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N a t i o n a l C a n c e r I n s t i t u t e
 

N a t i o n a l C a n c e r I n s t i t u t e

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    N a t i o n a l C a n c e r I n s t i t u t e N a t i o n a l C a n c e r I n s t i t u t e Document Transcript

    • National Cancer Institute Center for Excellence in Immunology Center for Cancer Research U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health
    • Table of contents The Center of Excellence in Immunology Letter from the Director . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Multi-Institutional/Multidisciplinary Focus Spotlight on Center of Excellence in Immunology . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Sustained Commitment A 50-Year Odyssey by a Quintessential Physician-Scientist . . . . . . . . . . . . . . . . . . . 4 Corridor Collaborations A Promoter and a Suppressor of Tumor Growth: The Complex Biology of Tgf-β . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Public Health Challenges Targeting the Virus That Causes Cervical Cancer: HPV Vaccine Will Have Global Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 HIV/AIDS: NCI Responds Swiftly to a Public Health Crisis . . . . . . . . . . . . . . . . . . . . 8 A Distinctive Research Setting Clinical Trials at CCR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Exploring the Power of Molecular Profiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Training T Cells To Attack Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Training for Tomorrow Teaching the Art of Inquiry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 CEI Contact Information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
    • Letter from the Director The Center of Excellence in Immunology snapshots attempt to capture CEI’s strategic academia to provide prolonged funding are (CEI), part of the National Cancer use of the immune system to detect cancer sustained at the NCI. Current clinical trials Institute's intramural research program in earlier, diagnose it more precisely, and of adoptive cell therapy illustrate this well. the Center for Cancer Research (CCR), is a prevent or treat it more effectively-all with Without NCI’s two decades of support for community of scientists who integrate an eye toward the NCI Challenge Goal: To cellular therapy research, cancer patients discovery with the development of novel, eliminate the suffering and death due to today might not be benefiting from the immune-based treatments for cancer and cancer by 2015. remarkable progress evident in treatment AIDS. Based in Maryland, on the Bethesda The distinctive infrastructure of the NCI for advanced melanoma. and Frederick campuses of the National intramural research program is also CEI has made impressive advances. Its Institutes of Health, the CEI is home to a captured in this publication. Here an success flows from a distinctive research critical mass and unique mix of basic, trans- enabling infrastructure empowers CEI environment: one in which a critical mass of lational, and clinical scientists who work in scientists to do innovative work. Teaming able researchers unselfishly pool their multidisciplinary teams to aggressively within the NCI intramural program, they diverse talents to create a “culture of the pursue new approaches for the prevention invent new tools or harness existing ones to corridors” that fosters and produces a and treatment of cancer and AIDS. translate their discoveries about cancer and center of research excellence. As the Considered one of the leading communities the immune system into treatment interven- Director of the CEI, I am privileged to share of immunology researchers in the world, tions. Using cutting-edge technologies such with you some of our accomplishments. CEI scientists bring a distinguishing strength as functional imaging, genomics, proteomics, to the CCR. They already have produced CEI researchers drive their discoveries from Robert H. Wiltrout, PhD. Director, Center of Excellence in many immune-based interventions that are the bench, to early phase clinical studies, all Immunology offering relief to those with cancer and the way to a benefit for cancer patients. Director, Center for Cancer Research AIDS. Their integrated research also lays a Ground-breaking advances in genomics, National Cancer Institute strong foundation for new advances and for example, were quickly applied to the National Institutes of Health brings hope for the future. The stories in this molecular profiling of lymphoma and have booklet provide a glimpse of their contribu- revolutionized diagnosis and treatment for tions to our progress against cancer. today’s patients with this disease. Several key areas of research emphasis at Another key attribute of the NCI’s intra- the CEI are illustrated in this booklet, mural research program that benefits CEI including cell-based therapy, immuno- scientists is its longstanding support for therapy with antibodies, cytokine-based high-risk research that has potential for treatments, as well as vaccines to prevent or making a major impact. Projects that might treat cancer and HIV/AIDS. These research be considered too risky for industry or Center for Cancer Research 1
    • MULTI-INSTITUTIONAL/MULTIDISCIPLINARY FOCUS Preempting Cancer at the Earliest Opportunity Spotlight on Center of Excellence in Immunology A premier community of immunologists In 2003, four Centers of Excellence emerged from a The CCR is home to one of the strongest with a wide range of expertise, work as a reengineering process that optimized the NCI’s immunology and virology communities in think-tank, proactively mapping the future intramural research infrastructure. Through these the world with renowned scientists of immunology research at the CCR. With a new Centers, NCI’s intramural researchers formed performing basic, transnational, and clinical global reach and vision, they have identified teams engaged in transnational research. CCR research. In 2003, the Center of Excellence opportunities and barriers to progress and leads three of the Centers: in Immunology (CEI), a 250-member are collaborating with extramural investiga- • Advanced Biomedical Technology faculty headed by Dr. Robert Wiltrout, tors, academia, and the pharmaceutical • Immunology • Molecular Oncology brought these investigators together within industry worldwide to harness the power of a collaborative unit to further the discovery, the immune system to fight cancer and development, and delivery of novel improve patient care. immunologic approaches for the preven- CEI members have made groundbreaking tion, diagnosis, and treatment of cancer and