1124 NATURE MEDICINE • VOLUME 5 • NUMBER 10 • OCTOBER 1999

NEWS & VIEWS

THE DISCOVERY OF distinct antigenic fea-tures of neoplastic cells has suggested

that it may be possible to create anti-tumor vaccines1. Vaccine strategies haveused tumor-derived cells2, or cellular ma-terial3, containing cryptic or unidentifiedantigens to induce specific immune recog-nition of these tumor-associated antigens(TAAs). Alternatively, several recently dis-covered tumor-associated antigens havebeen tested directly as immunogens invaccine formulations4,5. To improve anti-gen presentation, vaccine ap-proaches have also includedadjuvant agents to potentiateimmune recognition of theTAA. These adjuvants haveevolved to improve immune ac-tivation, and are the result ofmany years of research directedtowards understanding of themechanisms of anti-tumor im-munity6. Bendandi et al., onpage 1171 of this issue7, report aTAA vaccination protocol that,with granuloyte-monocytecolony-stimuting factor (GM-CSF) as an immune adjuvant,achieves an effective anti-tumor response.

A variety of anti-tumor vac-cine clinical trials have been re-cently undertaken. In spite ofthe large number of these tri-als, and the plethora of distinctapproaches investigated, therehas been little evidence of clin-ical efficacy3,4. Furthermore,precise correlates of clinical ef-fects and immunological re-sponses have been lacking. Theselimitations reflect several shortcomings inthe design of the studies. Studies haveoften used cohorts of patients with ad-vanced stage disease, for which a full re-sponse is unlikely for various biologicalreasons. Moreover, many of the adjuvantstested lacked the potential to effectivelyovercome intrinsic immunosuppressiveactivity of the tumor. Finally, precise as-says to monitor clinical response and,most importantly, immune responseshave been lacking. Thus, despite a largebody of work in this area, many tumorvaccine protocols tested to date have not

proven effective or yielded large amountsof useful information.

The study by Bendandi et al. makes alarge advance over previous tumor vac-cine trials. Idiotypic determinants of theIg synthesized by a clonal B-cell cancer,such as follicular lymphoma (FL) areunique, and are thus useful as TAAs (refs.

4,8,9). The vaccine strategy of Bendandi etal. included a new group of follicular lym-phoma (FL) patients that were in com-plete remission after chemotherapy. MostFL patients in remission still have chro-mosomal translocation-bearing tumorcells, and are therefore at risk for relapse.The authors created a vaccine that com-bined an FL-associated idiotype IgG withkeyhole limpet hemocyanin (KLH) (Fig.1). The inclusion of KLH provided addi-tional epitopes for T-helper-cell recogni-tion, allowing for optimal CTL activation,and also provided a positive control anti-gen, allowing the authors to monitor T-

cell priming. The vaccine was adminis-tered in conjunction with the molecularadjuvant GM-CSF, which is very effectivein induction of immune effector cells6,8.The protocol also included highly sensi-tive assays to carefully monitor detectabletranslocations in the blood and quantifythe tumor-specific T-cell response, thehallmark of true anti-tumor immuniza-tion.

This study included 20 FL patients,eleven of which possessed the chromoso-

mal translocations characteris-tic of FL. After six monthsrecovery from chemotherapy,patients were vaccinated withfour monthly injections of theirown lymphoma Ig idiotypic de-terminant, along with recombi-nant GM-CSF. Aftervaccination, patients weremonitored for chromosometranslocation-bearing cells byPCR. Anti-tumor immunity wasdetermined by assays to mea-sure cytolysis and cytokine re-lease in response to autologoustumor cells. Of the eleven pa-tients evaluated, eight clearedthe residual chromosomaltranslocation-bearing cells inresponse to vaccination.Nineteen of the twenty pa-tients tested showed specificCD8+ and CD4+ T-cell reactivityto the tumor. Evidence of anti-tumor immunity correlatedwith clinical evidence of a re-duction of tumor burden.

