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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESNational Institutes of Health

Center for Excellence in ImmunologyCenter for Cancer Research

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

Table of contents

The Center of Excellence in Immunology

The Center of Excellence in Immunology(CEI), part of the National CancerInstitute's intramural research program inthe Center for Cancer Research (CCR), is acommunity of scientists who integratediscovery with the development of novel,immune-based treatments for cancer andAIDS. Based in Maryland, on the Bethesdaand Frederick campuses of the NationalInstitutes of Health, the CEI is home to acritical mass and unique mix of basic, trans-lational, and clinical scientists who work inmultidisciplinary teams to aggressivelypursue new approaches for the preventionand treatment of cancer and AIDS.Considered one of the leading communitiesof immunology researchers in the world,CEI scientists bring a distinguishing strengthto the CCR. They already have producedmany immune-based interventions that areoffering relief to those with cancer andAIDS. Their integrated research also lays astrong foundation for new advances andbrings hope for the future. The stories in thisbooklet provide a glimpse of their contribu-tions to our progress against cancer.

Several key areas of research emphasis atthe CEI are illustrated in this booklet,including cell-based therapy, immuno-therapy with antibodies, cytokine-basedtreatments, as well as vaccines to prevent ortreat cancer and HIV/AIDS. These research

snapshots attempt to capture CEI’s strategicuse of the immune system to detect cancerearlier, diagnose it more precisely, andprevent or treat it more effectively-all withan eye toward the NCI Challenge Goal: Toeliminate the suffering and death due tocancer by 2015.

The distinctive infrastructure of the NCIintramural research program is alsocaptured in this publication. Here anenabling infrastructure empowers CEIscientists to do innovative work. Teamingwithin the NCI intramural program, theyinvent new tools or harness existing ones totranslate their discoveries about cancer andthe immune system into treatment interven-tions. Using cutting-edge technologies suchas functional imaging, genomics, proteomics,CEI researchers drive their discoveries fromthe bench, to early phase clinical studies, allthe way to a benefit for cancer patients.Ground-breaking advances in genomics,for example, were quickly applied to themolecular profiling of lymphoma and haverevolutionized diagnosis and treatment fortoday’s patients with this disease.

Another key attribute of the NCI’s intra-mural research program that benefits CEIscientists is its longstanding support forhigh-risk research that has potential formaking a major impact. Projects that mightbe considered too risky for industry or

academia to provide prolonged funding aresustained at the NCI. Current clinical trialsof adoptive cell therapy illustrate this well.Without NCI’s two decades of support forcellular therapy research, cancer patientstoday might not be benefiting from theremarkable progress evident in treatmentfor advanced melanoma.

CEI has made impressive advances. Itssuccess flows from a distinctive researchenvironment: one in which a critical mass ofable researchers unselfishly pool theirdiverse talents to create a “culture of thecorridors” that fosters and produces acenter of research excellence. As theDirector of the CEI, I am privileged to sharewith you some of our accomplishments.

Robert H. Wiltrout, PhD.Director, Center of Excellence inImmunologyDirector, Center for Cancer ResearchNational Cancer InstituteNational Institutes of Health

Center for Cancer Research 1

Letter from the Director

2 National Cancer Institute

The CCR is home to one of the strongestimmunology and virology communities inthe world with renowned scientistsperforming basic, transnational, and clinicalresearch. In 2003, the Center of Excellencein Immunology (CEI), a 250-memberfaculty headed by Dr. Robert Wiltrout,brought these investigators together withina collaborative unit to further the discovery,development, and delivery of novelimmunologic approaches for the preven-tion, diagnosis, and treatment of cancer andcancer-associated viral diseases. Thiscommunity of bench scientists and clinicians

with a wide range of expertise, work as athink-tank, proactively mapping the futureof immunology research at the CCR. With aglobal reach and vision, they have identifiedopportunities and barriers to progress andare collaborating with extramural investiga-tors, academia, and the pharmaceuticalindustry worldwide to harness the power ofthe immune system to fight cancer andimprove patient care.

CEI members have made groundbreakingdiscoveries in the fields of cytokines, cellularand innate immunity, viral immunology,and immunotherapy, including cancervaccines, immunotoxins, radioimmuno-therapy, and cellular therapy. Theircombined research has resulted in morethan 4,700 publications in scientific jour-nals since 1990. Having pioneered many ofthe approaches in use today, researchers inthe CEI stand at the forefront ofimmunotherapy. Some of their bench-to-bedside research “firsts” include:

Cytokine-Based TherapyDiscovery of IL-2, plus a subunit of the IL-2 receptor complex, and JAK3, a kinasecritical for IL-2 responses. These basicresearch findings have been translated to theclinic so that today, IL-2 is an FDA-approved treatment for metastatic renalcancer and melanoma. CEI members havealso developed antibodies to the IL-2receptor and used these for treatments ofsome forms of leukemia, autoimmunedisease and graft versus host disease. Thiswork was among the first to demonstratethe potential of monoclonal antibodytherapy in treating cancer. Now numerousmonoclonal antibodies are in clinical trials

MULTI-INSTITUTIONAL/MULTIDISCIPLINARY FOCUS

Preempting Cancer at the Earliest Opportunity

Researcher Tom Shelton harvests a patient’s tumorinfiltrating lymphocytes after they have been acti-vated and grown in vitro. Photo credit: Rhoda Baer

In 2003, four Centers of Excellence emerged from areengineering process that optimized the NCI’sintramural research infrastructure. Through thesenew Centers, NCI’s intramural researchers formedteams engaged in transnational research. CCRleads three of the Centers:

• Advanced Biomedical Technology• Immunology• Molecular Oncology

Spotlight on Center of Excellence in Immunology A premier community of immunologists


and monoclonal antibodies such as ritux-imab and trastizumab are routinely used fornon-Hodgkin’s lymphoma and breastcancer, respectively.