discoveries in the fields of cytokines, cellular cancer-associated viral diseases. This and innate immunity, viral immunology, community of bench scientists and clinicians and immunotherapy, including cancer vaccines, immunotoxins, radioimmuno- therapy, and cellular therapy. Their combined research has resulted in more than 4,700 publications in scientific jour- nals since 1990. Having pioneered many of the approaches in use today, researchers in the CEI stand at the forefront of immunotherapy. Some of their bench-to- bedside research “firsts” include: Cytokine-Based Therapy Discovery of IL-2, plus a subunit of the IL-2 receptor complex, and JAK3, a kinase critical for IL-2 responses. These basic research findings have been translated to the clinic so that today, IL-2 is an FDA- approved treatment for metastatic renal cancer and melanoma. CEI members have also developed antibodies to the IL-2 receptor and used these for treatments of some forms of leukemia, autoimmune disease and graft versus host disease. This Researcher Tom Shelton harvests a patient’s tumor work was among the first to demonstrate infiltrating lymphocytes after they have been acti- the potential of monoclonal antibody vated and grown in vitro. Photo credit: Rhoda Baer therapy in treating cancer. Now numerous monoclonal antibodies are in clinical trials 2 National Cancer Institute
    • clonal antibody approved by the FDA as a first clinical trial to combine radiation and a cancer treatment. cancer vaccine for treating prostate cancer. By showing that such combination therapy Immunotoxin Therapy is safe and well tolerated, CCR is leading the Several immunotoxins generated at the way toward finding alternative treatments CCR are in clinical trials. Treatment with for patients with localized disease who BL22 resulted in a very high complete receive radiation or surgery and then response rate among patients with hairy cell relapse. In several clinical trials, there is leukemia that was resistant to standard evidence that immune responses to vaccines therapy. CCR scientists are also conducting were associated with prolonged survival. clinical trials with the SS1P immunotoxin in Several vaccines and combination protocols mesothelioma, as well as ovarian and are being developed at NCI and are being pancreatic cancer. Collaborations with the evaluated at more than 60 cancer centers biotech company IVAX have also resulted in around the country for testing in clinical a Phase II multicenter trial treating malig- trials. At least two of these vaccines are Dr. Steven Rosenberg proudly displays his wall of illus- nant brain tumors with TP38, another progressing successfully from Phase II to trious alumnae, graduates of the Surgical Oncology immunotoxin. Phase III studies. Fellowship at CCR. Photo credit: Rhoda Baer Preventive Cancer Vaccines Fueled by NCI’s sustained support, the and monoclonal antibodies such as ritux- The development of vaccines to prevent capacity to arrange global collaborations, imab and trastizumab are routinely used for cancer is another area of intense investiga- and intellectual excellence in immunology, non-Hodgkin’s lymphoma and breast tion at the CEI that is poised to deliver rich investigators in the CEI continue to break cancer, respectively. rewards. Basic research into the assembly of new ground to deliver more effective, less HPV, the virus that causes cervical cancer, toxic treatments for cancer. Adoptive Cell Transfer Therapy has been translated into a A novel cell-based therapy that involves vaccine designed to prevent the removing infiltrating immune cells from the disease (see page 14). Results tumor, activating them in vitro, and of Phase II trials showed a high returning them to the patient. This approach level of protection against has resulted in improvement in 51 percent HPV infection, and Phase III of patients with metastatic melanoma that trials testing this vaccine are in had not responded to earlier treatments (see progress. page 31). Given the bleak prognosis for those with late-stage melanoma, these are Therapeutic Cancer Vaccines remarkable and promising results. The ever-expanding field of therapeutic cancer vaccines Radio-Immunotherapy also owes much to advances CCR scientists coupled radioactive mole- made by CEI researchers. They cules with monoclonal antibodies to enable have identified numerous novel radio-immunotherapy for patients with cancer antigens, devised novel refractory non-Hodgkin’s lymphoma and T approaches to vaccine design, cell leukemia. They then partnered with improved vaccine delivery, as Drs. Jeffrey Schlom (seated), Philip Arlen (right) and pharmaceutical companies to develop a well as discovered ways to optimize vaccine- James Gulley (left) evaluate the effectiveness of a product that was both safe and efficacious induced immune responses with cytokines breast cancer vaccine protocol. Photo credit: Rhoda Baer in clinical studies in patients. This CCR and costimulatory molecules. CEI clinicians effort yielded the first radio-labeled mono- recently initiated a pilot study that was the Center for Cancer Research 3
    • SUSTAINED COMMITMENT Developing Effective and Efficient Treatments A 50-Year Odyssey by a Quintessential Physician-Scientist “Nowhere in the nation do I see the ability Dr. Thomas Waldmann arrived at the NCI to do basic science, to take it to preclin- in 1956, just three years after the NIH Clinical Center opened. What was envisioned ical drug development and into the clinic as a 2-year fellowship became a 49-year as you can at the NCI. It is very exciting allegiance. He speaks with passion as he to see your patient get better with an describes how the close proximity of agent that you’ve developed yourself. patients to the research labs, the critical mass of scientists with a remarkable variety I cannot tell you how exhilarating it is of expertise, and the sense of collaboration to feel that you’ve made a difference.” and comradery among researchers and Thomas Waldmann physicians enticed him to stay. He describes the “culture of the corridors” of the Clinical Dr. Waldmann is now unraveling the role of IL-15, a Center as a unique interaction of infectious powerful cytokine that can prolong memory T-cells excitement and enthusiasm among basic and produce a long-lasting immune response. Photo credit: Rhoda Baer researchers and clinicians who want to make a difference. Dr. Waldmann has made high-impact contributions towards understanding and treating an astonishing array of diseases and clinical disorders. He sums up his five decades at the NCI as a fascinating odyssey. Prior to 1980, he focused primarily on metabolism of serum proteins. This body of work led to insight into ataxia telangiec- tasia, myotonic dystrophy, familial hyper- catabolic hyperproteinemia, Wiskott- Aldrich syndrome, allergic gastroentero- pathy and intestinal lymphangiectasia (also termed Waldmann’s disease). He then pioneered advances in how germ-cell tumors in the testis are diagnosed and treated, and how a type of human T cells, Dr. Waldmann and his colleagues Jing Chen Ph.D. immune cells called “suppressors” that act (facing camera on left) and Hiral Patel, Howard as regulators, behave in immunodeficiency Hughes Medical Scholar (back to camera on the right) examine a gel that confirms the purity of their diseases and some forms of leukemia. He preparation of IL-2 receptor. Photo credit: Rhoda Baer also devised a novel form of molecular 4 National Cancer Institute
