far use tumor cells themselves as a source of antigen.

The va-
lidity of cell-based cancer vaccine approaches depends upon
their capacity to induce stronger immunity against tumor-spe-
cific or tumor-selective antigens than against ubiquitously ex-
pressed self antigens within the tumor. Early generations of
cell-based cancer vaccines have consisted of killed tumor cells
or tumor cell lysates mixed with adjuvants such as Bacillus
Calmette Guerin (BCG) and Corymebacterium parvum, in an at-
tempt to amplify tumor- specific immune responsess
Subsequently, genetically modified tumor vaccines have
begun to replace the complex and inconsistent mixtures of
tumor cells and bacteria. The forerunner of these studies was
the work of Lindenman and KleinS", who showed that vacci-
nation with influenza virus-infected tumor cell lysates gener
ated enhanced systemic immune responses following
challenge with the original tumor cells. A more recent version
of this approach is the transduction of tumor cells with spe-
cific viral geness" and allogeneic MHC genes in order to en-
hance thelr immunogenicity. In some cases, animals which
rejected the tumor transfectants became immune to
challenge
with nontransfected tumor cells.
Currently, the most popular genetically modified cell-based
 ing cytokines and costimulatory mokcules". An important
Pniepnasay or thee sudesB that the Surs
elets
o tOXaty. Although
n t ny c

dously, it iseven to detect significant

rare

ot
amounts of cytokines in
numbers of ceis trans
the serum,. after injection
uced with cytokine genes.
large

h a olony stimulate
ing factor (GM-CSH) appears to be the most potent. The A D

iniquey ennanca immunoiogc eret or PancnneuML

to s
n mupie tumotaccine modes eepncally
he varinesite c.csE has heen identifiedacitical fac
u m e r vacEines
tor for inducing the ditferentiation of primitive hematopo-
ene
precursors into Ds, a P* OAP na dmnct rom
and
maactophages and that initiates the most
po
anuocyes
cell necessury for activating
virgin T cells, their role in prim
ng
A
imunologic responses now cosdefed entral B g 2 Cytokine cancer vaccines.For some tumon (cancers of colon,id
etically modifled whole-cell tumor vaccins usmk x n ny, vBYu n

Phase I trial in patients with advanced renal cancer provides tient cels with elther bystander cells that have been transduced with cy
preliminary
evdence of the immunologic activity of autolo- h oenebe d h
gous GM-CS gene tranduced vaccnes This trial, which gengetumorcels(derved lrom cell ines of the ame type as the pa
npared aM-CSP gETne tanwuceu ana to tient's tumor) that hMve been ransouced wn cy ra
anbgens shared by the
Aence oPpropriete
as measured by induction of delayed type hypersensitivity re patientt *
" * *

actions against autologous fumo.

Because direct transucthon of autoogous tufnos s gniy

indvuale.n nd a ne ave n
cytokine elaboration are currently being developed (Fig 2) ment requlres identification of the most potent tumor rejec
One approach, which takes advantage of the tact that the cy on antugens ana tne apptopate roure Vencie djuvant

tokine does not need to be produced by the tumor itsell, in by whch the antigen delivered to the immuneiem. As
tokines. This approach obviates the need for culture or definition of Immunogenicity so that vaccine optimization is
ransduction of each patients umor celln. Another appoacn a o n a arner than tmpieal
eptue vucCine. The n t antugen-pecic cancer vaccin o
urently under clinical lnvestigatkon uses standardized gene
nhe h emo ton nten e hared common HA llle Amost al oeptide sed vacines thus
rather than unique. This type of vaccine is often referred to as ar have ued MHC CA rsticted anugenk p
n
alogenec vaccine because he vacinaung ce n
presses MHC alleles foreign (alogenelc) to the vaccinated pa- class I binding peptides were first reported tor cytomegalovrus