Adoptive Cell Transfer TherapyA novel cell-based therapy that involvesremoving infiltrating immune cells from thetumor, activating them in vitro, andreturning them to the patient. This approachhas resulted in improvement in 51 percentof patients with metastatic melanoma thathad not responded to earlier treatments (seepage 31). Given the bleak prognosis forthose with late-stage melanoma, these areremarkable and promising results.

Radio-ImmunotherapyCCR scientists coupled radioactive mole-cules with monoclonal antibodies to enableradio-immunotherapy for patients withrefractory non-Hodgkin’s lymphoma and Tcell leukemia. They then partnered withpharmaceutical companies to develop aproduct that was both safe and efficaciousin clinical studies in patients. This CCReffort yielded the first radio-labeled mono-

clonal antibody approved by the FDA as acancer treatment.

Immunotoxin TherapySeveral immunotoxins generated at theCCR are in clinical trials. Treatment withBL22 resulted in a very high completeresponse rate among patients with hairy cellleukemia that was resistant to standardtherapy. CCR scientists are also conductingclinical trials with the SS1P immunotoxin inmesothelioma, as well as ovarian andpancreatic cancer. Collaborations with thebiotech company IVAX have also resulted ina Phase II multicenter trial treating malig-nant brain tumors with TP38, anotherimmunotoxin.

Preventive Cancer VaccinesThe development of vaccines to preventcancer is another area of intense investiga-tion at the CEI that is poised to deliver richrewards. Basic research into the assembly ofHPV, the virus that causes cervical cancer,has been translated into avaccine designed to prevent thedisease (see page 14). Resultsof Phase II trials showed a highlevel of protection againstHPV infection, and Phase IIItrials testing this vaccine are inprogress.

Therapeutic Cancer VaccinesThe ever-expanding field oftherapeutic cancer vaccinesalso owes much to advancesmade by CEI researchers. Theyhave identified numerous novelcancer antigens, devised novelapproaches to vaccine design,improved vaccine delivery, aswell as discovered ways to optimize vaccine-induced immune responses with cytokinesand costimulatory molecules. CEI cliniciansrecently initiated a pilot study that was the

first clinical trial to combine radiation and acancer vaccine for treating prostate cancer.By showing that such combination therapyis safe and well tolerated, CCR is leading theway toward finding alternative treatmentsfor patients with localized disease whoreceive radiation or surgery and thenrelapse. In several clinical trials, there isevidence that immune responses to vaccineswere associated with prolonged survival.Several vaccines and combination protocolsare being developed at NCI and are beingevaluated at more than 60 cancer centersaround the country for testing in clinicaltrials. At least two of these vaccines areprogressing successfully from Phase II toPhase III studies.

Fueled by NCI’s sustained support, thecapacity to arrange global collaborations,and intellectual excellence in immunology,investigators in the CEI continue to breaknew ground to deliver more effective, lesstoxic treatments for cancer.

Dr. Steven Rosenberg proudly displays his wall of illus-trious alumnae, graduates of the Surgical OncologyFellowship at CCR. Photo credit: Rhoda Baer

Drs. Jeffrey Schlom (seated), Philip Arlen (right) andJames Gulley (left) evaluate the effectiveness of abreast cancer vaccine protocol. Photo credit:Rhoda Baer


SUSTAINED COMMITMENT

Developing Effective and Efficient Treatments

A 50-Year Odyssey by a Quintessential Physician-Scientist

Dr. Thomas Waldmann arrived at the NCIin 1956, just three years after the NIHClinical Center opened. What was envisionedas a 2-year fellowship became a 49-yearallegiance. He speaks with passion as hedescribes how the close proximity ofpatients to the research labs, the criticalmass of scientists with a remarkable varietyof expertise, and the sense of collaborationand comradery among researchers andphysicians enticed him to stay. He describesthe “culture of the corridors” of the ClinicalCenter as a unique interaction of infectiousexcitement and enthusiasm among basic

researchers and clinicians who want tomake a difference.

Dr. Waldmann has made high-impactcontributions towards understanding andtreating an astonishing array of diseases andclinical disorders. He sums up his fivedecades at the NCI as a fascinating odyssey.Prior to 1980, he focused primarily onmetabolism of serum proteins. This body ofwork led to insight into ataxia telangiec-tasia, myotonic dystrophy, familial hyper-catabolic hyperproteinemia, Wiskott-Aldrich syndrome, allergic gastroentero-pathy and intestinal lymphangiectasia (alsotermed Waldmann’s disease). He thenpioneered advances in how germ-celltumors in the testis are diagnosed andtreated, and how a type of human T cells,immune cells called “suppressors” that actas regulators, behave in immunodeficiencydiseases and some forms of leukemia. Healso devised a novel form of molecular

“Nowhere in the nation do I see the ability

to do basic science, to take it to preclin-

ical drug development and into the clinic

as you can at the NCI. It is very exciting

to see your patient get better with an

agent that you’ve developed yourself.

I cannot tell you how exhilarating it is

to feel that you’ve made a difference.”

Thomas Waldmann

Dr. Waldmann is now unraveling the role of IL-15, apowerful cytokine that can prolong memory T-cellsand produce a long-lasting immune response.Photo credit: Rhoda Baer

Dr. Waldmann and his colleagues Jing Chen Ph.D.(facing camera on left) and Hiral Patel, HowardHughes Medical Scholar (back to camera on theright) examine a gel that confirms the purity of theirpreparation of IL-2 receptor. Photo credit: Rhoda Baer


genetic analysis to improve diagnosis andtreatment of leukemia.