    • “One of the great aspects of the NCI is it allows you to experience serendipity. The chance observation in a patient that cannot be explained in the way we already think about a disease may open up a whole new scientific field!” Thomas Waldmann genetic analysis to improve diagnosis and treatment of leukemia. In the late 1970s, a serendipitous discovery turned Dr. Waldmann and coworkers’ attention to the newly born field of cytokines. Cytokines are a class of proteins that act as signaling regulators in the immune system. His group was trying to generate an antibody to CD4, a marker Dr. Waldmann carefully places an important paper in “You’ll see a patient and take that infor- protein on the surface of T cells. They ended a safe place in his office. Photo credit: Rhoda Baer up instead with an antibody to an unknown mation into the laboratory. From the protein. Quickly, they determined the laboratory, you learn new insights that protein was important to T-cell activation. can be translated into rational drug So they cloned it and found it was part of development. The ability to move back the IL-2 receptor complex, where cytokines ducing IL-15 into cancer therapy, and into bind to effect signaling. With this finding, and forth is very special here.” the design of vaccines for cancer and AIDS. they characterized the first cytokine Thomas Waldmann Dr. Waldmann’s studies pioneered and receptor, setting the stage for understanding propelled the use of monoclonal antibodies for immunotherapy. Today hundreds of new the biology and biochemistry of this family antibodies are in clinical trials, and the Food of molecules. and Drug Administration already has Over the next 20 years, the Waldmann approved about a dozen monoclonal anti- lab demonstrated that antibodies specific bodies, including Herceptin and Rituxan, to for this receptor were useful in treating treat cancer and other diseases. For adult T-cell leukemia, prolonging survival of Waldmann, a chance discovery in the 1970s, transplant recipients, and treating multiple pursued with a prepared mind and sustained sclerosis. As part of an effort to unravel commitment, has had a far-reaching impact. paradoxical observations in these trials, Dr. Waldmann co-discovered the cytokine inter- leukin 15 that is critical for the survival of yet another type of T cell, the “memory” T, named for its ability to remember past inva- sions and respond quickly to a pathogen’s Dr. Waldmann explains possible side effects to Carol as she begins her combination chemotherapy and re-entry. Waldmann is translating these immunotherapy. Photo credit: Rhoda Baer latest observations to the clinic by intro- Center for Cancer Research 5
    • CORRIDOR COLLABORATIONS Understanding Causes and Mechanisms of Cancer A Promoter and a Suppressor of Tumor Growth: The Complex Biology of TGF-β β TGF-β (transforming growth factor-beta) was discovered three decades ago at CCR and has confounded and delighted researchers ever since When Drs. Anita Roberts and Michael cancer development, TGF-β often acts as a TIMELINE OF TGF-β COLLABORATIONS β Sporn (now at Dartmouth Medical School) tumor suppressor. Using a mouse model of 1980s discovered and characterized TGF-β in human breast cancer, CCR’s Dr. Lalage Identify and purify TGF-β CCR 1981, they called it “transforming” because Wakefield demonstrated that TGF-β TGF-β promotes CCR it can turn normal cells malignant, and switches from tumor suppressor to tumor wound healing because elevated levels of TGF-β predict promoter, and it supports metastasis when a Clone TGF-β CCR/Genentech poor outcomes in many types of cancer. breast cancer changes from histologically Dr. Roberts and her colleagues developed low- to high-grade—a shift to more aggres- TGF-β inhibits growth NCI mouse models to study the TGF-β-signaling sive disease. Dr. Wakefield went on to make 1990s pathway in inflammation, fibrosis, and the unexpected finding that certain TGF-β Crystal structures NIDDK/NIDR cancer. TGF-β regulates many cellular inhibitors can selectively block the tumor of TGF-β processes in normal cells, including tissue promoter effects of TGF-β, without TGF-β mouse models NINDS/NIDDK repair from injury. Intriguingly, mice lacking affecting its tumor suppressor activity. This First clinical trial with NINDS components of the TGF-β-signaling path- discovery with mouse models suggests that systemic TGF-β way heal faster from epithelial wounds and TGF-β inhibitors might be useful to treat 2000s are protected against skin injury caused by cancer metastasis in humans. CRADA to develop CCR/Genzyme ionizing radiation. CCR scientists are devel- CCR has established a cooperative TGF-β antibodies oping inhibitors of TGF-β to see if they can research agreement (CRADA) with TGF-β blockers suppress CCR speed epithelial tissue repair following Genzyme Corporation to develop TGF-β metastasis cancer radiotherapy. antibodies for testing in clinical cancer TGF-β switches from CCR Although TGF-β was originally discov- trials, both alone and in combination with suppressor to promoter ered for its tumor-promoting activity, it has other cancer treatments, such as chemo- become clear that during the early stages of therapy and cancer vaccines. CCR continues with an active program to target TGF-β in Negative cancer treatment, wound healing, and blood growth factors and immune system disorders. Mutated fibroblast (TGF-β) Dr. Wakefield is committed to deter- mining how TGF-β shifts from tumor suppressor to tumor promoter. “Under- Positive standing this problem will be critical if the Tumor growth promoter factors TGF-β system is to be exploited effectively Normal fibroblast Tumor in novel approaches to the treatment of suppressor breast cancer.” TGF-β Dr. Roberts’ leadership in creating receptor a world-renowned center of expertise in TGF-β biology‚ was Growth recognized by her recent award of Tumor receptor the Leopold Griffuel Prize and the Federation of American Societies During cancer progression, TGF-β signaling switches from producing growth negative to growth positive for Experimental Biology (FASEB) factors. Researchers are developing agents to selectively block this tumor promoting activity. Excellence in Science Award. 6 National Cancer Institute