e aro derived APCs ather than the Vaccination of tumor-bearing mke with MHC class I binding
vaccinating tumor itselfr", MHC compatibility between pa immunogenic peprides has been reported to resut in the in
Jent and tumor is not required tor this ype or vacctne uc pet
Peptide vaccination depends on the loading o empey MH
Although cell-based vaccines are currently the major form of peptide without a means of targeting activating APCs can po
cancer
vaccine tested
antigen-specitic clinically, innovative approaches to tentialy
vaccination are under way. The ability to ac lesslonallead
APCs.to loading oMHCreult
which coukd assmoeus on ndeed
in tolerance. nonpro
tivate immune tesponses agalnst elected immunodominant administration of some peptides at high does by an intfapefi
growth of tumors. The inTEsed tumor growth was paralleled The capacity of some viruses to directly infect ACs alows

d a e a enedanteensand tncao
tide/adjuvant vaccines induce tolerance by 'Teaking out od ratton of genes encoding costimulatory molecules or exam
the
reunds incomplete adjuvant into serum and binding to ple, inledon wtn reomounant accina virs at eprees
genes encoding minimal MHC cdas Lrestricted peptides results

raly APhae I trial uine an HiA-Aricted MAGE-3 peotide Grafting of endosomallvosomal sortingsignalsoato the sene
in Freund's incomplete adjuvant reported promsing preliminary encoding antigen enhances MHC class lI processing and CD4
cnicaingy,
eInduction
s n Patients wn vnced ean
ot MAGE-S pecinc c i l s could not be de
e Auvnon econant
of gene or the B
poviu n
costifmulatory protein and tor cytoins into

tients who undervent completeremisulon. Amre extensvePrelminaN esults of dinical trialswith recombinant viral
peptidevaccine trial carried out in melanoma patients evalaated cancer vccines are just now beginning to be evaluaated", One
Kplpepode analogue modiied at the Mcanchor rekdue or the major barrets lo etfectE VCinatOn win virues sucn
to produce higher alfnnity tor HlLA-A2 molecules. A urge pro-as vaccinia and adenovirus is nhibition of vaccine take by

ognizedthe wild-type gplo0 peptkde"immunization with the result of previous exposure to crOMSIeacting
viruses(aden-
anchor-modited 8pl0 peptie in Feunas incompieie dju ovirus ot ptevious mmunzaDon vaccinia). oitimaty, reak
ant inducd much greater spi, meanomareactve it C* aton ot the ruu cnical vale 0t FEon0inant itavhe
ivity (as assayed by tr vitro chromium release) than vaccination will require development of methods to transiently eliminate

anchor-modinedgpi00 vaccines produceclinical responser In mot indivduals have not been exposed.
contrast 4 pcent of melanoma patients recelving a combina combnant ucteria ccins One ot the most interesting
o n of hagh dose interieukin ( L phus the anchor-modifed recombinant vaccine approaches invoves the use o eng
p100 vaccine had a clinkcal respone, though larger randomited neered bacteria. A number of bacterial strains including

whether this combination s erioe Listerka monocytogenes" display wo

charactertstcs that make them promi
hugh dove l2 alone. interstingy, Pe ing vaccine vecto. s t , they poes
pheralbo0d
treated
ympnoye trom panof
combenation
with the
treated enfee roues o ntecton, prong
gpi00 vaccine demonstrated relatively tt Second, they Infect monocytes and

The complete lack of correlation between

these two vaccine trlals using defined MHC class I peptides calls coplc cancer with promising reults" This organhm makes a
into erlous question the relevance of classic chroenium eieae parhcur interesing vetor ecause o wo-pnAe i n t a e a r
asayas surrogate immunoogk measurenernt o antntaror e ponn n g s o hp E

activitymbnant viral vaccines. nogericity of

The intnn hoaues
iruses together with the development of standard techniques transit of becterla
transit bactera into
into the
the cytoplasn. The dual phagolysosomal-
to
cyioplasm.
engineer recombinant viruses has engenaeted brod inter iylopasnk
cst in recombinant viral vaccins Based on the earny w o rg o
e ee or
u Angens n
n cu y ng
pao-

cancer vaccines, More recently, adenoviral and other viral tivation of components of the innate immune reponse b
vectors nave Deen selected for cancet immunotnerapy e e o n n a t L. A o ey w

common enominator r al reDnant vaccies s nee ang cesu o

nirodctono the ne ncodin t noeA p

proaches adapted to the virus of interest by Liu and colleagues that naked DNA encoding influenza nu.

