical model to date these alterations. He found that KRAS mutations were present, just undetectable, before the patients even began their targeted treatment. Although the studies were in colon cancer, Vogelstein says the findings likely apply to all targeted therapies. “This means that the development of drug resistance with single-agent targeted therapies is a fait accompli,” Vogelstein concluded. “Long-term remissions of advanced cancers will be nearly impossible with single targeted agents.” It’s really just a matter of when they will recur. That, he says, simply depends on how long it takes cancer cells with the mutant genes to multiply.”
This latest research adds to the building body of evidence that metastatic cancers will be nearly impossible to control. The ideal opportunity to cure cancer lies in detecting it early when tumors are small and have fewer resistance genes or can be removed with surgery.
Multi-drug and method combinations that simultaneously attack a variety of genetic cancer drivers or reactivate silenced tumor suppressor genes are a better option, and Vogelstein is calling for a change in how the cancer world conducts early clinical trials whose participants are almost always patients with advanced cancers. “Since we know that single agents will not have long-term success, we need to start testing new drugs as combination therapies much earlier,” he says. “There are a limited number of gene signaling pathways that go awry in cancer, so it should be possible to develop a small number of agents that can be used in a large number of patients.”
In addition, Director William Nelson, wants to begin using the Kimmel Cancer Center’s clear edge in cancer genetics discovery and application to develop screening tests that would detect cancers when they are very new and before they cause any symptoms. “We need to move away from a system in which we see patients for the first time when they begin experiencing symptoms to one that detect, manages, and eradicates cancers before people even know they have them,” says Nelson.
“Imagine, for example, if we could find cancers early enough that we could burn them off much like we do with a wart,” says Nelson. “I think this is within the realm of possibility, and I think our Center is uniquely positioned to make it happen.” He points to colonoscopy. It is a screening test that, when performed correctly, detects precancerous polyps in the colon that can be removed during the screening to prevent a colon cancer from ever occurring. “We need similar types of strategies for all cancers,” says Nelson.
Once these techniques are developed, the challenge then is not to overdetect and overtreat cancers, and this is where he again believes Kimmel Cancer Center science can inform. The same molecular genetic information that is being used to personalize cancer treatments can be used to personalize cancer screening and detection. Rather than a one-size-fits-all, Nelson says the frequency and intervals of cancer screening can be determined by looking at the cellular cues. It will point us toward abnormal cells, like polyps, but also tell us which ones need attention and which ones can be left alone. The end result, says Nelson, is that that we will not only improve cancer outcomes, but also reduce the adverse affects that come with overscreening and overtreating. He says, “We will be able to preserve health by preventing cancer, very accurately predict who will get cancer, and personalize treatments to get the right treatments to patients who need them and spare those who will not benefit.”
The research described in this article was published in the June 13, 2012, issue of Nature and funded by the Virginia and D.K. Ludwig Fund for Cancer Research, The National Colorectal Cancer Research Alliance, Swim Across America, and the National Institutes of Health grants CA43460, CA57345, CA62924, N01-CN-43309, and CA006973. Bert Vogelstein, M.D., is the Clayton Professor of Oncology and a Howard Hughes Medical Institute Investigator.
Richard Zellars, M.D., associate professor of radiation oncology, and Dina George Lansey, M.S.N, R.N, O.C.N., Research Associate and Clinical Recruitment Specialist, are heading the Kimmel Cancer Center’s initiative to increase minority accrual to clinical trials. Zellars has been appointed Assistant Director for Clinical Trial Accrual and will develop and oversee initiatives to increase accrual to therapeutic clinical trials with a special emphasis on minority accrual. He will continue his academic and clinical positions as a breast and gynecologic cancer radiation oncologist. Lansey, who has extensive experience as both an outpatient clinic nurse and clinical trials research nurse has helped direct efforts to improve clinical trials communication, continuity of care, and data management.
Overcoming cultural and institutional barriers and increasing minority participation in clinical trials is a priority of the Kimmel Cancer Center, and Zellars and Lansey have a longstanding interest in addressing racial disparities in cancer. Zellars created and co-leads CUPID (Cancer in Under-Privileged Indigent or Disadvantaged), a summer training fellowship aimed at attracting to the specialty oncology medical students who have a demonstrated interest in caring for poor and underserved minority populations