    • PUBLIC HEALTH CHALLENGES Accelerating Progress in Cancer Prevention Targeting the Virus That Causes Cervical Cancer: HPV Vaccine Will Have Global Impact A vaccine to prevent cervical cancer is in final stages of testing A vaccine to prevent cervical cancer, based Hildesheim and Rolando Herrero from the on technology developed by CCR scientists Fondacion Inciensa in Costa Rica. The Douglas Lowy and John Schiller, is in final women in the study will be followed for at stages of testing. This vaccine offers great least 6 years, to obtain information about hope for reducing the global burden of cancer. the vaccine’s long-term safety and the extent Almost every cervical cancer in the United and duration of protection. States and abroad is caused by infection CCR’s involvement in HPV vaccine devel- HPV L1 virus-like particles morphologically look with human papillomavirus, or HPV. Once opment continues. Drs. Schiller, Lowy and very similar to authentic infectious [viral] particles NCI scientists in the Division of Cancer colleagues have developed the first high- except that they don’t contain any DNA. Epidemiology and Genetics (DCEG) estab- throughput assay to enable HPV vaccine lished the link between HPV and cervical developers to observe whether a vaccine can Cervical cancer strikes nearly half a million women each year worldwide. It is the second lead- cancer, CCR scientists went to work to induce potentially protective antibody ing cancer killer, claiming a quarter of a million devise a vaccine against the virus. They responses against other cancer-causing lives annually. The vast majority of deaths occur in found that multiple copies of a single HPV strains of HPV. They have made this assay the poorest regions of the world—South Asia, sub- protein could assemble into non-infectious available to other researchers to accelerate Saharan Africa, and parts of Latin America— virus-like particles to form the basis of a vaccine research. where access to screening services and medical vaccine. Immunization with these particles, In anticipation of approval of HPV care is limited. they learned, could stimulate production of vaccines, the Gates Foundation announced An NCI team of experts in virology, vaccine large quantities of antibodies that prevent in June 2005 that it would grant $12.9 development, epidemiology, immunology, patholo- virus infection in both animals and human million to the World Health Organization, gy, and cytology is helping to make cervical cancer volunteers. the International Agency for Research on prevention a reality. NCI licensed the technology to two phar- Cancer, Harvard University, and the maceutical companies—Merck and Glaxo- Program for Appropriate Technology in Smith-Kline (GSK)—to develop HPV vaccines Health to create systems to ensure quality commercially. Both companies are running control in vaccine distribution, monitor the large-scale Phase III trials of their versions impact of different HPV vaccination strate- of an HPV vaccine. GSK’s targets two HPV gies, and facilitate early introduction of the strains, 16 and 18, which together cause vaccines worldwide. about 70 percent of all cervical cancers. Merck’s targets strains 6, 11, 16, and 18. Phase II trials by both companies produced encouraging results. The VLP vaccines were 100 percent effective at preventing prema- lignant cervical abnormalities caused by the virus types in the vaccines, even up to four years after vaccination. The NCI is performing its own Phase III trial of the GSK vaccine in Costa Rica, The HPV prophylactic vaccine is highly immuno- GSK and NCI are running a Phase III trial of an HPV genic, prompting the production of antibodies that where cervical cancer rates are high. The vaccine to protect Costa Rican women from HPV interfere with binding of the intact HPV virus to a NCI study is being run by DCEG’s Allan infections that are linked to cervical cancer. patient’s cells and entry through a receptor. Center for Cancer Research 7
    • PUBLIC HEALTH CHALLENGES Developing Effective and Efficient Treatments HIV/AIDS: NCI Responds Swiftly to a Public Health Crisis A mysterious immunodeficiency disease “In retrospect, our work was an ideal In June 1981, the Centers for Disease team at the Pasteur Institute in France had demonstration of what the Clinical Control (CDC) published the first report of discovered the virus now known as human five cases of a mysterious immunodeficiency immunodeficiency virus (HIV) and impli- Center is all about. A laboratory could do disease. Two weeks later, a young man with cated it as the cause of AIDS. Intramural certain things and then, in effect, take a severe immune system disruption checked scientists also developed the first blood test the observation twenty feet down the into the NIH Clinical Center with the help to diagnose HIV infection and rapidly trans- hall into a clinical area and begin treating of an oncologist in NCI’s Intramural ferred materials to industry for the commer- Research Program. His condition was cate- cial production of a test that could be used patients. That kind of interaction and that gorized as a rare disease—and later turned for blood screening at the nation’s blood kind of ability is really very rare.” out to be one of the first cases of Acquired banks. Former NCI Director Dr. Sam Broder: Interview Immune Deficiency Syndrome (AIDS) in the Intramural researchers at NCI also played with Gretchen Case of History Associates, United States. The AIDS epidemic spread a key role in the development of the first Fall 1996 quickly; by the end of that year more than drugs for treating HIV infections and AIDS. 200 people had died of AIDS in the United An NCI-funded researcher had already States. synthesized zidovudine (AZT) as a possible The medical community faced a public anticancer drug. Drs. Samuel Broder, CCR’S AGILE INFRASTRUCTURE health crisis. The cause of the new disease Hiroaki Mitsuya, and Robert Yarchoan IDENTIFICATION of HIV as causative was unknown and there were no means to moved quickly to test AZT and other drugs: agent for AIDS treat or prevent it. Groundbreaking basic didanosine (ddI) and zalcitabine (ddC) for DEVELOPMENT of first blood test for research by investigators in NCI’s Intra- treating patients with AIDS. All three drugs HIV infection mural Research Program—and subsequent were licensed for treating HIV