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presented by HLA A24 molecules resides in the CEA signal peptide so that it is .... Even chimeric or humanized antibodies may induce recombinant anti-HER-2 ...
ANTICANCERRESEARCH2 2 :4 2 5 5 4 2 6 4( 2 0 0 2 )

Review

S i g n i f i c a n c eo fT u m o r a s s o c i a t e dA n t i g e n si nt h eD i a g n o s i sand Therapyo fC a n c e r :AnO v e r v i e w MASAHIDEKUROKI1ベ ARUTO UEN01,HISANOBUMATSUMOT01,HIRONORIABE1,TIELiL I 2 , TAKAYUKIIMAKIIRE1,YASUSHIYAMAUCHI1 ’ KOICHI UNO',KYOKOSHIROTA',HIROTOMOSHIBAGUCHI andMOTOMUKUROKI1' 2 1 D e p a r t m e n to fB i o c h e m i s t r y ,FukuokaUれiversity

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S c h o o lo fM e d i c i n e , O n c o l o g yC e n t e r ,7 4 5 1Nanakuma,l o n a n k u ,F u k u o k a ,8 1 4 0 1 8 0 ,Japan

A b s t r a c t .AnenormousR静rt using α wide v a r i e t yo fa p p r o a c h e s l附 been u n d e r t a k e no v e rt h el a s tt h r e ed e c a d e st ot r a n s f o r m b o t hb a s i candc l i n i c a lr e s e a r c hi n t oi m p r o v e dd i a g n o s e sand 仇erapies o fc a n c e r . T h i sb r i e fo v e r v i e ws u m m a r i z e st h e signポcance o ft u m o r a s s o c i a t e d antige附 （TAAs) i nt h e d i a g n o s i s and t h e r a p yo fc a n c e r .C u r r e n td a t as u g g e s tt h a t i m m u n o t h e r a p y and g e n et h e r a p yu s i n ga n t i b o d y r e c o g n i z e d TAAsa st h e i rt a r g e t sa r ep r o m i s i n g ,w h e r e a st h o s eu s i n gTc e l l ｭ r e c o g n i z e dp e p t i d ee p i t o p e sofTAAs a st h e i rt a r g e t sr e m a i n og e n e r a l c o n t r o v e r s i a lr e g a r d i n gt h e i re f f i c a c y ,mai功 due t o l e c u l e si ntumorc e l l s . l o s s e so fHLAm

ザpes. T hecarcinoembl)叩ic a n t i g e n(CEA)m o l e c u l e, shown i nF i g u r e1 ,i sarepresentative 巴xampl巴 which c a nformb o t h 旬pes ( 4 ,5 ) . Theo b j e c t i v eo ft h i sp a p e ri st op r o v i d ea n overvi巴W o ft h ec u r r e n ts i g n i f i c a n c eo fTAAsi nt h ed i a g n o s i s andt h e r a p yo fcanc巴r.

I .C a n c e rD i a g n o s i sandTAAs

V a r i o u sd i a g n o s t i cmethodspres巴ntly i nu s ear巴 shown i n F i g u r e2andt h emethodsi nw h i c hTAAsa st a r g e t sa r ee i t h e r o f t e no ra l w a y semployedt oi n c r e a s eth巴ir tumor-sp巴cificity a r eu n d e r l i n e d .I nt h e s ec a s e s ,antibody recognized TAAsa r e u s u a l l y山ed andt h e ya r eo f t e nc a l l e dtumorm a r k e r s( F i g u r e 2 )( 6 )o r canc巴r m a r k e r s( 7 ).I nr e c e n ty e a r s,i n s t e a do f p o l y c l o n a la n t i s e r a ,m o n o c l o n a la n t i b o d i e s(MAbs) a g a i n s t t h er e s p e c t i v eTAAsa r eu s e da sprob凶 in t h ed i a g n o s i so f c a n c e r( 7 ) . ”

Therea r enumerousmethodsc u r r e n t l yu s e df o rt h ed i a g n o s i s andtreatm巴nt o fc a n c e r ,w h i c ha r eu s e de i t h e rs i n g l yo ri n c o m b i n a t i o n.However,no method c a na l w a y sd i a g n o s e can印r e x a c t l yo r comp！巴tely e r a d i c a t em a l i g n a n tt u m o r s , b e c a u s ea l m o s ta l lo fthemar巴 not a b s o l u t e l yt u m o r s p e c i f i c . I nt h i sc o n t e x t ,TAAsa r eo f t e nu s e da st a r g e t sf o ri n c r e a s i n g t h etumors p e c i f i c i t yo fd i a g n o s t i co rt h e r a p e u t i ca p p r o a c h e s a g a i n s tc a n c e r .TAAsar巴 molecules w h i c ho c c u ri no ron tumorc e l l s anda r en o td e m o n s t r a b l eo rs i g n i f i c a n t l yl e s s conc巴附 trated i nn o r m a lt i s s u e s( 1 ) . TAAs c a nb eb r o a d l y categoriz巴d i n t ot w otyp巴s ( 2 ,3 ) :t h o s et h a ta r ei d e n t i f i e db y h e t e r o a n t i b o d i e so ra u t o a n t i b o d i e s, i . e .b yh u m o r a li m m u n i t y, and t h o s et h a ta r ec a p a b l eo fe v o k i n gc e l l u l a ri m m u n i t y, esp巴cially c y t o t o x i c T l y m p h o c y t e s ( C T L s ) , b y b e i n g p r e s e n t e donHLAc l a s sI Im o l e c u l e so fantigen-pres巴nting c e l l s(APCs)s u c ha sm a c r o p h a g e s(Mφ） andd e n d r i t i cc e l l s ( D C s ) .However,s e v e r a lTAAse x i s tw h i c hc a nformb o t h