This trial, along with otherrecent trials, has benefited from the ad-vances made in our understanding ofanti-tumor immunity. Most new im-munotherapeutic approaches aim to pro-mote the activation of CD8+ cytotoxic Tlymphocytes (CTLs), which have beenrecognized as the main effector cells in amultitude of murine tumor rejectionmodels. It is also known that tumors usea variety of mechanisms to induce hosttolerance and prevent TAA-specific CTLactivation6. Dendritic cells (DCs), whichexpress high levels of MHC molecules,co-stimulatory molecules, and T-cell-ac-tivating cytokines, may be useful in over-

Cancer vaccine strategies get bigger and betterMany anti-tumor vaccines have failed in recent clinical trials because they included the wrong patients and the wrongimmune adjuvants — and little was learned because the anti-tumor immune response was not carefully monitored. A

new tumor vaccine for lymphoma sets the stage for how future trials should be carried out (pages 1171–1177).

BY TANJA D. DE GRUIJL1 &DAVID T. CURIEL2

Blood KLH

GM-CSF

Ig-KLHvaccine

DCprecursor

recruitment

DCmaturation

Ag uptake& processing

Antigenpresentation

&T cell activation

(CTL)

DC migration

Lymphnode

TAA-specific(Id)

activated CTL

Fig. 1 Mechanisms of CTL activation after vaccination with a lym-phoma-associated idiotype (Id) IgG coupled to keyhole limpet hemo-cyanin (KLH) and mixed with GM-CSF. GM-CSF induces recruitment ofdendritic cell (DC) precursors from the blood to the vaccination site andstimulates local DC maturation. The Ig–KLH complex is internalized andprocessed by the DCs, and Id-derived epitopes are expressed on the cellsurface in the context of MHC-I and II molecules. DCs then migrate tothe lymph nodes (oval), where they present the antigen and activate aTAA-specific T-cell response.

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NATURE MEDICINE • VOLUME 5 • NUMBER 10 • OCTOBER 1999 1125

NEWS & VIEWS

coming these obstacles and activatingTAA-specific CTL responses (Fig. 1).Many new vaccines, therefore, alsoinclude autologous DCs that have beenloaded with TAA (refs. 3,4,6) in vitro. Thisstudy instead uses the DC stimulant GM-CSF.

GM-CSF functions to promote TAApresentation by antigen presenting cells(APCs) and CTL activation by recruitingperipheral DC precursors and inducingDC maturation (Fig. 1) (ref. 6). Recentstudies have also confirmed the role ofCD40-mediated activation of DCs inactivation of the TAA-specific CTL re-sponse10. Indeed, CTL-dependent rejec-tion of B-lymphomas in mice wasrecently reported after treatment with anagonistic antibody against CD40 (ref.11). Thus, GM-CSF and CD40 ligand mayprove to be a winning adjuvant combi-nation in future lymphoma, as well asother tumor vaccines.

The vaccine strategy reported byBendandi et al. does not represent a par-ticularly new approach, but its validationof therapeutic benefit, well-plannedstudy design, and careful execution

allow this study to stand as a hallmark inthe field of cancer vaccine development.Consideration of the patients’ diseasestage cannot be ignored in determiningthe potential of a vaccine to achieve abeneficial therapeutic outcome. Thesefindings suggest that in cancer therapy,early intervention with vaccine-basedapproaches is warranted. Furthermore,studies including specific TAAs as vac-cines should carefully monitor post-vac-cination immune responses. Futurestudies aimed at identification of TAAsfor other tumor types, and additionalcarefully- monitored tumor vaccine tri-als, should lead to the development ofnew, more effective vaccine strategies.

1. Rosenberg, S.A. A new era for cancer im-munotherapy based on the genes that encodecancer antigens. Immunity 10, 281–287 (1999).

2. Vermorken, J.B. et al. Active specific immunother-apy for stage II and stage III human colon cancer:a randomized trial. Lancet 353, 345–350 (1999).

3. Nestle, F.O. et al. Vaccination of melanoma pa-tients with peptide- or tumor lysate-pulsed den-dritic cells. Nature Med. 2, 52–58 (1998).

4. Hsu, F.J. et al. Vaccination of patients with B-celllymphoma using autologous antigen-pulsed den-dritic cells. Nature Med. 2, 52–58 (1996).

5. Rosenberg, S.A. et al. Immunologic and thera-peutic evaluation of a synthetic peptide vaccine

for the treatment of patients with metastaticmelanoma. Nature Med. 4, 321–327 (1998).