infection, DISCOVERY of first antibodies to kill HIV collaborations with industry—rapidly and today these agents are combined with IDENTIFICATION of many retroviral provided important answers. By 1984, Dr. protease inhibitors or non-nucleoside proteins, new HIV reservoirs, immune Robert Gallo’s group at NCI and a scientific reverse transcriptase inhibitors in combina- system receptors that recognize HIV, tion antiretroviral therapy, known as highly and human genes that influence HIV susceptibility and AIDS progression active antiretroviral therapy or HAART. This “cocktail” therapy has dramatically UNDERSTANDING of how HIV infects a cell reduced the number of deaths and new cases of AIDS since its introduction in 1995. The CONTRIBUTIONS to HIV vaccine development number of annual deaths among people PREVENTION and TREATMENT for with AIDS in the United States has dropped AIDS-related cancers to 15,600—less than one third the level at the height of the AIDS epidemic in 1995, when the disease killed 51,670 people in the United States. Prior to the onset of the AIDS pandemic, a cancer known as Kaposi’s sarcoma (KS) was a rare disease. With the spread of HIV, The virus that causes AIDS is shown budding out of however, KS now accounts for 10 percent of a human immune cell. cancers in countries such as Congo and 8 National Cancer Institute
    • Uganda. As part of its long-term commit- tion and AIDS are living longer but still face ment to reducing the cancer burden for significant health challenges. People infected medically underserved populations world- with HIV are at a 20-fold increased risk for wide, CCR researchers are developing new developing several forms of cancer, treatments for KS based on developing including KS, certain lymphomas, plus knowledge of how the Kaposi’s sarcoma cancers of the cervix, liver, lip, mouth and herpes virus (KSHV) causes the disease. Drs. pharynx, and several others. HAART Richard Little and Robert Yarchoan are therapy can reduce the incidence of some conducting clinical trials using novel thera- these cancers in HIV-infected patients, but pies to cut off the blood supply to the others are becoming more common. Often, Kaposi sarcoma lesions most often develop in the patient’s feet because they are often hypoxic (low tumors (called antiangiogenic therapy) these cancers are caused by co-infection oxygen). This condition induces replication in using agents such as thalidomide, beva- with other viruses, such as Epstein Barr KSHV-infected cells. cizumab, and a combination of IL 12—an virus or hepatitis C virus. CCR scientists are agent with antiangiogenic and immunologic actively involved in developing antiviral activity—and liposomal doxorubicin. and other approaches for these AIDS- In developed countries, the growing associated cancers. NCI’S AIDS VACCINE PROGRAM population of people living with HIV infec- In addition to conducting its own intra- mural research, the NCI’s AIDS Vaccine Program, headed by Dr. Jeffrey Lifson, saves the research community millions of Yesterday’s Achievement dollars and speeds research progress by developing and providing a broad range of Success of HAART for AIDS: 1985–2003 90 novel reagents, assays, and analytical 80 HAART methods to U.S. and international No. of Cases/Deaths is introduced 70 researchers who study AIDS and cancer. It (Thousands) 60 New Cases has more than 4,300 reagents (cell lines, 50 40 proteins, antibodies, viruses). More than 30 139,000 vials have been shipped to scien- 20 Deaths tists from the United States and 63 foreign 10 0 countries. 1985 1989 1993 1996 1999 2003 Today’s Challenge Population of AIDS Survivors at Risk for Cancers 450 HAART is Prevalence (Thousands) 400 introduced 350 300 250 200 150 100 50 0 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 Center for Cancer Research 9
    • CLINICAL RESEARCH AT CCR Developing Effective and Efficient Treatments Clinical Trials at the NIH Clinical Center CCR scientists are translating discoveries at Figure 1 the bench into new diagnostic approaches and new targeted therapies, collecting molecular profiles for many cancer types Other* Pilot and developing databases that eventually will serve the era of molecular medicine. CCR clinicians use a science-based rationale Phase I Specimen for treatment planning. With a patient- Treatm Collection focused approach to treatment research, they evaluate a patient’s case history and the en III t expression profiles of cancerous tissues— I/II Phase II when available—along with evidence-based Clinical research, an integral part of the CCR, is con- ducted in the new NIH Clinical Research Center pharmacological data. Clinicians try to (CRC) on the Bethesda campus of the NIH. This match patients with the appropriate avail- facility contains state-of-the-art diagnostic and able trials. The overarching goal is to detect therapeutic capabilities to support clinical research *Natural history, imaging, screening, programs in pediatric and adult oncology conducted and diagnose cancers earlier and more accu- follow-up, psychosocial, supportive care, epidemiology, surgery by clinical investigators in laboratories or branches rately and treat patients more effectively of the CCR. In fiscal year 2005, there were more than 30,000 total outpatient visits and over 1,000 in-patient than is possible with standard treatments. admissions to the CCR clinical research program. With the laboratory bench down the hall epidemiology, and surgery trials. Many of from the patient’s bedside, CCR scientists the new treatments are small molecules or can take a new agent that shows promise in biological agents (see Figure 2) developed at an early phase study and return to the bench the CCR or in collaboration with academic Throughout the day-to-day care of cancer patients, to improve its stability, or to develop a or industry partners. CCR clinicians train the next generation of radiolo- gists, oncologists, surgeons, pharmacologists, and better way to deliver the drug, or to design The majority of the treatment trials at nurses for careers in clinical research. Several better imaging agents to help monitor its CCR are early phase studies. CCR focuses CCR training programs lead to board certification action in the body. Areas of ongoing on proof-of-principle research. These small in cancer specialties (see Training, pg. 32). science-based trials include: early detection, trials answer some of the basic questions immunotherapy, adoptive cell transfer about optimizing a new drug’s effective dose therapy, molecular targets, innovative and manner of delivery. Well before any new combination treatment regimens, drug agent is placed in a Phase I trial, though, AVAILABLE CCR CANCER TRIALS resistance, local therapy, cancer genetics, massive preclinical data has been collected and molecular profiling. and studied carefully in anticipation of CCR’s cancer trials open for enrollment moving the treatment to patients. CCR are available at: New Territory researchers undertake these high-risk, high- http://www.cancer.gov/clinicaltrials. Approximately two-thirds of the clinical impact studies to develop new agents and research studies at CCR are testing novel deliver them as stable and effective drugs. treatments for cancer (see Figure 1). The rest Occasionally CCR works collaboratively are natural history studies, specimen collec- with pharmaceutical companies to improve tion, imaging and screening trials, plus the composition of their new agents. follow-up, psychosocial, supportive care, New protocol concepts undergo rigorous, 10 National Cancer Institute