C o r r e s p o n d e n c et o :D r .M a s a h i d eK u r o k i , Departm巴nt o f B i o c h e m i s t r y,FukuokaU n i v e r s i t yS c h o o lo fM e d i c i n e ,7 4 5 1 J o n a n k u,Fukuoka,8 1 4 0 1 8 0,J a p a n . T e l :+ 8 1 9 2 8 0 1 1 0 1 1 E x t .3 2 4 0,F a x : +81-92-801-3600， 巴－ mail: k u r o k i m a@f u k u o k a ｭ u . a c. j p Ke y Words.・

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l .S e r o l o g i c a le x a m i n a t i o nandT A A s . Asshowni nT a b l eI , a p p r o x i m a t e l yt w e n t yTAAsa r ew i d e l yu s e da sb i o c h e m i c a l m a r k e r sf o rt h eserumd i a g n o s i so fc a n c e r .Theb l o o dl e v e l s o fTAAsa r eu s u a l l yd e t e r m i n e db ye i t h e rar a d i o i m m u n o ｭ a s s a y(RIA)o ra nenzymeimmunoassay( E I A )( F i g u r e2 ) . A l t h o u g ht h es e n s i t i v i t yf o rd e t e c t i n ge a r l yc a n c e rb ytumor m a r k e r si sv e r yl o wandmanytumormark巴rs o r d i n a r i l yh a v e ah i g hf a l s e p o s i t i v er a t ef o rb e n i g nd i s e a s e, t h emeasurement o fe a c htumorm a r k e rl e v e li nb l o o di sc o n s i d e r e dt obea u s e f u ll a b o r a t o r ya i df o rt h ed i a g n o s i sandmanag巴ment o f p a t i e n t sw i t hv a r i o u sc a n c e r s ,p a r t i c u l a r l yi nm o n i t o r i n gth巴 r e s p o n s et oc a n c e rt h e r a p y( 8 ) .I ti so fi n t e r e s tt onot巴 that s e v e r a lt u m o r a s s o c i a t e dRNAs p e c i e s, i n c l u d i n g5T4mRNA, t y r o s i n a s emRNAandt e l o m e r a s eRNA,h a v er e c e n t l ybeen d e m o n s t r a t e di np l a s m aa nd serum ( F i g u r e2 )( 9 ) .I n a d d i t i o n ,i ti sa l s on o t e w o r t h yt h a t ap r o t e i nm i c r o a r r a y a n a l y s i si n c l u d i n ganti-TAAMAbsa sprob巴s w i l lf a c i l i t a t e h i g h t h r o u g h p u t prot巴omic s t u d i e so f human c a n c e r and c a r c i n o g e n e s i s(Figur巴 2) ( 1 0 ) .

i m m u n o d i a g n o s i s,i m m u n o t h e r a p y,g e n e 2 .P a t h o l o g i c a le x a m i n a t i o nandT A A s .I m m u n o h i s t o c h e m i c a l a n t i g e n, canc巴r.

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F i g u r e1 .Two 卯田 of TAAsont h ec a n c e rc e l lsuゆce a sp o t e n t i a lt a r g e t sf o rc a n c e rt h e r a p y ;t h eCEAm o l e c u l ea sar e p r e s e n t a t i v ee x a m p l ew h i c hf o r m s e p t i d ep r e s e n t e db yHLAc l a s sIm o l e c u l e ,w h i c hi sr e c o g n i z e db yTCRonCTL.T h r e erepresentatiνe CEApe p t i d e s ,w h i c ha r eknown b o t h砂'Pes. A,aCEAp t ob ep r e s e n t e db yHLAA2o rA24m o l e c u l e so ft u m o rc e ls ,a r ea l s os p e c i f i e d .B ,aw h o l eCEAm o l e c u l ee x p r e s s e di ntumorc e l l .Thenumbersi n d i c a t et he aminoa c i dnumb e r so ft h eCEAp o l y p e p t i d ec h a i n .N ,Al ,A2 ,A3 ,Bl ,B2andB3a陀 domain nameso ft h eCEAp o l y p e p t i d ec h a i n .OneMAb,w h i c h r e c o g n i z e sane p i t o peont heB3domain ,i si l l us t r a t e d . TwoCEApe p t i d e s(A24 :268277andA2:5 7 15 7 9 ) ,w h i c ha r ep r o c e s s e di ntumo rc e l l sand pr e s e n t e db yHLAA24o rA2m o l e c u l e s( s e eA) ,ar ea l s oshownont h eCEAp o l y p e p t i d ec h a i n( s had e do v a la陀as). AnotherCEAp e p t i d e( A 2 4 :652-66の p r e . 1 e n t e db yHLAA24m o l e c u l e sr e s i d e si nt h eCEAs i g n a lp e p t i d es ot h a ti ti sn o ti n d i c a t e di nB .

