National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 21, 2012 • Volume 9 / Number 4

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BREAKING NEWS

FDA Acts to Bolster Supply of Critical Cancer Drugs

The U.S. Food and Drug Administration today announced steps to increase the supply of critically needed cancer drugs. For more information, see the FDA Press Announcement.

NEWS

Routine Lynch Syndrome Screening Varies at U.S. Cancer Centers

An enzyme encircles the double helix to repair a broken strand of DNA (Illustration by Tom Ellenberger, Washington Univesrity School of Medicine) Screening practices for a condition called Lynch syndrome, which increases the risk of colorectal, endometrial, and other cancers, appear to vary substantially among different clinical centers in the United States, according to a new study.

Clinical guidelines developed by several different groups recommend routinely screening tumor samples from patients newly diagnosed with colorectal cancer for genetic markers of Lynch syndrome, although they differ with respect to exactly which patients should be screened. 

The study was published online today in the Journal of Clinical Oncology. Read more > >

IN DEPTH

UPDATES

  • Notes

    • National Cancer Advisory Board to Meet Next Week
    • Director's Consumer Liaison Group to Discuss Drug Shortages, Advocate Engagement
    • New Clinical Trials Portal and Apps Available

Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

Routine Lynch Syndrome Screening Varies at U.S. Cancer Centers

An enzyme encircles the double helix to repair a broken strand of DNA (Illustration by Tom Ellenberger, Washington University School of Medicine)An enzyme encircles the double helix to repair a broken strand of DNA. Without molecules that can mend such breaks, cells can become cancerous. Mutations in genes that regulate this DNA repair system are a hallmark of Lynch syndrome. (Illustration by Tom Ellenberger, Washington University School of Medicine)

Screening practices for a condition called Lynch syndrome, which increases the risk of colorectal, endometrial, and other cancers, appear to vary substantially among different clinical centers in the United States, according to a new study.

Clinical guidelines developed by several different groups recommend routinely screening tumor samples from patients newly diagnosed with colorectal cancer for genetic markers of Lynch syndrome, although they differ with respect to exactly which patients should be screened (see Table). In the study—published online February 20 in the Journal of Clinical Oncology, and the first to attempt to assess current screening practices for the condition—only 42 percent of the responding centers reported that they conducted any routine screening for Lynch syndrome. Another 16 percent reported that they planned to do so.

NCI-designated comprehensive cancer centers—most of which are large academic medical centers that provide clinical cancer care and perform basic and clinical research—were far more likely than smaller hospitals and community cancer programs to perform this testing, the study showed.

In conducting the NCI-supported study, researchers from the City of Hope Cancer Center and Ohio State University Comprehensive Cancer Center surveyed all 39 NCI-designated comprehensive cancer centers that provide adult oncology care, a random selection of hospital-based cancer centers accredited by the American College of Surgeons, and a randon selection of community-based cancer programs. Of the 24 NCI-designated comprehensive cancer centers that responded to the survey, 71 percent reported that they routinely screened tumor samples from colorectal cancer patients, known as reflex testing. By comparison, only 15 percent of smaller community-based cancer programs reported doing so.

"Like any new practice, routine screening for Lynch syndrome will take time to be widely adopted," said the study's senior author, Dr. Deborah MacDonald of the Division of Clinical Cancer Genetics at City of Hope. "I think it's becoming more common, but it's clearly something that providers and institutions need to become more educated about."

Identifying All at Risk

Also known as hereditary non-polyposis colon cancer, Lynch syndrome is caused by mutations in several genes involved in a DNA repair process called mismatch repair (MMR, see video). The familial syndrome accounts for 2 to 4 percent of colorectal cancer cases; these and other Lynch syndrome-related cancers typically occur in people aged 50 and younger. (See the related article in this issue.)

Identifying Lynch syndrome-related cancers is important for multiple reasons, said Drs. MacDonald and Laura Beamer, the study's lead author. A diagnosis of Lynch syndrome can influence how much of the colon is removed during surgery, and women may opt for a hysterectomy, as well as removal of the ovaries, to reduce the risk of Lynch syndrome-related endometrial and ovarian cancers.