    • Figure 2 usefulness of a therapy or compare an inves- The Phase O Initiative tigational treatment against standard treat- As part of CCR’s role in developing and ment, if there is one. testing new agents, the CCR is partnering Phase I trials generally involve a small with NCI’s Division of Cancer Treatment number of patients. These trials find a safe and Diagnosis (DCTD) to launch a Phase 0 dosage, decide how the agent should be Initiative. CCR’s strength in integrated Biologics Small Molecules immunotherapies molecularly targeted given, and observe how the agent affects the research and its clinical program will be agents patient’s body. Cancer patients who have no combined with DCTD’s expertise in drug known effective treatment options are development and its relationships with eligible for Phase I trials. Study participants pharmaceutical companies to create a joint- are divided into cohorts, and each cohort of program in drug development that will Other* participants is treated with an increased perform “first-in-human studies,” mini-trials dose of the new therapy or technique. called Phase 0 trials. These studies will vali- Phase II trials are designed to evaluate the date the initial scientific rationale that is effectiveness of the drug in a larger group of driving researchers to promote a new *Transplant, cell therapy, radiation, radiofrequency ablation, gene therapy, participants using the dosage determined to protocol by gathering pharmacological data surgery, exercise be safe in Phase I trials. Researchers often directly from human volunteer patients. The focus Phase II trials on cancers for which no goal is to subject promising new agents to effective treatment exists and/or cancers sophisticated, preliminary human toxicity timely reviews via relevant boards and that are most likely to show a response to (pharmacokinetic and pharmacodynamic committees. Modifications are made as therapy. If an acceptable percentage of the assays) and then, based on the results, select recommended to ensure optimal trial patients respond well to the drug in a Phase those that are most likely to succeed through designs that protect patient safety during II trial, the agent will go forward to a phase Phase I, II, and III trials. discovery and refinement of new and effec- III trial. tive cancer treatments. The CCR has an Phase III trials typically involve large administrative infrastructure to oversee and numbers of participants in order to deter- maintain all aspects of the highest quality mine whether a new therapy or technique is and ethical clinical research, including more effective or less debilitating than a regular refresher-training in clinical research, standard treatment. These trials are patient privacy safeguards, research nursing conducted at multiple institutions around and data management support, statistical the country, including community settings. evaluation, and outreach programs to The results of Phase III trials guide health promote and support patient accrual. care professionals and people with cancer in making treatment decisions. A Step-by-Step Process Clinical trials, or research studies in which humans participate, are conducted in Clinical Trials: From Bench to Bedside phases. There are many types of trials, including treatment, prevention, detection, Phase 0 Phase I Phase II Phase III diagnostic, and quality-of-life. The majority Avg. Years 0.5 1.5 2 3.5 of trials under way in the CRC are treatment Est. No. of Patients 6–10 20–100 30–200 150–5000 trials designed to test the safety and effec- tiveness of new drugs, biological agents, Purpose Validate Determine Evaluate Confirm techniques, or other interventions in people molecular safe dose, effectiveness, effectiveness, target side effects side effects monitor adverse who have been diagnosed with cancer. reactions These trials evaluate the potential clinical Center for Cancer Research 11
    • CLINICAL RESEARCH AT CCR Improving Early Detection and Diagnosis Exploring the Power of Molecular Profiling The pace at which scientific discovery and Profiles Inform Therapy its application to patient care is advancing Dr. Wyndham Wilson developed a novel has been aided by new technologies and far- treatment strategy for patients with diffuse reaching collaboration among scientists. large B-cell lymphomas (DLBCL) called Gene expression profiling and improved Dose-Adjusted EPOCH-Rituximab (DA- imaging techniques are two areas that have EPOCH-R). Results from several studies had huge impacts on clinical research, suggest that this new therapy may become enabling scientists to envision a near future the treatment of choice for DLBCL because when enough detail can be gleaned about cure rates increased by 20 to 30 percent each patient’s cancer to provide the right when compared to results with standard A CCR researcher loads a protein lysate to mass intervention for the right reason at the right treatment. An international Phase III trial is spectrometry equipment in search of unique protein time. now under way to carefully compare DA- profiles or marker proteins (called biomarkers). EPOCH-R to the standard. Already prelim- Patient Profiling Gene expression profiling or genomics Lymphochip (studies of the structure and function of multiple genes) and protein expression profiling or proteomics (analysis of complete sets of proteins to deter- mine their interactions and func- tions) are powerful new tools in biomedical A CCR researcher uses a gene chip to study cancer- research that ous tissue samples for changes in gene expression. CCR scientists are using to find differences “My basic vision is that every cancer between normal and cancer cells and to patient receive a molecular diagnosis,” understand how healthy cells says CCR’s Louis Staudt. “Then we could become malignant. With these tech- steer each patient to the optimal therapy, nologies, clinicians are moving to based on the characteristics of his or more targeted, science-based strategies for her tumor.” early detection and diagnosis, prognosis, The lymphochip holds small, tethered DNA and individualized therapy. CCR investiga- sequences (cDNAs) of known identity that repre- sent the entire lymphocyte genome. Using comple- tors are identifying different patterns of mentary DNA binding, CCR researchers use this gene and protein expression in cancer cells. chip to study the gene expression of thousands of These technologies and their patterns— genes simultaneously. In the Lymphoma/Leukemia Molecular Profiling Project, the Lymphochip will molecular profiles—are already improving help CCR researchers define the genomic profiles of the diagnosis and management of cancer. all types of human lymphoid malignancies. 12 National Cancer Institute