In the late 1970s, a serendipitousdiscovery turned Dr. Waldmann andcoworkers’ attention to the newly born fieldof cytokines. Cytokines are a class ofproteins that act as signaling regulators inthe immune system. His group was trying togenerate an antibody to CD4, a markerprotein on the surface of T cells. They endedup instead with an antibody to an unknownprotein. Quickly, they determined theprotein was important to T-cell activation.So they cloned it and found it was part ofthe IL-2 receptor complex, where cytokinesbind to effect signaling. With this finding,they characterized the first cytokinereceptor, setting the stage for understanding

the biology and biochemistry of this familyof molecules.

Over the next 20 years, the Waldmannlab demonstrated that antibodies specificfor this receptor were useful in treatingadult T-cell leukemia, prolonging survival oftransplant recipients, and treating multiplesclerosis. As part of an effort to unravelparadoxical observations in these trials, Dr.Waldmann co-discovered the cytokine inter-leukin 15 that is critical for the survival ofyet another type of T cell, the “memory” T,named for its ability to remember past inva-sions and respond quickly to a pathogen’sre-entry. Waldmann is translating theselatest observations to the clinic by intro-

ducing IL-15 into cancer therapy, and intothe design of vaccines for cancer and AIDS.

Dr. Waldmann’s studies pioneered andpropelled the use of monoclonal antibodiesfor immunotherapy. Today hundreds of newantibodies are in clinical trials, and the Foodand Drug Administration already hasapproved about a dozen monoclonal anti-bodies, including Herceptin and Rituxan, totreat cancer and other diseases. ForWaldmann, a chance discovery in the 1970s,pursued with a prepared mind and sustainedcommitment, has had a far-reaching impact.

“You’ll see a patient and take that infor-

mation into the laboratory. From the

laboratory, you learn new insights that

can be translated into rational drug

development. The ability to move back

and forth is very special here.”

Thomas Waldmann

Dr. Waldmann explains possible side effects to Carolas she begins her combination chemotherapy andimmunotherapy. Photo credit: Rhoda Baer

“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

Dr. Waldmann carefully places an important paper ina safe place in his office. Photo credit: Rhoda Baer

When Drs. Anita Roberts and MichaelSporn (now at Dartmouth Medical School)discovered and characterized TGF-β in1981, they called it “transforming” becauseit can turn normal cells malignant, andbecause elevated levels of TGF-β predictpoor outcomes in many types of cancer.

Dr. Roberts and her colleagues developedmouse models to study the TGF-β-signalingpathway in inflammation, fibrosis, andcancer. TGF-β regulates many cellularprocesses in normal cells, including tissuerepair from injury. Intriguingly, mice lackingcomponents of the TGF-β-signaling path-way heal faster from epithelial wounds andare protected against skin injury caused byionizing radiation. CCR scientists are devel-oping inhibitors of TGF-β to see if they canspeed epithelial tissue repair followingcancer radiotherapy.

Although TGF-β was originally discov-ered for its tumor-promoting activity, it hasbecome clear that during the early stages of

cancer development, TGF-β often acts as atumor suppressor. Using a mouse model ofhuman breast cancer, CCR’s Dr. LalageWakefield demonstrated that TGF-βswitches from tumor suppressor to tumorpromoter, and it supports metastasis when abreast cancer changes from histologicallylow- to high-grade—a shift to more aggres-sive disease. Dr. Wakefield went on to makethe unexpected finding that certain TGF-βinhibitors can selectively block the tumorpromoter effects of TGF-β, withoutaffecting its tumor suppressor activity. Thisdiscovery with mouse models suggests thatTGF-β inhibitors might be useful to treatcancer metastasis in humans.

CCR has established a cooperativeresearch agreement (CRADA) withGenzyme Corporation to develop TGF-βantibodies for testing in clinical cancertrials, both alone and in combination withother cancer treatments, such as chemo-therapy and cancer vaccines. CCR continueswith an active program to target TGF-β incancer treatment, wound healing, and bloodand immune system disorders.

Dr. Wakefield is committed to deter-mining how TGF-β shifts from tumorsuppressor to tumor promoter. “Under-standing this problem will be critical if theTGF-β system is to be exploited effectivelyin novel approaches to the treatment ofbreast cancer.”

6 National Cancer Institute6 National Cancer Institute6 National Cancer Institute

CORRIDOR COLLABORATIONS

Understanding Causes and Mechanisms of Cancer

A Promoter and a Suppressor of Tumor Growth:The Complex Biology of TGF-ββTGF-β (transforming growth factor-beta) was discovered three decadesago at CCR and has confounded and delighted researchers ever since

During cancer progression, TGF-β signaling switches from producing growth negative to growth positive factors. Researchers are developing agents to selectively block this tumor promoting activity.

Dr. Roberts’ leadership in creatinga world-renowned center ofexpertise in TGF-β biology‚ wasrecognized by her recent award ofthe Leopold Griffuel Prize and theFederation of American Societiesfor Experimental Biology (FASEB)Excellence in Science Award.

Growthreceptor

TGF-βreceptor

Tumorsuppressor

Tumorpromoter

Normal fibroblast

Mutated fibroblast

Negativegrowth factors

(TGF-β)

Tumor

Positivegrowthfactors

TIMELINE OF TGF-ββ COLLABORATIONS

1980sIdentify and purify TGF-β CCR

TGF-β promotes CCRwound healing

Clone TGF-β CCR/Genentech

TGF-β inhibits growth NCI

1990sCrystal structures NIDDK/NIDRof TGF-β

TGF-β mouse models NINDS/NIDDK

First clinical trial with NINDSsystemic TGF-β

2000sCRADA to develop CCR/GenzymeTGF-β antibodies

TGF-β blockers suppress CCRmetastasis

TGF-β switches from CCRsuppressor to promoter


A vaccine to prevent cervical cancer, basedon technology developed by CCR scientistsDouglas Lowy and John Schiller, is in finalstages of testing. This vaccine offers greathope for reducing the global burden of cancer.