to naked
Vaccinesto initlate immune respons. Fint,
the cellular dam (ee Liu, page s1). In additon inlectlous diseases
ct ht ae de em m
In
the context of costimulatory molecules. Aecond mecha
nism lor ome teconotnant vraccines n v o e s ore ni
In general the potency of naked DNA vaccines is less than
or recomnant vunvccne Tns o e e potency
that
prood
tion of bone marrow derived APPCs, which allows for effkient bly attributable to the fact that naked DNA does not undergo a
processing ot endogenousiy symthesiaed antigens lin the M catampicate
and bacterial vaccines there it
 O antigen
Heatshock protcins ae
cancer vaccination.
uvants that
display
teticulum) and hsp70 (n the cytosh e
unogc ouvantG s e heathoOCk pruteins, of cfapef
onins, have the capacity
to bina a w a
artay o P p s
w n etner ative KP76 or hsp70 purihed from
tumor cel (whic
More s8ner
K antitumor immunityi
s p u tethered to a model peptkde antigen

acity of certain beathock proteins to act as

adjuwants
u gp6 has been
ahown in vitro int
to etfectively

east ancer asprocessing pathway. Thus, gph6 and possibly otherheat

nOxA proens may epresent important molkcular conduits for

intigens into both the MHC Class T and class n ptnway o

the DNA ot bacterai vectors of
Done marrow derived mhages induces
macrophages induo
ta birding Kp6 to

o
chanisms yet to be elucidated, tokines. Thus, heatshock protelns may augment the hunction
stimulate mactopthages to ot cels to which they are
largeting peptdes.
al1z tret.
107). The
al for their capacity to induce As o
ps,additional strategles to block inhibitory nathwas o
V have been explored. One of the most
of the ce n Dinas B with about a 10-tokd highet affinity

P P P a r to be rspons counter the effects ot CD28 on Tcell activation and bm.

n phoineinduction The importance of CTLA4 in T-cell

els ot
Mn molecules han
homeusasis m
vw most aamancany eempuuu
o ie, whch develop a wvere lymphoprolferative
mulatory molecules critical for CTLA4 could be transuently blocked in vive, it might be ponsi-
noDe
.acka to o ennancE vccine peotency while limiting the collateral
thne st or teatures
hatanag in tne co u *O
Indeed, intusion of anti-CtLA4 antibodles elicits an en
hae t eithet
er han
ced DCs as antigen carriers for models without overt toxictty in the treated animals"
n u y ILA 0Ck WA touna to e most elective
papneoprotetn when given together with a cancer vaccine", Thus, CTLA4
an a means
red es wm transdation b provies
tication-defective recombinant ing antigen while limiting induction of undesirable irmmune

Tesponss
nical testing In one
y ancer

otype-specific immunity with There has been more ientitie es

rOgress in cancet vaC
Cne o
ent vaccine trial in melanoma velopment over the past decade than in the *I yearn that fok

GM-CSF and IL4, puled with new

vaccines will quickly revolutionie cancer therapy mut be
mpet hemocyanin as a helper imimunologk tuletanKe to thelr antigens and develup reu
deiayd p e n y p e i e v ance to n n u n e c o

Tehall aad ithe

mber of different methods for transation of thew advances into reprcoduc tbie cinkal i e
ul comparative studies to deter This wil involve careful opeimizatiorn ot the most promiing
ing conditions will ultimately strategies, thoughtful selection ot patient populations and care