s t a i n i n go ft h eTAAsl i s t e di nT a b l eIu s i n gsurgにally- o r b i o p s i c a l l y r e m o v e dsp巴cimens i sa l s oh e l p f u la sad i a g n o s t i c a i di np a t i e n t sw i t hv a r i o u sc a n c e r s(Figur巴 2). Ont h eo t h e r hand, t h efailur巴 to r e d u c eth巴 mortality o fp a t i e n t sw i t hs o l i d t u m o r si sm a i n l yt h er es u l to ft h ee ar l yd i ss em i n a t i o no f c a n c e rc e l l st os e c onda r ys i t e s,w h i c hi su s u a l l ymis s edb y c o n v e n t i o n a ld i a g n o s t i cp r o c e d u r e su s e df o rtumors t a g i n g . R e v e r s et r a n s c r i p t i o n p o l y m e r a s ec h a i nr e a c t i o n(RT-PCR) hasb e e ns hownt ob es u p e r i o rt oc o n v e n t i o n a lt e c h n i q u e si n d e t e c t i n gc i r c u l a t i n gtumorc巴lls andm i c r o m e t a s t a s e s ,t h u s 7 a l l o w i n gt h ei d e n t i f i c a t i o no fonetumorc e l ld i l u t e dw i t h1 0 n o r m a lc e l l si nv a r i o u ss o u r c e ss u c ha sb l o o d,bon巳 marrow , lymphnod巴s, u r i n eo rs t o o l( F i g u r e2 )( 1 1,1 2 ) .Th巴 m巴thods

4 2 5 6

u s e da r eb a s e d on t he det巴ction o fe i t h e rt h e mRNA e x p r e s s i o nofTAAg e n e so rgenomica l t e r a t i o n si noncog巴nes andtumors u p p r es s org e n e s( 1 1,1 2 ) .TheTAAg e n e sa r ea l s o u s e f u lf o rinsituh y b r i d i z a t i o nandaDNAm i c r oa r r a ya n a l y s i s f o rc o n f i r m i n gm a l i g n a n c yi nv ar i o u sc a n c e r s( F i g u r e2 )( 1 3 , 1 4 ) .

3 . Tumorimagingand TAAs. Theu s eo fMAbsa g a i n s tt h e r es p e c t i v eTAAsha sb e e nshownt ob eo fp a r t ia lu t i l i t yf o r tumori m a g i n gb yi m m u n o s c i n t i g r a p h y( F i g u r e2 )a sw e l la s f o r i m m u n o t h e r a p e u t i c p r o c e d u r e s b a se d on th 巴 admin ( 1 5 ) .S巴V巴ral a t t e m p t sh a v er e c e n t l ybeenmadet od e v e l o p

K u r o k ie ta l :S i g n i f i c a n c eo fT u m o r A s s o c i a t e dA n t i g e n si nt h eD i a g n o s i sa n dT h e r a p yo fC a n c e r

S e r o l o g i c a lExamination R I A .E I A :Tumormarker PCR:C i r c u l a t i n gONA RT-PCR:C i r c u l a t i n gmRNA P r o t e i nm i c r o a r r a ya n a l y s i s

P h y s i c a lExamination I n s p e c t i o n P a l p a t i o n Percussion A u s c u l t a t i o n EndoscopicExamination Fiberscope E l e c t r o n i cendoscope

P a t h o l o g i c a lExamination H i s t o c h e m i c a ls t a i n i n g lmmunohistochemicals t a i n i n g RT-PCR:C i r c u l a t i n gtumorc e l l s I ns i t uhybridization DNAm i c r o a r r a ya n a l y s i s

Imaging X r a yexamination C o n t r a s tr a d i o g r a p h y CT,MRI lmmunoscintigraphy PET,SPECT

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F i g u r e2 .V a r i o u sd i a g n o s t i cm e t h o d sf o rc a n c e r .C a n c e rs h o u l db ed e t e c t e da se a r l ya sp o s s i b l e . PCR,p o l y m e r a s ec h a i nr e a c t i o n ;C T , COYI'.ψuted t o m o g r a p h y ;MRI,m a g n e t i cr e s o n a n c ei m a g i n g .Ford e s c r i p t i o n so ft h eo t h e ra b b r e v i a t i o n s ,s e et e x t . Theu n d e r l i n e dw o r d sd e n o t et h em e t h o d si nw h i c h f t e no ra l w a y su s e dt oi n c r e a s et h e i rtumor 司pecificity. TAAs( t u m o rm a r k e r s )a陀 either o