The larger impact, said Dr. Michael Hall, director of the Gastrointestinal Risk Assessment Program at Fox Chase Cancer Center in Philadelphia, may be on post-treatment surveillance for Lynch syndrome-related cancers, and on patients' close family members, who have up to a 50 percent chance of having the condition and may require more intense cancer screening than the general population.

"That's a critical point," said Dr. Hall. "This screening process allows us to identify many more people with an increased cancer risk."

A Complex Undertaking

Testing typically involves one or two different methods—DNA microsatellite instability (MSI) testing and immunohistochemistry (IHC) testing—to identify molecular changes that suggest MMR gene mutations. If these tests detect abnormalities, DNA mutational analyses are typically done to determine whether MMR gene mutations are present.

Just as clinical guidelines differ with respect to exactly which patients should be screened for Lynch syndrome, cancer centers—even the largest centers—differ in how they approach screening, the study found.

Some responding comprehensive cancer centers used the IHC test only, others used the MSI test only, and some used both. At City of Hope, tumor samples from all newly diagnosed patients younger than 60 are screened using the IHC test, with MSI testing performed as well in certain circumstances. At Ohio State, which has been at the forefront of Lynch syndrome screening, all newly diagnosed cases of colorectal cancer, regardless of the patient's age, have been screened using the IHC test since 2006.

"I do anticipate that things will become more uniform in the future as additional studies help elucidate the best, most cost-effective screening protocol," said study co-author Heather Hampel of the Clinical Cancer Genetics Program at Ohio State.

Regardless of a center's size, establishing a process for Lynch syndrome reflex testing is a complicated undertaking, and the process may take a year or longer, noted Dr. Hall. Decisions must be made about how samples will be tested and how positive screening results are communicated to patients. Not surprisingly, smaller centers, which often have fewer resources for laboratory testing or genetic counseling, can have more difficulty establishing a screening program.

And even when reflex testing is performed, there is no guarantee that the intended result, identifying people with Lynch syndrome, will be achieved, Dr. Hall stressed. "A big part of it is how many patients actually come in and get genetic counseling and have the genetic test performed," he said. In a 2009 Ohio State study, for instance, only about one-quarter of patients with suspected Lynch syndrome based on IHC testing made an appointment with a genetic counselor to follow up on the findings.

In an effort to improve the study and establishment of universal screening programs, Ms. Hampel and representatives from three other institutions recently launched the Lynch Syndrome Screening Network. Network leaders have developed a database to anonymously track screening outcomes, as well as educational materials for cancer programs trying to initiate universal screening, Ms. Hampel said.

Clinical Guidelines on Screening for Lynch Syndrome

GuidelinesDateNotes
Revised Bethesda Guidelines2004Developed as a result of NCI-sponsored workshops
Evaluation of Genomic Applications in Practice and Prevention2009Recommendations from Centers for Disease Control and Prevention working group
National Comprehensive Cancer Network Guidelines on Colorectal Cancer Screening2011Free registration required

 

—Carmen Phillips

Cancer Research Highlights

Contrary to Evidence, Some Doctors Recommend Ovarian Cancer Screening

One in three doctors believes that screening for ovarian cancer is effective, according to a recently published survey of practicing physicians, even though substantial evidence to the contrary exists. The findings, published February 7 in the Annals of Internal Medicine, suggest that some women may be exposed to the risks of screening, such as unnecessary surgeries and procedures that result from false-positive tests, and may incur unnecessary costs.

No professional organization supports ovarian cancer screening, regardless of a woman’s risk. Moreover, the U.S. Preventive Services Task Force has recommended against routine screening for ovarian cancer since 2004, and more evidence against screening for ovarian cancer emerged last year. Transvaginal ultrasound, the CA-125 blood test, or both are used to screen for ovarian cancer.

In the new study, family physicians, general internists, and obstetrician-gynecologists answered a questionnaire that included a vignette about a woman’s annual examination. Overall, 65 percent reported that they “sometimes” or “almost always” offered or ordered ovarian cancer screening tests for medium-risk women, and 29 percent did so for low-risk women. Moreover, 24 percent routinely (almost always) ordered or offered tests for medium-risk women, and 6 percent did so even for low-risk women. Physicians were more likely to report that they ordered screening tests when the patient in the vignette requested it.