    • inary insights are being gained from Genomic Profiling of DLBCL biomarkers in this trial. For some patients whose biomarkers predict a poor response to standard treatment, these same biomarkers Diffuse Large B Cell do not predict failure with DA-EPOCH-R. Lymphoma Such discoveries show how individual (DLBCL) profiles may be used to guide treatment choices for a patient. Dr. Louis Staudt used genomic tech- nology to explain why some patients with Activated Germinal Center Primary B Cell-like (ABC) Mediastinal B Cell-like (GCB) B Cell diffuse large B-cell lymphomas (DLBCL) DLBCL DLBCL Lymphoma live longer and respond better to therapy IRF4 PIM2 than others. Under the microscope, the CCND2 BCL2 DLBCL cancer cells from every patient look PRKCB1 the same. The Staudt lab profiled the genes PDE4B CD39 expressed in patients with DLBCL and High CD10 CR2 found important differences, leading him to Genes BCL6 LRMP identify three molecularly and clinically SERPINA11 distinct subclasses of the disease: germinal LMO2 MYBL1 center B-cell-like (GCB), activated B cell-like Low SLAM Gene (ABC), and primary mediastinal B-cell Expression CD30 TARC lymphoma (PMBL). PDL2 These lymphoma subclasses arise in B MAL IL4I1 cells at different stages of maturation and follow different molecular pathways that Lymphoma Biopsies lead to cancer development. Their discovery revealed new molecular targets and new The genomic profiling of diffuse large B-cell lymphoma provides clear proof of principle that microarray technology can reach beyond a tissue slide and dramatically improve a clinician’s ability to diagnose lymphoid treatment approaches based on subclass. Dr. malignancies more precisely. Staudt’s group is developing new therapies to inhibit the NF-kB pathway, which is crit- ical to cancer growth and survival in two of Children’s Oncology Group, and other produced by treatment with the immunosu- the DLBCL subclasses, ABC and PBML. extramural partners, identified a molecular pressant rapamycin, had the best prognosis. These new therapies are being tested in the profile of RMS tumors that responds well to Further analysis of the children’s tumor clinic by Dr. Wilson’s team. therapy. Using reverse-phase protein profiles identified key proteins—such as 4E- microarrays and antibodies that indicate the BP1, and the phosphorylated forms of 4E- Profiles Inform Prognosis presence of a dozen key signaling proteins in BP1 and AKT—that could completely Until recently, there was no reliable indi- the cell, the Helman-Liotta teams examined segregate responders from non-responders. cator to predict treatment outcomes for chil- tumor samples from children with non- Lymphoma and rhabdomyosarcoma are dren with rhabdomyosarcoma (RMS), a metastatic and metastatic forms of this just two examples of cancers being studied fast-growing, highly malignant soft tissue cancer. CCR clinicians found a strong corre- by CCR scientists by using genomic or tumor—yet treatment fails 30 percent of lation between successful treatment and proteomic profiles of individual tumors. By these young patients. Clinicians may now suppression of a cellular system called the improving patient profiling, clinicians will have their indicator. Using proteomics tech- “AKT/Target of Rapamycin pathway be able to make a more accurate diagnosis, nology, Drs. Lance Liotta and Lee Helman (AKT/mTOR),” a major regulator of cell prescribe the best treatment, and improve and their research teams, in collaboration growth. Patients with AKT/mTOR suppres- the patient’s chances of long-term survival. with the Food and Drug Administration, the sion profiles, which resembled the ones Center for Cancer Research 13
    • CLINICAL RESEARCH AT CCR Developing Effective and Efficient Treatments Training T Cells To Attack Cancer In a mouse model, Dr. Nicholas Restifo has demon- A critical component of the CCR’s strength strated that T cells that mature after being returned in transnational research is an infrastructure to the mouse’s body are better tumor killers. This that facilitates bench-to-bedside-to-bench insight is being applied to improve the ex vivo research at the clinical center. This environ- enhancement phase for TILs. ment is enabling CCR’s physician scientist Dr. Steven A. Rosenberg to develop and refine an innovative approach to immuno- therapy. By closely coordinating the roles of the pathologist, surgeon, and nurses, the Rosenberg team, in experimental studies of Before treatment After treatment their new approach, is saving lives, producing dramatic results in patients with advanced melanoma. with a high dose of interleukin-2 (IL-2), a Dr. Rosenberg’s goal is to optimize each protein that stimulates the immune system. patient’s immune response, so that immune The researchers have faced many hurdles operatives called T cells will circulate in developing this therapy—all of which throughout the patient’s body, recognize they’ve been able to overcome. At first, the markers on the surface of a tumor, and TILs did not last long enough in the body to Drs. John Wunderlich and Rosenberg converse as the TILs are excised from the patient’s cancerous attack and kill the cancer cells. They are do their work, they could not multiply into tumor. Photo credit: Rhoda Baer testing this approach, called “adoptive cell large enough numbers to be effective, and transfer therapy” against melanoma and they failed to reach the target cancer cells. kidney cancer. Dr. Rosenberg’s team solved these formi- The scientists identify a specific kind of dable problems one by one. T cell called tumor-infiltrating lymphocytes In their most recent experimental study, (TILs) that the patient’s immune system has 35 patients with metastatic melanoma generated in response to his or her cancer. underwent the adoptive cell