Almost every cervical cancer in the UnitedStates and abroad is caused by infectionwith human papillomavirus, or HPV. OnceNCI scientists in the Division of CancerEpidemiology and Genetics (DCEG) estab-lished the link between HPV and cervicalcancer, CCR scientists went to work todevise a vaccine against the virus. Theyfound that multiple copies of a single HPVprotein could assemble into non-infectiousvirus-like particles to form the basis of avaccine. Immunization with these particles,they learned, could stimulate production oflarge quantities of antibodies that preventvirus infection in both animals and humanvolunteers.

NCI licensed the technology to two phar-maceutical companies—Merck and Glaxo-Smith-Kline (GSK)—to develop HPV vaccinescommercially. Both companies are runninglarge-scale Phase III trials of their versionsof an HPV vaccine. GSK’s targets two HPVstrains, 16 and 18, which together causeabout 70 percent of all cervical cancers.Merck’s targets strains 6, 11, 16, and 18.Phase II trials by both companies producedencouraging results. The VLP vaccines were100 percent effective at preventing prema-lignant cervical abnormalities caused by thevirus types in the vaccines, even up to fouryears after vaccination.

The NCI is performing its own Phase IIItrial of the GSK vaccine in Costa Rica,where cervical cancer rates are high. TheNCI study is being run by DCEG’s Allan

Hildesheim and Rolando Herrero from theFondacion Inciensa in Costa Rica. Thewomen in the study will be followed for atleast 6 years, to obtain information aboutthe vaccine’s long-term safety and the extentand duration of protection.

CCR’s involvement in HPV vaccine devel-opment continues. Drs. Schiller, Lowy andcolleagues have developed the first high-throughput assay to enable HPV vaccinedevelopers to observe whether a vaccine caninduce potentially protective antibodyresponses against other cancer-causingstrains of HPV. They have made this assayavailable to other researchers to acceleratevaccine research.

In anticipation of approval of HPVvaccines, the Gates Foundation announcedin June 2005 that it would grant $12.9million to the World Health Organization,the International Agency for Research onCancer, Harvard University, and theProgram for Appropriate Technology inHealth to create systems to ensure qualitycontrol in vaccine distribution, monitor theimpact of different HPV vaccination strate-gies, and facilitate early introduction of thevaccines worldwide.

PUBLIC HEALTH CHALLENGES

Accelerating Progress in Cancer Prevention

Targeting the Virus That Causes Cervical Cancer:HPV Vaccine Will Have Global ImpactA vaccine to prevent cervical cancer is in final stages of testing

HPV L1 virus-like particles morphologically lookvery similar to authentic infectious [viral] particlesexcept that they don’t contain any DNA.

GSK and NCI are running a Phase III trial of an HPVvaccine to protect Costa Rican women from HPVinfections that are linked to cervical cancer.

The HPV prophylactic vaccine is highly immuno-genic, prompting the production of antibodies thatinterfere with binding of the intact HPV virus to apatient’s cells and entry through a receptor.

Cervical cancer strikes nearly half a millionwomen each year worldwide. It is the second lead-ing cancer killer, claiming a quarter of a millionlives annually. The vast majority of deaths occur inthe poorest regions of the world—South Asia, sub-Saharan Africa, and parts of Latin America—where access to screening services and medicalcare is limited.

An NCI team of experts in virology, vaccinedevelopment, epidemiology, immunology, patholo-gy, and cytology is helping to make cervical cancerprevention a reality.


PUBLIC HEALTH CHALLENGES


In June 1981, the Centers for DiseaseControl (CDC) published the first report offive cases of a mysterious immunodeficiencydisease. Two weeks later, a young man witha severe immune system disruption checkedinto the NIH Clinical Center with the helpof an oncologist in NCI’s IntramuralResearch Program. His condition was cate-gorized as a rare disease—and later turnedout to be one of the first cases of AcquiredImmune Deficiency Syndrome (AIDS) in theUnited States. The AIDS epidemic spreadquickly; by the end of that year more than200 people had died of AIDS in the UnitedStates.

The medical community faced a publichealth crisis. The cause of the new diseasewas unknown and there were no means totreat or prevent it. Groundbreaking basicresearch by investigators in NCI’s Intra-mural Research Program—and subsequentcollaborations with industry—rapidlyprovided important answers. By 1984, Dr.Robert Gallo’s group at NCI and a scientific

team at the Pasteur Institute in France haddiscovered the virus now known as humanimmunodeficiency virus (HIV) and impli-cated it as the cause of AIDS. Intramuralscientists also developed the first blood testto diagnose HIV infection and rapidly trans-ferred materials to industry for the commer-cial production of a test that could be usedfor blood screening at the nation’s bloodbanks.

Intramural researchers at NCI also playeda key role in the development of the firstdrugs for treating HIV infections and AIDS.An NCI-funded researcher had alreadysynthesized zidovudine (AZT) as a possibleanticancer drug. Drs. Samuel Broder,Hiroaki Mitsuya, and Robert Yarchoanmoved quickly to test AZT and other drugs:didanosine (ddI) and zalcitabine (ddC) fortreating patients with AIDS. All three drugswere licensed for treating HIV infection,and today these agents are combined withprotease inhibitors or non-nucleosidereverse transcriptase inhibitors in combina-tion antiretroviral therapy, known as highly

active antiretroviral therapy or HAART.This “cocktail” therapy has dramaticallyreduced the number of deaths and new casesof AIDS since its introduction in 1995. Thenumber of annual deaths among peoplewith AIDS in the United States has droppedto 15,600—less than one third the level atthe height of the AIDS epidemic in 1995,when the disease killed 51,670 people in theUnited 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,however, KS now accounts for 10 percent ofcancers in countries such as Congo and

HIV/AIDS: NCI Responds Swiftly to a Public Health CrisisA mysterious immunodeficiency disease

The virus that causes AIDS is shown budding out ofa human immune cell.