“These findings are cause for concern, given that the risks of ovarian cancer screening outweigh the benefits,” said lead investigator Dr. Laura-Mae Baldwin of the University of Washington. “Sometimes physicians are enthusiastic about cancer screening before the [scientific] evidence shows that the benefits outweigh the risks.”

As with all surveys, this study included potential sources of bias, noted Dr. Barnett Kramer, director of NCI’s Division of Cancer Prevention and editor-in-chief of the NCI Physician Data Query (PDQ) Screening and Prevention Editorial Board. Nonetheless, he echoed concerns about how often doctors do not follow current screening recommendations and the “prevalence of faith in the effectiveness of screening.”

“A substantial proportion of the health professionals who responded to the survey may have been unaware that the only randomized controlled trial of ovarian cancer screening, published last year, showed no reduction in risk of dying from ovarian cancer in the general population,” Dr. Kramer wrote in an e-mail. “But the study did show harms associated with screening.”

The survey, he continued, shows the need for “enhanced educational efforts for the professional community regarding what is known about the balance of benefits and harms associated with ovarian cancer screening.”

Lynch Syndrome Tied to Increased Risk of Breast and Pancreatic Cancers

The first prospective cohort study of families with Lynch syndrome provides the strongest evidence to date that people with this inherited condition have an increased risk of breast cancer and pancreatic cancer. The study is also the first to show that, within Lynch syndrome families, relatives who lack gene mutations that cause this syndrome have no higher risk of cancer than people in the general population, suggesting that these individuals do not require more intense cancer screening. In addition, the study confirms that affected individuals have an increased risk of several cancers previously thought to be associated with the syndrome. The study results were published February 13 in the Journal of Clinical Oncology.

Lynch syndrome is caused by inherited mutations in one of four DNA mismatch repair (MMR) genes, which are involved in fixing errors in DNA that are made when a cell’s genetic material is copied in preparation for cell division. People with these mutations are known to have a higher-than-normal risk for colorectal cancer and a variety of other cancers, and they are generally diagnosed with these cancers at a younger age (see related article).

But previous studies had yielded inconsistent evidence on the risk of pancreatic cancer and “only weak or circumstantial evidence” of increased breast cancer risk in these individuals, senior study author Dr. Mark Jenkins of the University of Melbourne, Australia, noted in an e-mail message.

Dr. Jenkins, Dr. Aung Ko Win, and their colleagues followed MMR-mutation carriers and their non-carrier relatives from NCI’s Colon Cancer Family Registry to provide estimates of carriers’ future risk for numerous cancers, including breast, colorectal, endometrial, kidney, ovarian, pancreatic, and stomach cancer. They found that carriers had from 4 to 30 times the normal risk, depending on the cancer type.

People with Lynch syndrome are usually advised to undergo colonoscopy at an earlier age and more often than the general population. “Further clarification of the risk of breast cancer for a range of ages is needed to determine the recommended ages for mammographic screening or whether methods such as MRI are warranted for women with Lynch syndrome,” Dr. Jenkins wrote.

Radiation Therapy after Surgery for Lung Cancer May Not Improve Survival

Radiation treatment after surgery does not appear to improve the survival of some elderly patients with lung cancer, according to results from an NCI-supported study. The study looked specifically at patients ages 65 and older with stage III non-small cell lung cancer (NSCLC) that had spread to nearby lymph nodes. There was no difference in survival between patients in the study who received postoperative, or adjuvant, radiation therapy and those who did not. The study was published online February 13 in Cancer.

The study’s authors, led by Dr. Juan Wisnivesky of the Mount Sinai School of Medicine in New York, acknowledged that they could not determine from their work—a retrospective analysis of data on more than 1,300 patients in NCI’s SEER-Medicare database—whether adjuvant radiation therapy improved progression-free survival or quality of life.

Long-term survival is substantially decreased in patients with NSCLC that has spread to nearby lymph nodes, the authors noted, but there are no data from clinical trials to show that adjuvant radiation therapy improves survival in such patients, Dr. Wisnivesky noted in an interview.

Yet in this study, he continued, more than half of the patients received postoperative radiation therapy. The findings were the same even when the analysis was limited to patients in certain subgroups, such as those who also received postoperative chemotherapy or who were treated during different time periods. (The study covered patients treated from 1992 to 2005.)