transfer These TILs are removed from the patient’s process. Fifty one percent of the patients tumor right after the tumor is removed. This responded—Three experienced a complete population of TILs is then tested against response and 15 had a partial response tumor samples from the patient, and the lasting from 2 months to 2 years. Over half most potent TILs are collected and of these patients entered the study with expanded in the laboratory, or ex vivo. tumors resistant to chemotherapy and all Meanwhile, the patient is given chemo- but one were resistant to high-dose IL-2 therapy drugs to eliminate any ineffective therapy. This study is a dramatic proof- T cells that remain in the body, so that the of-principle that immunotherapy has Dr. Rosenberg and Azam Nahvi inspect the growth enhanced population of TILs being grown tremendous potential against cancer that of a patient’s TILs and estimate when they will be ex vivo will have the chance to rebuild the has advanced to stages once considered ready for harvesting. Photo credit: Rhoda Baer patient’s immune system. Once the TILs beyond help. have multiplied to sufficient numbers in the lab, they are returned to the patient along 14 National Cancer Institute
    • TRAINING AT CCR Teaching the Art of Inquiry The Office of Training Education, headed opportunities in anatomic pathology, by Dr. Jonathan Wiest, plays an integral emphasizing the art of establishing clinical CCR POSTDOCTORAL part of the CCR mission to support young correlations to disease mechanism. FELLOWSHIPS AND TRAINING PROGRAMS scientists as they become independent s ACGME Medical Oncology Fellowship— researchers. In addition to managing about provides transnational research training ACGME Clinical Residency Programs: 900 post-doctoral and 150 post-baccalau- in medical oncology. Fellows develop s Residency in Radiation Oncology reate students, the program supports the their expertise over a 3-year period. This s Residency in Anatomic Pathology next generation of clinical investigators, is the oldest training fellowship in the s Residency in Dermatology minority researchers, and high-school and intramural program. ACGME Clinical Fellowship Programs: college students who come to CCR to work s ACGME Pediatric Hematology/Oncology s Medical Oncology as summer interns. Fellowship—pairs the Johns Hopkins s Johns Hopkins University/ Individuals at every level of training expe- University and the NCI Pediatric NCI Pediatric Hematology/Oncology rience scientific enrichment. CCR investiga- Oncology Branch to prepare researchers s Hematopathology tors-in-training have access to cutting edge adept in laboratory and/or clinical s Cytologic Pathology technologies and computational services research in this area. Additional Clinical Fellowship along with exceptional online library Programs: resources to fortify their pursuit of cancer’s Some resources useful to CCR’s postdocs s Surgical Oncology biology. They are groomed in the essentials include: s Urological Oncology for the conduct of ethical and informative s Fellows Editorial Board—run by the s HIV and AIDS Malignancy clinical and laboratory research and in the fellows, provides editorial services and s Gynecologic Oncology skills needed for lab management. They also review for scientific papers. s Neuro-Oncology receive training in writing professional s transnational Research in Clinical papers and presenting their data. The CCR Oncology (TRACO) is a course for post- Translational Fellowships: s Multidisciplinary Fellowship in Breast has taken several steps to broaden the doctoral fellows to enable strong collabo- Cancer Research training experience across the NIH campus. ration between basic and clinical scientists s Gynecologic Cancer Foundation/ Investigators can participate, for example, to develop novel approaches for the treat- NCI Fellowship in Gynecologic Oncology in transnational fellowships in molecular ment of cancer. This Web-cast course has s Postdoctoral Fellowships in pathology, radiation sciences, biostatistics, been adapted for training young investiga- Radiation Sciences or chemistry. tors in Spain. s Biostatistics/Mathematics Training Fellowship (Informatics CCR’s labs and clinics at the clinical Training Program) center are equally important training More information on training opportunities s Program for Interdisciplinary grounds for clinical fellows—young oncolo- at CCR can be found at: Training in Chemistry (PITC) gists, radiologists, and surgeons who have CCR Office of Training and Education: s Comparative Molecular Pathology decided to specialize in cancer care. They http://ccr.nci.nih.gov/careers/office_training_ Research Training Program s University of Cambridge/ come to NCI for up-to-3-year rotations that education.asp GlaxoSmithKline Oncology Fellowship permit them to combine clinical experience Training Opportunities at NCI: http:// with investigator-initiated research in www.cancer.gov/researchandfunding/ Basic Science Fellowships: nearby labs. fellowships s Cancer Research Training Awards s ACGME Clinical Residency in Anatomic Research and Training Opportunities at s Visiting Fellow Program Pathology—offers training and research NIH: http://www.training.nih.gov Center for Cancer Research 15
    • Web Sites With More Information About CCR CENTER FOR CANCER RESEARCH http://ccr.cancer.gov For information on CEI research http://home.ccr.cancer.gov/coe/immunology Office of the Director http://ccr.cancer.gov/about/default.asp Office of the Clinical Director http://ccr.cancer.gov/trials/clinical_director.asp Office of Communications http://ccr.cancer.gov/news/ooc.asp Office of Science and Technology Partnerships http://ccr.cancer.gov/research/ostp/ Office of Training and Education http://ccr.nci.nih.gov/careers/office_training_education.asp PATIENT INFORMATION ON CANCER AND CLINICAL TRIALS Open NCI Clinical Trials http://www.cancer.gov/clinicaltrials How to Refer a Patient http://bethesdatrials.cancer.gov/professionals/refer.asp NCI Cancer Information Service http://cis.nci.nih.gov/ 1-800-4-CANCER (1-800-422-6237) For deaf and hard-of-hearing 1-800-332-8615 Understanding Cancer Series http://www.cancer.gov/cancertopics/understandingcancer Clinical Studies Support Center (CSSC) http://ccr.cancer.gov/trials/cssc/staff/services.asp ADDITIONAL LINKS National Cancer Institute (NCI) http://www.cancer.gov Working at the NCI http://www.cancer.gov/aboutnci/working National Institutes of Health (NIH) http://www.nih.gov 16 National Cancer Institute
    • Center for Cancer Research Bldg. 31, Room 3A11 MSC 2440 31 Center Drive Bethesda, MD 20892-2440 Phone: 301-496-4345 Fax: 301-496-0775
    • NIH Publication Number 06-5736S Printed October 2005