CCR’S AGILE INFRASTRUCTURE

IDENTIFICATION of HIV as causativeagent for AIDS

DEVELOPMENT of first blood test for HIV infection

DISCOVERY of first antibodies to kill HIV

IDENTIFICATION of many retroviral proteins, new HIV reservoirs, immune system receptors that recognize HIV, and human genes that influence HIV susceptibility and AIDS progression

UNDERSTANDING of how HIV infects a cell

CONTRIBUTIONS to HIV vaccine development

PREVENTION and TREATMENT for AIDS-related cancers

“In retrospect, our work was an ideal

demonstration of what the Clinical

Center is all about. A laboratory could do

certain things and then, in effect, take

the observation twenty feet down the

hall into a clinical area and begin treating

patients. That kind of interaction and that

kind of ability is really very rare.”

Former NCI Director Dr. Sam Broder: Interviewwith Gretchen Case of History Associates, Fall 1996


Uganda. As part of its long-term commit-ment to reducing the cancer burden formedically underserved populations world-wide, CCR researchers are developing newtreatments for KS based on developingknowledge of how the Kaposi’s sarcomaherpes virus (KSHV) causes the disease. Drs.Richard Little and Robert Yarchoan areconducting clinical trials using novel thera-pies to cut off the blood supply to thetumors (called antiangiogenic therapy)using agents such as thalidomide, beva-cizumab, and a combination of IL 12—anagent with antiangiogenic and immunologicactivity—and liposomal doxorubicin.

In developed countries, the growingpopulation of people living with HIV infec-

tion and AIDS are living longer but still facesignificant health challenges. People infectedwith HIV are at a 20-fold increased risk fordeveloping several forms of cancer,including KS, certain lymphomas, pluscancers of the cervix, liver, lip, mouth andpharynx, and several others. HAARTtherapy can reduce the incidence of somethese cancers in HIV-infected patients, butothers are becoming more common. Often,these cancers are caused by co-infectionwith other viruses, such as Epstein Barrvirus or hepatitis C virus. CCR scientists areactively involved in developing antiviraland other approaches for these AIDS-associated cancers.

2003

Population of AIDS Survivors at Risk for Cancers

HAART is introduced

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Kaposi sarcoma lesions most often develop in thepatient’s feet because they are often hypoxic (lowoxygen). This condition induces replication inKSHV-infected cells.

Yesterday’s Achievement

Today’s Challenge

NCI’S AIDS VACCINE PROGRAM

In addition to conducting its own intra-mural research, the NCI’s AIDS VaccineProgram, headed by Dr. Jeffrey Lifson,saves the research community millions ofdollars and speeds research progress bydeveloping and providing a broad range ofnovel reagents, assays, and analyticalmethods to U.S. and internationalresearchers who study AIDS and cancer. Ithas more than 4,300 reagents (cell lines,proteins, antibodies, viruses). More than139,000 vials have been shipped to scien-tists from the United States and 63 foreigncountries.


CCR scientists are translating discoveries atthe bench into new diagnostic approachesand new targeted therapies, collectingmolecular profiles for many cancer typesand developing databases that eventuallywill serve the era of molecular medicine.CCR clinicians use a science-based rationalefor treatment planning. With a patient-focused approach to treatment research,they evaluate a patient’s case history and theexpression profiles of cancerous tissues—when available—along with evidence-basedpharmacological data. Clinicians try tomatch patients with the appropriate avail-able trials. The overarching goal is to detectand diagnose cancers earlier and more accu-rately and treat patients more effectivelythan is possible with standard treatments.

With the laboratory bench down the hallfrom the patient’s bedside, CCR scientistscan take a new agent that shows promise inan early phase study and return to the benchto improve its stability, or to develop abetter way to deliver the drug, or to designbetter imaging agents to help monitor itsaction in the body. Areas of ongoingscience-based trials include: early detection,immunotherapy, adoptive cell transfertherapy, molecular targets, innovativecombination treatment regimens, drugresistance, local therapy, cancer genetics,and molecular profiling.

New TerritoryApproximately two-thirds of the clinicalresearch studies at CCR are testing noveltreatments for cancer (see Figure 1). The restare natural history studies, specimen collec-tion, imaging and screening trials, plusfollow-up, psychosocial, supportive care,

epidemiology, and surgery trials. Many ofthe new treatments are small molecules orbiological agents (see Figure 2) developed atthe CCR or in collaboration with academicor industry partners.

The majority of the treatment trials atCCR are early phase studies. CCR focuseson proof-of-principle research. These smalltrials answer some of the basic questionsabout optimizing a new drug’s effective doseand manner of delivery. Well before any newagent is placed in a Phase I trial, though,massive preclinical data has been collectedand studied carefully in anticipation ofmoving the treatment to patients. CCRresearchers undertake these high-risk, high-impact studies to develop new agents anddeliver them as stable and effective drugs.Occasionally CCR works collaborativelywith pharmaceutical companies to improvethe composition of their new agents.

New protocol concepts undergo rigorous,

CLINICAL RESEARCH AT CCR


Clinical Trials at the NIH Clinical Center

IIII/II

Pilot

Phase II

Phase ISpecimenCollection

Other*

*Natural history, imaging, screening,follow-up, psychosocial, supportive care, epidemiology, surgery

Treatment

Figure 1

Clinical research, an integral part of the CCR, is con-ducted in the new NIH Clinical Research Center(CRC) on the Bethesda campus of the NIH. Thisfacility contains state-of-the-art diagnostic andtherapeutic capabilities to support clinical researchprograms in pediatric and adult oncology conductedby clinical investigators in laboratories or branchesof the CCR. In fiscal year 2005, there were more than30,000 total outpatient visits and over 1,000 in-patientadmissions to the CCR clinical research program.

Throughout the day-to-day care of cancer patients,CCR clinicians train the next generation of radiolo-gists, oncologists, surgeons, pharmacologists, andnurses for careers in clinical research. SeveralCCR training programs lead to board certificationin cancer specialties (see Training, pg. 32).