“We were expecting that radiation therapy would be associated with improved survival. But we’ve shown that this is not the case, to the extent that we could with our data,” Dr. Wisnivesky said. “And [radiation] treatments are not without costs or risks.”

Because the study is retrospective with incomplete data, the findings should be interpreted with caution, stressed Dr. Giuseppe Giaccone of NCI’s Center for Cancer Research. Nevertheless, he said, the data support the idea that if there are any survival differences from adjuvant radiation, “they are likely to be small.”

A phase III clinical trial being conducted in Europe, called Lung ART, is testing whether post-surgical radiation in this same patient population improves overall survival.

High Platelet Levels Linked with Poor Survival in Ovarian Cancer

Excessively high platelet levels are associated with poor survival in women with ovarian cancer, according to findings from a new study. Funded in part by NCI, the study showed that women with elevated platelet levels (thrombocytosis) had substantially worse progression-free survival and overall survival, and were more likely to have advanced cancer at diagnosis, than women with normal platelet levels. The findings were published February 16 in the New England Journal of Medicine.

The researchers identified the association between thrombocytosis and survival through an analysis of blood samples from more than 600 women with ovarian cancer. Experiments using mouse models of ovarian cancer confirmed the findings and suggested a potential mechanism by which tumors can cause platelet levels to climb.

According to the study’s senior author, Dr. Anil Sood of the University of Texas M. D. Anderson Cancer Center, the findings point to potential new treatment avenues for ovarian cancer and suggest that platelet levels could possibly serve as diagnostic and prognostic markers. “We need to do much more work to further evaluate all of these findings and develop them,” he cautioned.

Researchers found that thrombocytosis was also associated with increased levels of thrombopoietin, a hormone that regulates platelet production, and the cytokine interleukin-6 (IL-6), which can increase thrombopoietin production.

In the mouse model experiments, the research team found that IL-6 secreted by tumor cells and thrombopoietin are critical components of a “feed-forward loop” that promotes thrombocytosis and tumor growth. They also showed that an investigational monoclonal antibody that targets IL-6 called siltuximab slowed ovarian tumor growth in mice, and that siltuximab was even more effective when used in combination with the chemotherapy drug paclitaxel.

In a small clinical trial that was part of the larger multi-institutional study, 3 weeks of siltuximab treatment substantially reduced platelet levels in 18 women with ovarian cancer.

Additional studies are ongoing, Dr. Sood explained, including those focused more closely on how platelets may promote tumor growth. Additional early stage clinical trials to test anti-IL-6 treatment in women with ovarian cancer are being planned, he noted.

Profiles in Cancer Research

Dr. Gordon Hager: From Chromatin to Cancer

Chief, Laboratory of Receptor Biology and Gene Expression
NCI Center for Cancer Research

Dr. Gordon Hager Dr. Gordon Hager

Dr. Gordon Hager likes to know how things work. As a boy growing up in Hepler, Kansas (population 160), he built radios and conducted experiments with electricity. These days, he investigates a far more complex and dynamic subject: the cell.

Since arriving at NCI as a postdoctoral fellow in 1977, Dr. Hager has focused on a fundamental aspect of cell biology: how cells regulate genes. As genetics research has grown, it has become increasingly clear that a better understanding of the process of gene regulation could lead to new approaches for studying and treating cancer.

"Cancer is largely a disease of control," said Dr. Hager, chief of NCI's Laboratory of Receptor Biology and Gene Expression. "The cell goes bananas because it's out of control, and the genetic networks working in those cells begin to fail. But we can now watch this process in real time with new technologies."

What's more, it may be possible to correct these kinds of failures, Dr. Hager noted. Unlike mutations in DNA, which cannot be fixed, some abnormalities in gene regulation may respond to epigenetic treatments. Drugs that target these kinds of epigenetic changes are available, though developments in this area are still in their infancy.

Unconventional Wisdom

Since the 1980s, Dr. Hager's lab has played an important role in defining mechanisms that cells use to precisely control their genetic programs, particularly mechanisms related to chromatin structure and reorganization.

Chromatin is the substance of chromosomes. It consists of long strands of DNA wrapped tightly around protein particles called nucleosomes, which are composed of four different types of histone proteins.