MAbsendowedw i t hamore ' d e f i n e ds p e c i f i c i t yandal o w e r e n e t i c a l l y ｭ i m m u n o g e n i c i t y i n m a n . I n t h i s cont巴xt, g r e c o m b i n a n t a n t i b o d i e s s u c h a s c h i m e r i c a n t i b o d y , humanizeda n t i b o d yo rs i n g l e c h a i nv a r i a b l ef r a g m e n t( s c F v ) a n t i b o d yd e s e r v ec o n s i d e r a b l ea t t e n t i o n( 1 6 ) . S e v e r a l new i m a g i n g a p p r o a c h e s u s i n g s i n g l e p h o t o n e m i s s i o nc o m p u t e rt o m o g r a p h y( S P E C T ) ,p o s i t r o ne m i s s i o n a m e r a s t o m o g r a p h y( P E T ) ,a n d new h y b r i d SPE口/PET c c a p a b l eo fp e r f o r m i n gb o t ht y p e so fi m a g i n gh a v eb e e n d e v e l o p e d( 1 7 ) .Ra d i ol a b e l e dMAbsa g a i n s tTAAsa r eo f t e n fv a r i o u st u m o r s( F i g u r e2 ) .With u s e df o rt h eSPE口 imaging o SPECT,i ti sp o s s i b l et ol o c a l i z et h es i t eo ft h el e s i o nmore d i s t i n c t l ya n dt op r e d i c tt h ea c c u m u l a t i o no ft h ea n t i b o d yi nt h e t u m o ra sat r e a t m e n ta p p l i c a t i o n .A l lo ft h e s ee f f o r t se n h a n c e t h ed i a g n o s i s ,s t a g i n g,f o l l o w u p ,d e t e c t i o no fr e c u r r e n c ea n d i a b l et u m o r( 1 8 ) . d i f f e r e n t i a ld i a g n o s i sb e t w e e nn e c r o s i sversusv I I. C a n c e rT h e r a p yandTAAs

c a n c e rt h e r a p ya st h et a r g e t sa n dt h e i rr e l a t e dc o m p o n e n t s u s e df o rc a n c e rt h e r a p y .MAbsa g a i n s tTAAsa r ew e l l k n o w n t ob eu s e f u la ss el e c t i v ec a r r i e r sf o rd e l i v e r i n gr a d i o a c t i v e i s o t o p e so ra n t i c a n c e rd r u g st om a l i g n a n tc e l lp o p u l a t i o n s ( F i g u r e3 ) ,a n dt h e s es t r a t e g i e sa r ec a l l e d radioimmuno・ t h e r a p y( 1 5 )o r chemoimmunotherapy ( 1 9 ) ,r e s p e c t i v e l y . Radioimmunoguided s u r g e r y u s i n g r a d i o l a b e l e d MAbs a g a i n s tTAAsa l s os e e m st oi n c r e a s et h ea c c u r a c yo fs t a g i n g n f o rv a r i o u st y p e so fc a n c e rb yt h es u r g e o n( F i g u r e3 )( 2 0 ) .I e i t h e rp h o t o d y n a m i co rs o n o d y n a m i c th巴rapy f o rc a n c e r , r MAbs a g a i n s t TAAs c o n j u g a t e dw i t h photosen凶izer o s o n o s e n s i t i z e ra r eu s e dt oi n c r e a s et h e i rtumors p e c i f i c i t y ( F i g u r e3 ) ,a n dt h e s ea p p r o a c h e sa r ec a l l e dphotoimmunoｭ 2 2 ) . t h e r a p y( 2 1 )o r sonoimmunotherapy，民spectively ( l lb ec l a s s i f i e da s H o w e v e r ,a s thes巴 methods may a immunotherapy i nt h eb r o a ds e n s e , we h e r e i n make an a s e don o v e r v i e wo fimmunotherapya sw e l la sgen巴 therapy b t h eu s eo fTAAsa st h e i rt a r g e t s .

V a r i o u st h e r a p e u t i c methods f o rc a n c e ra r ei l l u s t r a t e di n F i g u r e3andt h emethodsi nw h i c hTAAsa st a r g e t sa r ee i t h e r oft巴n o ra l w a y se m p l o y e dt oi n c r e a s et h e i rt u m o r s p e c i f i c i t y a r es p e c i f i e d .T a b l eI Is u m m a r i z e sm a j o rTAAs u s e df o r

1 .CancerimmunotherapyandTMs.T a b l eI I Is u m m a r i z e st h e m a j o rs t r a t e g i e so fimmunotherapyf o rc a n c e r ,w h i c hc a nbe b r o a d l yc l a s s i f i e di n t oe i t h e ra c t i v eo rp a s s i v eimmunotherapy ( 2 3 ,2 4 ) .

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C o l o r e c t a lc a n c e r , g a s t n c c a n c e r , l u n g