AVAILABLE CCR CANCER TRIALS

CCR’s cancer trials open for enrollment are available at: http://www.cancer.gov/clinicaltrials.


timely reviews via relevant boards andcommittees. Modifications are made asrecommended to ensure optimal trialdesigns that protect patient safety duringdiscovery and refinement of new and effec-tive cancer treatments. The CCR has anadministrative infrastructure to oversee andmaintain all aspects of the highest qualityand ethical clinical research, includingregular refresher-training in clinical research,patient privacy safeguards, research nursingand data management support, statisticalevaluation, and outreach programs topromote and support patient accrual.

A Step-by-Step ProcessClinical trials, or research studies in whichhumans participate, are conducted inphases. There are many types of trials,including treatment, prevention, detection,diagnostic, and quality-of-life. The majorityof trials under way in the CRC are treatmenttrials designed to test the safety and effec-tiveness of new drugs, biological agents,techniques, or other interventions in peoplewho have been diagnosed with cancer.These trials evaluate the potential clinical

usefulness of a therapy or compare an inves-tigational treatment against standard treat-ment, if there is one.

Phase I trials generally involve a smallnumber of patients. These trials find a safedosage, decide how the agent should begiven, and observe how the agent affects thepatient’s body. Cancer patients who have noknown effective treatment options areeligible for Phase I trials. Study participantsare divided into cohorts, and each cohort ofparticipants is treated with an increaseddose of the new therapy or technique.

Phase II trials are designed to evaluate theeffectiveness of the drug in a larger group ofparticipants using the dosage determined tobe safe in Phase I trials. Researchers oftenfocus Phase II trials on cancers for which noeffective treatment exists and/or cancersthat are most likely to show a response totherapy. If an acceptable percentage of thepatients respond well to the drug in a PhaseII trial, the agent will go forward to a phaseIII trial.

Phase III trials typically involve largenumbers of participants in order to deter-mine whether a new therapy or technique ismore effective or less debilitating than astandard treatment. These trials areconducted at multiple institutions aroundthe country, including community settings.The results of Phase III trials guide healthcare professionals and people with cancer inmaking treatment decisions.

The Phase O InitiativeAs part of CCR’s role in developing andtesting new agents, the CCR is partneringwith NCI’s Division of Cancer Treatmentand Diagnosis (DCTD) to launch a Phase 0Initiative. CCR’s strength in integratedresearch and its clinical program will becombined with DCTD’s expertise in drugdevelopment and its relationships withpharmaceutical companies to create a joint-program in drug development that willperform “first-in-human studies,” mini-trialscalled Phase 0 trials. These studies will vali-date the initial scientific rationale that isdriving researchers to promote a newprotocol by gathering pharmacological datadirectly from human volunteer patients. Thegoal is to subject promising new agents tosophisticated, preliminary human toxicity(pharmacokinetic and pharmacodynamicassays) and then, based on the results, selectthose that are most likely to succeed throughPhase I, II, and III trials.

Small Moleculesmolecularly targeted

agents

Other*

Biologicsimmunotherapies

*Transplant, cell therapy, radiation,radiofrequency ablation, gene therapy, surgery, exercise

Clinical Trials: From Bench to Bedside

Phase 0 Phase I Phase II Phase III

Avg. Years 0.5 1.5 2 3.5

Est. No. of Patients 6–10 20–100 30–200 150–5000

Purpose Validate Determine Evaluate Confirm molecular safe dose, effectiveness, effectiveness, target side effects side effects monitor adverse reactions

Figure 2



Improving Early Detection and Diagnosis

The pace at which scientific discovery and

its application to patient care is advancing

has been aided by new technologies and far-

reaching collaboration among scientists.

Gene expression profiling and improved

imaging techniques are two areas that have

had huge impacts on clinical research,

enabling scientists to envision a near future

when enough detail can be gleaned about

each patient’s cancer to provide the right

intervention for the right reason at the right

time.

Patient ProfilingGene expression profiling or genomics(studies of the structure and function ofmultiple genes) and protein expressionprofiling or proteomics (analysis ofcomplete sets of proteins to deter-mine their interactions and func-tions) are powerfulnew tools inb i o m e d i c a lresearch thatCCR scientistsare using tofind differencesbetween normaland cancer cells and tounderstand how healthy cellsbecome malignant. With these tech-nologies, clinicians are moving tomore targeted, science-based strategies forearly detection and diagnosis, prognosis,and individualized therapy. CCR investiga-tors are identifying different patterns ofgene and protein expression in cancer cells.These technologies and their patterns—molecular profiles—are already improvingthe diagnosis and management of cancer.

Profiles Inform TherapyDr. Wyndham Wilson developed a noveltreatment strategy for patients with diffuselarge B-cell lymphomas (DLBCL) calledDose-Adjusted EPOCH-Rituximab (DA-EPOCH-R). Results from several studiessuggest that this new therapy may becomethe treatment of choice for DLBCL becausecure rates increased by 20 to 30 percentwhen compared to results with standardtreatment. An international Phase III trial isnow under way to carefully compare DA-EPOCH-R to the standard. Already prelim-

Exploring the Power of Molecular Profiling

A CCR researcher loads a protein lysate to massspectrometry equipment in search of unique proteinprofiles or marker proteins (called biomarkers).

A CCR researcher uses a gene chip to study cancer-ous tissue samples for changes in gene expression.

“My basic vision is that every cancer

patient receive a molecular diagnosis,”

says CCR’s Louis Staudt. “Then we could

steer each patient to the optimal therapy,

based on the characteristics of his or

her tumor.” The lymphochip holds small, tethered DNAsequences (cDNAs) of known identity that repre-sent the entire lymphocyte genome. Using comple-mentary DNA binding, CCR researchers use thischip to study the gene expression of thousands ofgenes simultaneously. In the Lymphoma/LeukemiaMolecular Profiling Project, the Lymphochip willhelp CCR researchers define the genomic profiles ofall types of human lymphoid malignancies.