Illustration showing chromosomes, histones, and DNA A close-up view of the spool-like proteins called histones that tightly package DNA in chromosomes. Without such packaging, the DNA would not fit into the cell's nucleus. [Enlarge]

The strength of the interaction between nucleosomes and the associated DNA plays a role in determining whether the DNA is expressed. Nucleosome–DNA interactions, and therefore gene activity, can be controlled in part by changing the structure of histones in nucleosomes. This process of altering the interaction of nucleosomes and DNA is known as chromatin remodeling, and it occurs constantly within cells.

In 1987, Dr. Hager's group proposed that chromatin remodeling contributed to gene regulation. "At the time, nobody wanted to believe that modifying chromatin structure was important in gene regulation," he said. The idea would not gain broad acceptance until the next decade.

Today, there's also increasing awareness of the role of chromatin remodeling in cancer. Last month, for instance, researchers identified recurring mutations in genes associated with chromatin remodeling in childhood brain tumors.

Given the potential to treat tumors driven by chromatin-related changes, Dr. Hager believes the field could benefit from having an "atlas" of cancer-related abnormalities in chromatin for many types of cells, similar to The Cancer Genome Atlas.

Science Camp

Dr. Hager's introduction to biology came in graduate school at the University of Washington, where he switched from studying chemistry to genetics. "This was 1969, and DNA was just taking off," he recalled. "I had never taken a biology course in my life, but I could see that this research was going to be a big deal for years to come."

While graduate school provided the launch pad for Dr. Hager's career, his interest in science can be traced back to his freshman year in high school. That was when his mother found an advertisement in the newspaper for a science camp at the University of Kansas, which was about 100 miles from their hometown.

Dr. Hager earned a scholarship and spent the summer after his freshman year at the camp. One of the camp "advisors" was Dr. F. Sherwood Rowland, a physical chemist who would later win the 1995 Nobel Prize in Chemistry for his work on ozone depletion. Dr. Rowland became Dr. Hager's mentor, inviting him to work in his lab during his remaining summer vacations.

Dr. Hager believes that his background in chemistry has served him well. "Biology is chemistry," he said. "And we can now investigate the fundamentals of the cancer process, including the complexities of gene regulation."

Looking to the future, Dr. Hager hopes to see more research on living cells. Many cellular processes are fundamentally altered by experimental procedures that isolate parts of the cell. As a result, the biology of dead cells differs markedly from that of live cells.

Although most experiments are done on dead cells, some researchers, including Dr. Hager, have created tools that make it possible to study processes such as chromatin remodeling in living cells in real time.

Like a Tornado

In a recent study, Dr. Hager's team used these tools to monitor the binding of proteins called transcription factors to DNA sites on chromatin in real time. These binding events regulate the activity of target genes. The researchers found that two transcription factors that bind to the same DNA site did not compete with one another, as some previous experiments with dead cells had suggested.

Instead, each transcription factor occupied the DNA binding site only briefly. What's more, the results suggest that the binding of one transcription factor to the DNA site may facilitate the binding of another factor.  This process, called "assisted loading," likely involves chromatin remodeling.

"Everything in the cell is moving," said Dr. Hager, who compares the inner workings of a cell to a tornado. "Chromatin remodeling and gene regulation are dynamic processes, and to see them you have to study living cells."

Seeing these processes in cancer cells is a step toward new treatments. "Only if you understand how the cell works, can you hope to make it behave the way you want it to," said Dr. Hager.

Edward R. Winstead

For more about Dr. Hager's work see "Don't Throw Out the Packing Materials."

You must have flash installed and enabled to view the video.

Featured Clinical Trial

Surgical Removal of Primary Tumor for Metastatic Breast Cancer

Name of the Trial
Phase III Randomized Study of Early Local Therapy Comprising Surgery versus Standard Palliative Therapy for the Intact Primary Tumor in Patients with Stage IV Breast Cancer (ECOG-E2108). See the protocol summary.

Dr. Seema KhanDr. Seema Khan

Principal Investigator
Dr. Seema Khan, Eastern Cooperative Oncology Group

Why This Trial Is Important
Women diagnosed with breast cancer that has already spread (metastasized) to other parts of the body are usually treated with systemic therapy, which may include chemotherapy, hormonal therapy, and targeted therapy.
                      