b r e a s tc a n c e r ,p a n c r e a t i c c a n c er , t h y r o i dmed u l la r y c a r c i noma,e s o pha g e al c a n c e r ,g a l lbladd巴r c a nc e r , o v a r i a nc a n c e r , u t e r m e c a n c e r AFPαーfetoprotein H e p a t o c e l l u l a rcarcmoma, he p a t o b l a s t o m a, y ol ks a ctumo r TPA T i s s u ep o l y p e p t i d ea n t i g e n V a r i o u scane巴rs CA1 99 C a r b o h y d r a t ea n t i g e n1 9 9 P a n c r e a t i cc a n c e r , c a r c i n o m ao ft h eb i l i a r y t r a c t , g a s t r i cc a n c e r , c o l o r e c t a lc a n c e r , o v a r i a n c a n c e r CA5 0 C a r b o h y d r a t ea n t i g e n5 0 P a n c r e a t i cc a n c e r , c a r c inomao ft h eb i l i a r y t r a c t ,g a s t r i cc a n c e r , c o l o r r e c t a lc a nc e r , o v a r i a n c a n c e r CA1 2 5 C a r b o h y d r a t eantige日 125 O v a r i a nc a n c e r ,utenn巴 c a n c e r ’ hu v , B r e a s tc a n c e r ,o v a r i a n c a n c e r r e a s tc a n c e r , o v a r i a n BCA2 2 5 B r e a s tc a r c inomaa n ti g en2 2 5 B c a n c e r CYFRA2 1 C y t o k e r a ti n1 9f r a g m e n t N o n s m a l lc e l ll u n gc a n c e r , b l a d d e rc a n c e r P r o s t a t i cc a n c e r PSA P r o s t a t e s p e c i f i ca n t i g e n y-Sm y s e m i n o p r o t e i n P r o s t a ! I cc a n c e r h CG~ Humanchor削1ic g o n a d o t r o p i n~ Ch o r i o c a r c i n o ma CA7 2 4• C a r b o h y d r a t ea n t i g e n7 2 4 G a s t r i cc a n c e r ,c ol o r e c t a l c an c e r ,ovananc a n c e r , p a n c r e a l i ccanc巴r STN S i a l y lTn G a s t r i cc a n c e r ,c o l o r e c t al c a n c e r , o v a r i a n c a n c e r ,p a n c r e a t i cc a n c e r S i a l y lLewi s x ia n t ig e n Lunga d e n o c a r c i n o m a , SLX p a n c r e a t i cc a n c e r , C o l o r e c t al c a n c e r S m a l lc e l ll u n gc a n c e r , NSE N巴uron-specific enolas巴 n e u r o e n d o c r i n et u m o r s s c c SquamouscellcarcinomaantigenSquamouscelllungcancer, u t er i n ec e r v i c a lcane巴r, h e a da ndn e c k c a nc e r PIVKAI IP r o t e i ni n d u c e db yv i tami nK H e p a t o c e l l u l a rc a r c i n o ma , a b s e n c eo fa n t a g o ni s tI I h e p a t o b l a s t o ma HER2 ム Human e p i d e r m al g r o wthf a c t o r Br巴ast c a n c e r r e c e p t o r2 J

T a b l eI I .M勾or tumor-associated 仰t忽ms a st a r g e t sf o rc a n c e rt h e r a p yand t h e i rr e l a t e dc o m p o n e n t su s edf o rc a n c e rt h e r a p y .

knowna sHER2 / neuo rCe r bB 2 .

CA7 2 4

MAb,a n t i i d i o t y p i ca n t i b o d y ,a n t i b o d yg e n e

s c c

MAb,a n t i g e n ep e p t i d e

1 7 l A2

MAb( e d r e c o l o m a b) ,a nt i i d i o t y p i ca n t i b o d y , a n ti b odyg e n e

MUC-1

Antiーidiotypic

p53

A n t i i d i o t y p i ca n t i b o d y ,a n t i g e np e p t i d e ,ant1g巴n g e ne

HER2

MAb( t r a n s t u z u m a b = H e r c e p t i n ) ,a n t i g e npep t i d e , a n t i g e np r o m o t e r / e n h a nc e rg e n e

G250

MAb,antトidiotypic

a n t i b o d y ,a nt i g e nep e p t i d e ,a n t i g e n en h a n c e rg e n e g e ne ,a n t i g e np r o m o t e rI

a nt ibo d y ,a n t i b odyg e n e,

a nt i g e np e p t i d e CD20

MAb( r i t u x i m a b, i b r i tumomab,t o s i t u m o m a b )

CD22

MAb( e p r a t u z u m a b)

CD52( g p 2 0 )

MAb(Campath-lH )

g p l O O

A n t i g e np e p t i d e , a n t ig e ng e ne

MAGE

Anti g e np e p t i d e ,a nt i g eng e ne

GAGE

A n t i g e npe p t i de p e p t i d e

BAGE

Antig巴n

SART

A n t i g e npeptid巴

MART

A n t i g e np e p t i d e , a n t i g e ng e ne

MYCN

An t i g e np e p t i d e

HPV16

A n t i g e np e p t i d e ,a n t i g e ng e n e

BCR-ABL

A n t i g e np e p t i d e , a n t i g e ng e n e

TRP

A n t i g e np e p t i d e

本 1

'A b b r e v i a t i o n su s e d : MAGE , me l a n oma a nt i g e ne n c o d i n gg e n e p r o t e i n ;g p -1 00 ,g l y c op r o t e i n 1 0 0 ;SART ,s i t e s p e c i f i cr e t r o t r a ns poｭ s o n s ; MART ,mel a noma a n ti gen r e c o g n i z e db yT c el s ; HPV16 , human p a p i l l o m a v i r u st y p e1 6p r o t e in;TRP, t y r o s i n a s e r e l a t e d p r o t e i n .Ford e s c r i p ti o n so ft h eo t h e ra b b r e v i a t i o n s ,s e eT a b leI .

2A l s oknowna sGA 7 3 32 ,EGP-2 ,Ep-CAMo rM K 1 .