6. Pardoll, D.M. Cancer vaccines. Nature Med.(suppl.) 4, 525–531 (1998).

7. Bendandi, et al. Molecular complete remissionsinduced by patient-specific vaccination plus GM-CSF against lymphoma. Nature Med. 5,1171–1177 (1999).

8. Levitsky, H.I. et.al. Immunization with granulo-cyte-macrophage colony stimulating factor-trans-duced, but not B7.1-transduced, lymphoma cellsprimes idiotype-specific T cells and generates po-tent systemic antitumor immunity. J. Immunol.156, 3858–3865 (1996).

9. Nelson, E.l. et al. Tumor-specific, cytotoxic T-lym-phocyte response after idiotype vaccination for B-cell, non-Hodgkin’s lymphoma. Blood 88,580–589 (1996).

10. Mackey, M.F. et al. Dendritic cells require matura-tion via CD40 to generate protective antitumorimmunity. J. Immunol. 161, 2094–2098 (1998).

11. French, R.R. et al. CD40 antibody evokes a cyto-toxic T-cell response that eradicates lymphoma andbypasses T-cell help. Nature Med. 5, 548–553(1999).

1Department of Pathology and Medical Oncology

University Hospital Vrije Universiteit

1007 MB Amsterdam, The Netherlands2Gene Therapy Center

The University of Alabama at Birmingham,

1824 6th Avenue South

Birmingham, Alabama 35294-8627, USA

E-mail: david.curiel@ccc.uab.edu

Unraveling hepatitis B virus infection of mice and men(and woodchucks and ducks)

The development of liver diseases in patients suffering from chronic hepatitis B infection is determined by thenature of the host immune response. Several factors have made this immune response difficult to study,

but recently developed animal models will help clear the way.

STEPHAN MENNE & BUD C. TENNANT

INFECTION OF ADULT humans with the hepati-tis B virus (HBV) characteristically results

in self-limited disease and in clinical recov-ery. Persistent or chronic infection is anoutcome that usually accounts for less than5% of adult HBV infections. Children oftendevelop persistent infection, which later inlife causes chronic hepatitis, cirrhosis ofthe liver, and, in some, primary hepatocel-lular carcinoma (HCC). Although safe andeffective HBV vaccines are now available,over 300 million people worldwide arechronically infected with HBV, and theseindividuals have a high relative risk of de-veloping life-threatening liver disease.

Substantial evidence now suggests thatdifferences in outcome of HBV infectionare determined by variations in the im-mune response. Cell-mediated immunityinvolving T-helper (Th) cells and cyto-toxic T lymphocytes (CTL) determineswhether HBV infection is followed by re-covery or viral persistence (Fig. 1). Duringacute self-limited virus infection, patients

show vigorous, polyclonal Th and CTL re-sponses against epitopes of viral capsidand envelope proteins1, leading to theclearance of viral DNA and envelope pro-teins from the serum. Patients who de-velop chronic HBV infection have beenreported to have less-vigorous Th re-sponses, characterized by low frequencyof HBV-specific Th cells in the peripheralblood and the liver, and weak or unde-tectable virus-specific CTL responses1. Aweak CTL response is also believed tocause the hepatic injury that occurs inchronically infected patients.

The immunopathogenesis of HBV infec-tion has been difficult to investigate. HBVhas a narrow host range limited to endan-gered animal species. Tissue culture sys-tems used to study most other viralpathogens are not yet available for HBV.

The original studies of HBV im-munopathogenesis were limited to in-fected patients at varying stages of diseasefollowing accidental exposure, and to ex-perimentally infected chimpanzees1,2.

In recent years, new animal models ofHBV infection have contributed substan-tially to our understanding of this virus3.The woodchuck (Marmota monax) and thePekin duck (Anus domesticus) both havenaturally occurring infections withviruses that belong to the familyHepadnaviridae, of which HBV is the pro-totype virus. Woodchucks with naturallyor experimentally acquired, persistentwoodchuck hepatitis virus infection de-velop chronic hepatitis and HCC similarto those associated with HBV infection.Duck hepatitis B virus, is not typically as-sociated with liver disease. Although boththe duck and the woodchuck have beenvaluable in molecular studies of viral repli-cation and have been useful in the pre-clinical evaluation of prospective antiviral

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