Conventional wisdom holds that, once the cancer has spread beyond the breast, local therapy—treatment such as surgery or radiation therapy that targets the primary tumor in the breast and nearby tissues—will no longer have a positive effect on survival. Therefore, surgical resection should be carried out only as palliative therapy. However, several retrospective studies suggest that removing the primary tumor in women with previously untreated metastatic breast cancer may help them live longer.

Whether these studies reflect an improvement in survival due to surgery or whether patients who undergo surgery have a better prognosis for other reasons is unclear. Retrospective studies are subject to many biases and uncertainties that can make some treatments appear to be more effective than they are. For example, it is possible that women who were predicted to do well because they were healthier and had less aggressive tumors were selectively offered surgery, and the surgical treatment was not actually responsible for their longer survival.

Moreover, scientists do not yet fully understand the complex relationships between primary tumors and metastatic tumors. Some researchers have suggested that a primary tumor may promote the expansion of metastatic disease by seeding new metastatic tumors more efficiently than existing metastatic tumors. In addition to the retrospective studies of breast cancer mentioned previously, a clinical trial in patients with metastatic kidney cancer lends support to this hypothesis. In the trial, the median survival of patients who underwent surgical resection of their primary tumor (in this case, nephrectomy) followed by systemic therapy was 3 months longer than that of patients who received systemic therapy alone.

On the other hand, some animal studies have shown that removing a primary tumor may actually enhance the growth of metastatic tumors. These studies suggest that primary tumors make proteins that are released into the bloodstream and appear to restrain the growth of metastatic tumors. However, this effect has yet to be observed in human studies. Given the conflicting hypotheses generated by these various studies, it is important to address this question in a randomized clinical trial.

In this clinical trial, women with newly diagnosed metastatic breast cancer who are undergoing systemic therapy and whose disease does not progress within 16 weeks of starting that therapy will be randomly assigned to continue systemic therapy or to undergo surgical resection of their primary tumor. Depending on the type of surgery received and other clinical considerations, they may also receive radiation therapy. Women randomly assigned to continue systemic therapy will undergo surgery only if it is deemed necessary to alleviate pain or other symptoms caused by the primary tumor.  Doctors want to see whether early removal of the primary tumor will help women live longer.

"Randomized clinical trials are only justified if there are good reasons to think that a particular treatment will be more effective at controlling disease, but there is an almost equal possibility that it will not," said Dr. Khan. "The importance of the treatment of the primary tumor in metastatic breast cancer fits this situation perfectly; there is good reason to think it will help women with stage IV breast cancer, but there are also ways it could harm them, and the only way to find out [if the intervention is truly beneficial] is to conduct a clinical trial.

"The potential for harm comes from the fact that women receiving chemotherapy will need to interrupt this therapy while they receive surgery and radiation, from the possibility that the primary tumor really does restrain the growth of metastases, and from the possible side effects of surgery and radiation, particularly if [local therapy] does not improve patients' survival or quality of life," she added.

For More Information
See the lists of entry criteria and trial contact information or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/featured.

Community Update

Clinical Trials Network Aims to Strengthen Cancer Immunotherapy Pipeline

A T cell (green) killing a cancer cell (blue) A T cell (green) killing a cancer cell (blue)

Later this year, the first clinical trials will be launched under a new NCI-funded initiative to spur the development of cancer treatments that work by revving up the immune system's response to tumors. The Cancer Immunotherapy Trials Network (CITN) includes the foremost researchers in cancer immunotherapy from 27 top U.S. cancer centers and universities who are working collectively to identify promising agents and to formulate and run the trials in which they will be tested.

The first immunotherapy agents to enter CITN trials have been selected, and several trials are moving closer to launch. The first two agents, interleukin-15 (IL-15) and CP-870,893, were selected "based on broad consensus and the field's collective experience and 'wisdom,'" explained Dr. Martin A. "Mac" Cheever, the CITN's principal investigator and director of the CITN Central Operating and Statistical Center (COSC), located at the Fred Hutchinson Cancer Research Center in Seattle.

All CITN trials will be phase I or phase II trials. The network's aim is to establish a pipeline of agents to test in the large phase III trials that ultimately determine whether a new treatment will make it to the clinic, said Dr. Cheever, who, along with co-investigator Dr. Kim Margolin, runs the network's day-to-day operations. Correlative science studies, such as those that look for biomarkers that indicate which patients are likely to respond to a treatment and that assess the extent to which treatments stimulate an immune response, will be built into the trials. These studies will be performed under the direction of Dr. Cheever's other co-investigator, Dr. Mary L. "Nora" Disis.