A c t i v ei m m u n o t h e r a p y .Withactiveimmunotherapy ,t r eatment r e l i e sonth巴 in v i v ostimulationofthehostimmunesystemto I I )(23).Th巴 activated tumorｭ r e a c ta g a i ns ttumors(TableI s p e c i f i cCTLsornaturalk i l l e r(NK)ce l l saref i n a le f f e c t o r c e l l s agai n s t tumors. The administration of b i o l o g i c a l s or response modifier s (BRMs ) , such a s bact巴rial product

K u r o k ie tal：目

Significance

o fT u m o r A s s o c i a t e dA n t i g e n si nt h eD i a g n o s i sa n dT h e r a p yo fC a n c e r

Imm山~apy\I＞一一：raov 川 UllJUI一円＼／

Sonodynamic Therapy

_ .

Photodynamic/ ’

虫盟

/

＼／一＇

‘一一

. . . . , . '

I n t e r v e n t i o na l R a d i o l o g i cTherapy

い… Therapy

H e m a t o p o i e t i c Hypeパherm i at h e r a p y StemC e l l T r a n s p l a n t ; t i o n LaserTherapy Figur巴 3. Vario則的atrnent m ethods/ 0 1cancer.Cancershouldhopefulか be eradicatedeveni fi ti sd e t e c t e da tanadνanced s t a g e .Theu n d e r l i n e dwor , ' s l w a y su s e da st h e i r似rgets. d e n o t et h emethodsi nwhichTAAsa r ee i t h e ro戸en 01a

c y t o k i n e s ,i sanon叩ecific a c t i v eimmunotherapy( T a b l eI I I ). h e r a p yi nmanh a v en o tbeen Mosta t t e m p t sa tsyst巳mic t n o t i c e a b l ys u c c e s s f u l ,b u ti n t r a l e s i o n a lBCGandn o n c s p e c i f i c g a i n s tS巴veral l o c a li m m u n i z a t i o nw i t hBCGar巴 effective a k i n d so ft u m o r s( 2 5 ,2 6 ) .M e a n w h i l e ,i m m u n i z a t i o nu s i n g rtumorc e l le x t r a c t s ,t h es o c a l l e d i n a c t i v a t e dtumorc巴lls o c a n c e rv a c c i n e, i sas p e c i f i ca c t i v eimmunotherapy( T a b l eI I I ) . P u r i f i e do rr e c o m b i n a n tTAAs,o ra n t i i d i o t y p i ca n t i b o d i e s m i m i c k i n gt h ee p i t o p e sont h eTAAsh a v ea l s obeenu s e df o r a c t i v ei m m u n i z a t i o n .Morer e c e n t l y ,i ti sa l s oi n t e r e s t i n gt o n o t et h a t tumor a n t i g e np e p t i d e p u l s e d DCs h a v e been administ巴red t os e v e r a lk i n d so fc a n c e rp a t i e n t st oi n d u c e tumor叩ecific C TLs( T a b l eI I I )( 2 7 ).T h e s es p e c i f i ca c t i v e a p p r o a c h e sh a v e shown some s u c c e s si ne l i c i t i n gt u m o r ｭ s p e c i f i cCTLst h a tr e c o g n i z etumora n t i g e np e p t i d e s( T a b l e I I )onHLAc l a s sIm o l e c u l e s( F i g u r elA)o ft h et a r g e ttumor a nf i n a l l yk i l lt h et a r g e t c e l l s . Th巴 tumor-specific CTLs c tumor c e l l s. by s e v e r a lc y t o l y t i cm e c h a n i s m ss u c ha st h e p e r f o r i n / g r a n z y m e -and F a sl i g a n d / F a s m e d i a t e dp a t h w a y s

byHLAc l a s sIm o l e c u l e sont a r g e ttumorc e l l s .Asar e s u l t , HLAc l a s sIm o l e c u l e sseemt obeav e r yi m p o r t a n tc r o s s r o a d i na c t i v eimmunotherapyf o rc a n c e r( 2 9 ) .