Lymphochip


inary insights are being gained frombiomarkers in this trial. For some patientswhose biomarkers predict a poor responseto standard treatment, these same biomarkersdo not predict failure with DA-EPOCH-R.Such discoveries show how individualprofiles may be used to guide treatmentchoices for a patient.

Dr. Louis Staudt used genomic tech-nology to explain why some patients withdiffuse large B-cell lymphomas (DLBCL)live longer and respond better to therapythan others. Under the microscope, theDLBCL cancer cells from every patient lookthe same. The Staudt lab profiled the genesexpressed in patients with DLBCL andfound important differences, leading him toidentify three molecularly and clinicallydistinct subclasses of the disease: germinalcenter B-cell-like (GCB), activated B cell-like(ABC), and primary mediastinal B-celllymphoma (PMBL).

These lymphoma subclasses arise in Bcells at different stages of maturation andfollow different molecular pathways thatlead to cancer development. Their discoveryrevealed new molecular targets and newtreatment approaches based on subclass. Dr.Staudt’s group is developing new therapiesto inhibit the NF-kB pathway, which is crit-ical to cancer growth and survival in two ofthe DLBCL subclasses, ABC and PBML.These new therapies are being tested in theclinic by Dr. Wilson’s team.

Profiles Inform Prognosis Until recently, there was no reliable indi-cator to predict treatment outcomes for chil-dren with rhabdomyosarcoma (RMS), afast-growing, highly malignant soft tissuetumor—yet treatment fails 30 percent ofthese young patients. Clinicians may nowhave their indicator. Using proteomics tech-nology, Drs. Lance Liotta and Lee Helmanand their research teams, in collaborationwith the Food and Drug Administration, the

Children’s Oncology Group, and otherextramural partners, identified a molecularprofile of RMS tumors that responds well totherapy. Using reverse-phase proteinmicroarrays and antibodies that indicate thepresence of a dozen key signaling proteins inthe cell, the Helman-Liotta teams examinedtumor samples from children with non-metastatic and metastatic forms of thiscancer. CCR clinicians found a strong corre-lation between successful treatment andsuppression of a cellular system called the“AKT/Target of Rapamycin pathway(AKT/mTOR),” a major regulator of cellgrowth. Patients with AKT/mTOR suppres-sion profiles, which resembled the ones

produced by treatment with the immunosu-pressant rapamycin, had the best prognosis.Further analysis of the children’s tumorprofiles identified key proteins—such as 4E-BP1, and the phosphorylated forms of 4E-BP1 and AKT—that could completelysegregate responders from non-responders.

Lymphoma and rhabdomyosarcoma arejust two examples of cancers being studiedby CCR scientists by using genomic orproteomic profiles of individual tumors. Byimproving patient profiling, clinicians willbe able to make a more accurate diagnosis,prescribe the best treatment, and improvethe patient’s chances of long-term survival.

IRF4PIM2CCND2

PRKCB1PDE4B

CD10CR2

LRMP

LMO2MYBL1SLAMCD30TARCPDL2MALIL4I1

PrimaryMediastinal

B CellLymphoma

Diffuse Large B CellLymphoma

(DLBCL)

High

LowGene

Expression

Germinal CenterB Cell-like (GCB)

DLBCL

ActivatedB Cell-like (ABC)

DLBCL

Lymphoma Biopsies

Gen

es BCL6

BCL2

SERPINA11

CD39

Genomic Profiling of DLBCL

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 lymphoidmalignancies more precisely.


Training T Cells To Attack Cancer



A critical component of the CCR’s strengthin transnational research is an infrastructurethat facilitates bench-to-bedside-to-benchresearch at the clinical center. This environ-ment is enabling CCR’s physician scientistDr. Steven A. Rosenberg to develop andrefine an innovative approach to immuno-therapy. By closely coordinating the roles ofthe pathologist, surgeon, and nurses, theRosenberg team, in experimental studies oftheir new approach, is saving lives,producing dramatic results in patients withadvanced melanoma.

Dr. Rosenberg’s goal is to optimize eachpatient’s immune response, so that immuneoperatives called T cells will circulatethroughout the patient’s body, recognizemarkers on the surface of a tumor, andattack and kill the cancer cells. They aretesting this approach, called “adoptive celltransfer therapy” against melanoma andkidney cancer.

The scientists identify a specific kind of T cell called tumor-infiltrating lymphocytes(TILs) that the patient’s immune system hasgenerated in response to his or her cancer.These TILs are removed from the patient’stumor right after the tumor is removed. Thispopulation of TILs is then tested againsttumor samples from the patient, and themost potent TILs are collected andexpanded in the laboratory, or ex vivo.Meanwhile, the patient is given chemo-therapy drugs to eliminate any ineffective T cells that remain in the body, so that theenhanced population of TILs being grownex vivo will have the chance to rebuild thepatient’s immune system. Once the TILshave multiplied to sufficient numbers in thelab, they are returned to the patient along

with a high dose of interleukin-2 (IL-2), aprotein that stimulates the immune system.

The researchers have faced many hurdlesin developing this therapy—all of whichthey’ve been able to overcome. At first, theTILs did not last long enough in the body todo their work, they could not multiply intolarge enough numbers to be effective, andthey failed to reach the target cancer cells.Dr. Rosenberg’s team solved these formi-dable problems one by one.

In their most recent experimental study,35 patients with metastatic melanomaunderwent the adoptive cell transferprocess. Fifty one percent of the patientsresponded—Three experienced a completeresponse and 15 had a partial responselasting from 2 months to 2 years. Over halfof these patients entered the study withtumors resistant to chemotherapy and allbut one were resistant to high-dose IL-2therapy. This study is a dramatic proof-of-principle that immunotherapy hastremendous potential against cancer thathas advanced to stages once consideredbeyond help.