"The goal," Dr. Cheever explained, "is to design trials that can quickly demonstrate proof of concept and patient benefit, ultimately helping to define a path toward regulatory approval."

The Field Comes Together

The concept of using a patient's own immune system to destroy tumors has enticed researchers for decades. Until quite recently, however, regimens focused on boosting patient immune responses to their own cancers, although effective in some patients, have failed to produce many broadly effective treatments. (For years, blood and bone marrow transplants, which restore or replace patients' immune systems, have been highly effective treatments for leukemia and lymphoma, and some monoclonal antibodies, such as trastuzumab [Herceptin], are believed to work, in part, by stimulating an antitumor immune response.)

But a confluence of events has propelled the field forward, said Dr. William Merritt of NCI's Division of Cancer Treatment and Diagnosis (DCTD) and NCI program director for the CITN. Chief among them has been the "vastly improved understanding of tumor immunology and the number of agents known to modify the immune response to tumors," Dr. Merritt said.

A major tipping point was the first NCI-sponsored Immunotherapy Agents Workshop, held in 2007, which brought together leading cancer immunologists to identify the most promising immunotherapy agents for further study and development. From more than 120 candidates, 20 agents were chosen. NCI held additional workshops to help further prioritize agents for development, with an emphasis placed on agents with the greatest potential for broad usage by multiple investigators in different regimens, Dr. Cheever explained.

"Everything that's happened progressed from that first workshop," Dr. Cheever added.

Not long after the series of prioritization workshops, a group of immunotherapy researchers approached then-NCI Director Dr. John E. Niederhuber and urged him to increase the institute's support for efforts to facilitate the development of high-priority agents, Dr. Merritt recalled. Dr. Niederhuber and DCTD leaders agreed, and the CITN concept was born.

Cancer Immunotherapy Trials Network logo

In addition, the Food and Drug Administration last year approved two cancer immunotherapies: ipilimumab (Yervoy) to treat advanced melanoma and sipuleucel-T (Provenge) for the treatment of advanced prostate cancer.

The impact of those approvals was enormous, said Dr. Jedd Wolchok, a CITN investigator at Memorial Sloan-Kettering Cancer Center. "For pharmaceutical companies and the industry to see a successful immunotherapy that can be administered in a doctor's office has really changed the field," Dr. Wolchok said.

Researchers have historically had difficulty gaining access to the diverse array of investigational immunotherapy agents that have shown significant promise in laboratory testing as well as early phase clinical trials. In some cases, the company that developed an agent prioritized its development for a disease other than cancer, or the agent needed to be developed in combination with other agents as part of a multi-component regimen.

Availability has "definitely been a major bottleneck," said Dr. Thomas Gajewski, a CITN investigator at the University of Chicago Medical Center. 

That is now beginning to change. Numerous companies are more interested in making agents available for study and developing new investigational immunotherapy agents, Dr. Wolchok said. Several are even establishing immuno-oncology departments.

"And we, as a community of cancer immunotherapy investigators, need to be prepared to help them test [these agents] in a thoughtful way," he continued. "And that's where the CITN can play a major role."

Collaboration Pushing Science Forward

Having a network of investigators and centers "means that we can initiate trials in a timely way," Dr. Merritt explained. "We don't have to wait for individual grants to get funded, with  [researchers] doing their own trials at their own institutions." And having multiple centers involved in each trial, he added, will significantly improve how quickly trials can accrue patients and be completed.

But the potential benefits go well beyond speedier trials, Dr. Gajewski stressed.

"With a network, data are shared, and data management and statistical analysis are all uniform," he explained. "Before data are published, we'll all be exchanging this information, so the cross-fertilization potential will be huge. Ideas will move much more readily among investigators and among projects."

The CITN has benefitted greatly from the support of staff from another NIH-funded clinical trials initiative run out of Fred Hutchinson, the HIV Vaccine Trials Network supported by the National Institute of Allergy and Infectious Diseases, Dr. Cheever noted. And potential research collaborations are already being discussed between the CITN and a similar international cancer immunotherapy trials network led by Dr. Wolchok, the Cancer Vaccine Collaborative.