P a s s i v e i m m u n o t h e r a p y . With p a s s i v e immunotherap y , i t h t r e a t m e n ti n v o l v e st h ed e l i v e r yo fb i o l o g i c a lreag巴nts w . e .a c t i v a t e dimmune e s t a b l i s h e dtumor-immuner e a c t i v i t y ,i d i a t ea n t i ｭ c e l l so ra n t i b o d i e s, t h a tc a nd i r e c t l yo rindir巴ctly me tumore f f e c t sa n ddon o tn e c e s s a r i l ydependont h ei nt a c t T a b l eI I I )( 2 3 ) .Whenp e r i p h e r a lb l o o d h o s timmunesyst巴m ( m o n o n u c l e a rc e l l s (PBMCs) o rt u m o r i n f i l t r a t i n gl y mphoｭ h e ybecome c y t e s( T I L s )a r ec u l t u r e di nv i t r ow i t h IL・2, t h i g h l yc y t o t o x i ct oaw i d ev a r i e t yo ftumorc e l ls ,man yo f w h i c ha r er e s i s t a n tt of r e s h l yi s o l a t e d NK c e l l s. Such p r o m i s c u o usk i l l e rc e l l sa r et e r m e dl y m p h o k i n e a c t i v a t e d k i l l e r(LAK)c e l l sandc o n s i s tm a i n l yo fNK(NK-LAK)c e l l s a n d / o rT(T-LAK)c e l l s .I n i t i a lc l i n i c a le x p e r i m e n t s ,i nw h i c h e l l swere r e i n f u s ed,h a v e shown some good t hes巴 LAK c L 2wasg i v e na tt h esame t i m e r e s u l t s , esp巴cially when I ( T a b l eI I I ) ( 3 0 ) . However, w e l l c o n t r o l l e dt r i a l s ha v e ( 2 8 ). H o w e v e r ,humantumorc e l l sa r ew e l l k n o w nt oo f t e nl o s e p r o d u c e dl e s se n c o u r a g i n gr e s u l t s and t h i sn o n -s p e c i f i c HLAc l a s sIm o l e c u l e s( 2 9 ) .TheseHLAl o s s e sa r ede t e c t e d t h e r a p y ,i n vo l v i n gh i g h d o s eI L 2 ,a l s oha ss i g n i f i c a n tt o x i c i t y whent h ep r i m a r ytumorb r e a k st h eb a s a lmembranei n v a d e s ( 3 1 ) . t h es u r r o u n d i n g tissu巴s a n ds t a r t st om e t a s t a s i z e . These S e v e r a lp a s s i v e,s p e c i f i ci m m u n o t h e r a p i e su s i n g MAbs a l t e r e dHLAc l a s sIp h e n o t y p e sp r o b a b l yc o n s t i t u t et h em a j o r a g a i n s t TAAs seem t o be v e r yp r o m i s i n g , b巴cause TAA tumor e s c a p e mechanism f a c i n g t u m o r s p e c i f i c CTLｭ e e l l sa r ee a s i l yc o n f i r m e dby x p r e s s i o n son targ巴t tumorc m m u n o s t a i n i n g a n d / o r f l o w c y t o m e t r y u s i n g t h e m e d i a t e dr e s p o n s e s .T h e s ef a c t sa l s oi m p l yt h a ti ti sn o ts o i o r r e s p o n d i n gMAbs( F i g u r el B ) .Ea r l ya t t e m p t sa tpas s i v e e a s yt oe l i m i n a t et h et a r g e tt u m o r sbyg e n e r a t i n gt u m o r ｭ c s p e c i f i cCTLsi np a t i e n t so rbyadop t i v e l yt r a n s f e r r i n ge xvivo・ immunothe r a p yw i t hp o l y c l o na lh e t e r oa n t i b o d ie sha v ebe e n a c t i v a t e dCTLsi n t op a t i e n t s .B e s i d e s ,i ti snowi m p o s s i b l et o l i m i t e db e c a u s eo ft h ed i f f i c u l t yi na c h i e v i n gh i g ht i t r eand pr巴cisely c o n f i r mth巴 presentation o ftumora n t i g e np e p t i d e s specificit)人 The a d v e n to fMAbsp r o m i s e st oov巴rcome thes巴

4259

ANTICANCERRESEARCH22:4 2 5 5 4 2 6 4( 2 0 0 2 ) t r a t e g i e sofimmunotherapyf o rc a n c e r . T a b l eIII.M勾or s

1 .A c t i v ei m m u n o t h e r p y( i n d u c t i o no fh o s ti m m u n er e s p o n s e )

1 )N o n s p e c i f i ct h e r a p y :BRMs • Activate Mψ， CTLs a n d / o rNKc e l l s a . Bact巴rial p r o d u c t s(BCG" ' , C o r y n e b a c t e r i u mpmvum,l e v a m i s o l e, e t c . ) b .Cyto凶 es ( I F N y, I L 2 ,TNFα， etc.) 事1