In a mouse model, Dr. Nicholas Restifo has demon-strated that T cells that mature after being returnedto the mouse’s body are better tumor killers. Thisinsight is being applied to improve the ex vivoenhancement phase for TILs.

Before treatment

Drs. John Wunderlich and Rosenberg converse asthe TILs are excised from the patient’s canceroustumor. Photo credit: Rhoda Baer

After treatment

Dr. Rosenberg and Azam Nahvi inspect the growthof a patient’s TILs and estimate when they will beready for harvesting. Photo credit: Rhoda Baer


The Office of Training Education, headedby Dr. Jonathan Wiest, plays an integralpart of the CCR mission to support youngscientists as they become independentresearchers. In addition to managing about900 post-doctoral and 150 post-baccalau-reate students, the program supports thenext generation of clinical investigators,minority researchers, and high-school andcollege students who come to CCR to workas summer interns.

Individuals at every level of training expe-rience scientific enrichment. CCR investiga-tors-in-training have access to cutting edgetechnologies and computational servicesalong with exceptional online libraryresources to fortify their pursuit of cancer’sbiology. They are groomed in the essentialsfor the conduct of ethical and informativeclinical and laboratory research and in theskills needed for lab management. They alsoreceive training in writing professionalpapers and presenting their data. The CCRhas taken several steps to broaden thetraining experience across the NIH campus.Investigators can participate, for example,in transnational fellowships in molecularpathology, radiation sciences, biostatistics,or chemistry.

CCR’s labs and clinics at the clinicalcenter are equally important traininggrounds for clinical fellows—young oncolo-gists, radiologists, and surgeons who havedecided to specialize in cancer care. Theycome to NCI for up-to-3-year rotations thatpermit them to combine clinical experiencewith investigator-initiated research innearby labs. ■ ACGME Clinical Residency in Anatomic

Pathology—offers training and research

opportunities in anatomic pathology,emphasizing the art of establishing clinicalcorrelations to disease mechanism.

■ ACGME Medical Oncology Fellowship—provides transnational research trainingin medical oncology. Fellows developtheir expertise over a 3-year period. Thisis the oldest training fellowship in theintramural program.

■ ACGME Pediatric Hematology/OncologyFellowship—pairs the Johns HopkinsUniversity and the NCI PediatricOncology Branch to prepare researchersadept in laboratory and/or clinicalresearch in this area.

Some resources useful to CCR’s postdocsinclude: ■ Fellows Editorial Board—run by the

fellows, provides editorial services andreview for scientific papers.

■ transnational Research in ClinicalOncology (TRACO) is a course for post-doctoral fellows to enable strong collabo-ration between basic and clinical scientiststo develop novel approaches for the treat-ment of cancer. This Web-cast course hasbeen adapted for training young investiga-tors in Spain.

More information on training opportunitiesat CCR can be found at:

CCR Office of Training and Education:http://ccr.nci.nih.gov/careers/office_training_education.asp

Training Opportunities at NCI: http://www.cancer.gov/researchandfunding/fellowships

Research and Training Opportunities atNIH: http://www.training.nih.gov

Teaching the Art of Inquiry

TRAINING AT CCR

CCR POSTDOCTORALFELLOWSHIPS AND TRAINING PROGRAMS

ACGME Clinical Residency Programs:■ Residency in Radiation Oncology■ Residency in Anatomic Pathology■ Residency in Dermatology

ACGME Clinical Fellowship Programs:■ Medical Oncology■ Johns Hopkins University/

NCI Pediatric Hematology/Oncology■ Hematopathology■ Cytologic Pathology

Additional Clinical FellowshipPrograms:

■ Surgical Oncology■ Urological Oncology■ HIV and AIDS Malignancy■ Gynecologic Oncology■ Neuro-Oncology

Translational Fellowships:■ Multidisciplinary Fellowship in Breast

Cancer Research■ Gynecologic Cancer Foundation/

NCI Fellowship in Gynecologic Oncology■ Postdoctoral Fellowships in

Radiation Sciences■ Biostatistics/Mathematics

Training Fellowship (InformaticsTraining Program)

■ Program for Interdisciplinary Training in Chemistry (PITC)

■ Comparative Molecular PathologyResearch Training Program

■ University of Cambridge/GlaxoSmithKline Oncology Fellowship

Basic Science Fellowships:■ Cancer Research Training Awards■ Visiting Fellow Program


Web Sites With More Information About CCR

CENTER FOR CANCER RESEARCHhttp://ccr.cancer.gov

For information on CEI researchhttp://home.ccr.cancer.gov/coe/immunology

Office of the Directorhttp://ccr.cancer.gov/about/default.asp

Office of the Clinical Directorhttp://ccr.cancer.gov/trials/clinical_director.asp

Office of Communicationshttp://ccr.cancer.gov/news/ooc.asp

Office of Science and Technology Partnershipshttp://ccr.cancer.gov/research/ostp/

Office of Training and Educationhttp://ccr.nci.nih.gov/careers/office_training_education.asp

PATIENT INFORMATION ON CANCER AND CLINICAL TRIALS

Open NCI Clinical Trialshttp://www.cancer.gov/clinicaltrials

How to Refer a Patienthttp://bethesdatrials.cancer.gov/professionals/refer.asp

NCI Cancer Information Servicehttp://cis.nci.nih.gov/1-800-4-CANCER (1-800-422-6237)For deaf and hard-of-hearing 1-800-332-8615

Understanding Cancer Serieshttp://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 NCIhttp://www.cancer.gov/aboutnci/working

National Institutes of Health (NIH)http://www.nih.gov

Center for Cancer ResearchBldg. 31, Room 3A11 MSC 244031 Center DriveBethesda, MD 20892-2440Phone: 301-496-4345Fax: 301-496-0775

NIH Publication Number 06-5736SPrinted October 2005

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