The CITN is funded for 5 years, Dr. Cheever said, and he has had encouraging discussions about obtaining additional funding from industry and philanthropy groups.

Getting the initial trials up and going is an important step, Dr. Merritt said. But it's just the beginning. "Several CITN working groups and its steering committee are now discussing the trial concepts for the next group of agents to move forward," he noted. "I'm very encouraged by the progress so far."

Carmen Phillips

The First Agents

Numerous types of immunotherapeutic agents have been developed, including T-cell and NK-cell growth factors like IL-15, others that stimulate T cells or activate dendritic cells, so-called immune checkpoint inhibitors like ipilimumab, and others that inhibit or neutralize factors secreted by tumors that suppress the immune system.

The first two agents to be tested in CITN-led trials, selected from the 20 identified in the 2007 workshop, will be IL-15 and a dendritic cell-activating  monoclonal antibody called CP-870,893.

The first human trial of IL-15 was recently launched at NCI by Dr. Thomas Waldmann, who co-discovered IL-15 nearly 18 years ago, and Dr. Kevin Conlon. For these first trials, NCI is manufacturing IL-15 at its drug production facility on the NCI-Frederick campus. The CITN trial of IL-15 is separate from Dr. Waldmann and Dr. Conlon's trial, but CITN investigators are working closely with Dr. Waldmann on IL-15's development, Dr. Cheever noted.

The Pfizer-developed CP-870,893—which targets the CD40 antigen on certain immune cells—has already shown efficacy in a small phase I trial of patients with advanced pancreatic cancer. The CITN trial, to be led by Dr. Robert Vonderheide of the University of Pennsylvania, will test the CD40-targeted antibody as a presurgical treatment in patients with operable pancreatic cancer.

Planning and negotiations are underway to test several other treatment strategies, including the cytokine IL-7 and an agent in development that targets the immune checkpoint protein PD-1 on the surface of certain immune cells.

Notes

National Cancer Advisory Board to Meet Next Week

The National Cancer Advisory Board (NCAB) will meet February 27–28 in Bethesda, MD. The agenda is available online, and the proceedings will be broadcast live online.

Presentations include a report from NCI leadership, as well as updates on the President’s Cancer Panel from Dr. Barbara Rimer and cooperative group reorganization from Dr. Jeff Abrams.

An archived videocast will be posted a few days after the meeting. Videocasts of past meetings are available here.

Director's Consumer Liaison Group to Discuss Drug Shortages, Advocate Engagement

The NCI Director's Consumer Liaison Group (DCLG) will hold its first meeting of the new year February 29–March 1 in Bethesda, MD. The agenda, which will be posted soon, includes presentations on understanding cancer drug shortages and advocate engagement at NCI. The meeting is open to the public. 

The DCLG provides informed, non-scientific perspectives to the NCI director on promoting research outcomes that are in the best interest of cancer patients. Specifically, DCLG members focus on identifying new approaches, promoting innovation, recognizing unforeseen risks or barriers, and identifying unintended consequences that could result from NCI decisions or actions.

The group also provides insight into enhancing input, optimizing outreach, and promoting strong collaborations, all with respect to non-scientist stakeholders, in the interest of meeting common institute and community goals.

New Clinical Trials Portal and Apps Available

Screenshot of NIH Clinical Research Trials and You

A new portal, NIH Clinical Research Trials and You, provides information about the risks and benefits of taking part in a clinical trial, how to find a trial, and questions to ask when considering participation in a trial. The site also features stories from researchers and volunteers who have participated in clinical trials and downloadable materials for professionals interested in raising awareness about trials.

In a related effort, NCI's Center for Cancer Research (CCR) recently launched NCITrials@NIH, a free application (app) for the iPhone, iPod touch, and iPad that provides mobile access to CCR's list of cancer clinical trials. The app enables oncologists, patients, and families to find and share information about NCI-sponsored clinical trials at CCR. The app allows users to search more than 150 clinical trials, save pages as favorites, and share information via Twitter and e-mail.

In addition, the Centers for Disease Control and Prevention (CDC) has also launched its own free iPad app, which allows users to access a wealth of CDC resources, including information on cancer prevention and screening.