2 )S p e c i f i ct h e r a p y :canc巳r 四ccines → Induce C T L sa g a i n s tTAA a .T u m o rc e l l so rt u m o rc e l le x t r a c t s b .P u r i f i e do rr e c o m b i n a n ta n t i g e n s c . A n t i i d i o t y p ea b t i b o d i e s D b a s e dv a c c i n e s d .T u m o ra n t i g e np e p t i d e p u l s e dDCs= C 2 .P a s s i v ei m m u n o t h e r a p y( P a s s i v et r a n s f e ro fa c t i v a t e di m m u n ec e l l so rs p e c i f i ca n t i b o d y ) 1 )Non 叩ecific th巴rapy a .LAKc e l l sa n dI L 2 h e r a p y 2 )Spec凶c t a .A n t i b o d ya l o n e(MAb, c h i m e r i cA b ,h u m a n i z e dAb, s c F v, h u m a nMAb) b. 加tibodi陀s coup！巴d t od r u g s( adrian明 ycir 1 3 1I 99m 9 1 1 1I 1 8 8Re， 6 7臼） ， p 叩boxypept尚se G2，句tosine deamina札前）， r a d i o i s o t o p e s( , T c,0Y, n, h o t o s e n s i f ( p h t h a l o c y a n i n e , c h l o r i n e 6, e t c . ) ,sonosensit田rs ( A T X 7 0 ,e t c . )o rs u p e r a n t i g e n s( S E A, e t c . ) c .A n t i b o d yf u s i o np r o t e i n s( A b / I L 2, Ab / I L 1 2, Ab / G M C S F ,A b / T N F, Ab/ B 7 . l, Ab / SEA, Ab / R N a s e, Ab尽ANTES , e t c . ) d . Bispeci白c a n t i b o d i e st oTAAa n dNKc e l l s( C D 1 6 ) ,o rt oTAAa n dTc e l l s( C D 3 ) e t c . ) e .C T L s( C T L si n d u c e db yp e p t i d e p u l s e dD C s ,o rF l up e p t i d e s e n s i t i z e dC T L sp u l s e dw i t ht u m o r s p e c i f i cAb / HLAc o m p l e x e s, ' 1 A b b r e v i a t i o n su s e d :B C G ,b a c i l l u sC a l m e t t e G u e r i n ;I F N,int巴rferon ; I L 2,i n t e r l e u k i n 2 ;i n t e r g e r o n;TNF,t u m o rn e c r o s i sf a c t o r;PEA , p s e u d o m o n a se x o t o x i nA ;SEA,s t a t h y l o c o c c a le n t e r o t o x i nA ;GM-CSF,g r a n u l o c y t e m a c r o p h a g ec o l o n ys t i m u l a t i n gf a c t o r;RANTES,r e g u l a t e d u p o na c t i v a t i o n, n o r m a lTe x p r es s e d, a n dp r e s e u m a b l ys e c r e t e d; HLA, h u m a nl e u k o c y t ea n t i g e n .F o rd e s c r i p t i o n so ft h eo t h e ra b b r e v i a t i o n s ,s e et e x t . T h ei m m u n o t h e r a p ys t r a t e g i e si nw h i c ht h er e c o m b i n a n tg e n e st h e m s e l v e so rth巴 gene-transfected c e l l sa r ei n j e c t e di nt h eb o d ya r ei n c l u d e di ng e n e t h e r a p y( s e eT a b l eI V ) .

d i f f i c u l t i e s( T a b l eI I )( 3 2 ) .MAbsmayb eu s e de凶er a l o n e ,o r y t o k i n e so ri s o t o p e s c o u p l e dt od r u g s , pro-drugsラ toxins, c ( T a b l eI I I ) .F u r t h e r m o r e ,r e c e n ta d v a n c e si nt h eg e n e t i c e n g i n e e r i n gf i e l dh a v el e dt or a p i dp r o g r e s si nt h e dev巴lopment o fa n t i b o d i e sf u s e dt oo t h e rp r o t e i n s( 3 3 ). T h e s e a n t i b o d yf u s i o np r o t e i n s ,s u c ha s Ab/IL・2, Ab/IL・ 12, etc. ( T a b l eI I I ) ,maya l s ob ep o t e n t i a l l yu s e f u li nt h et r e a t m e n to f humanc a n c e r( 3 3 3 6 ). T h e r ea r e ,h o w e v e r ,s e v e r a ll i m i t a t i o n s t o a n t i b o d yt h e r a p y , a sf o l l o w s ( 2 4 ) . F i r s t , a n t i b o d y p e n e t r a t i o ni n t ol a r g etumorm a s s e si so f t e np o o r .T h i sm i g h t b eo v e r c o m eb ys m a l l e rm o l e c u l e st h a tr e t a i ns p e c i f i ca n t i g e n b i n d i n g ,s u c ha sFab'f r a g m e n to re n g i n e e r e ds c F va n t i b o d i e s ( T a b l eI I I )( 1 6 ) .S e c o n d ,mouseMAbsa r eimmunogenici n h u m a n s .Theymayt h e r e f o r eb ea t t a c k e db yt h eh o s timmune s y s t e m .Evenc h i m e r i co rh u m a n i z e da n t i b o d i e smayi n d u c e a nimmuner e s p o n s et ot h e i ri d i o t y p e .I nt h i sc o n t e x t ,i ti s v e r yi n t e r e s t i n gt on o t et h a ti th a sbecomee a s yt og e n e r a t e human MAbs t oa n y human TAAs u s i n gC r o s s b r e d TransChromo( T C )m i c ea n dt h eu s u a lh y b r i d o m atechn叩巴S ( T a b l eI I I )( 3 7 ) .F i n a l l y ,a n t i b o d i e sa r eboundb yo t h e rc e l l s 4 2 6 0

i n c l u d i n ga n yn o r m a lc e l l se x p r e s s i n gt h et a r g e ta n t i g e n ,a n d n o n s p e c i f i c a l l yb yc e l l sb e a r i n g Fc r e c e p t o r s .C h e m i c a l ft h ea n t i b o d ym o l e c u l e s m o d i f i c a t i o no rg e n e t i cengine巴ring o mayn e e dt oo v e r c o m et h e s ed i f f i c u l t i e s .I ns p i t eo ft h e s e p r o b l e m st h e r eh a v er e c e n t l yb e e nsomee n c o u r a g i n gr e s u l t s . I nar a n d o m i z e ds t u d y,MAb1 7 l A( e d r e c o l o m a b )h a sb e e n u s e dt ot r e a tc o l o nc a n c e rf o l l o w i n gs u r g e r yt oremovet h e I ) .Thea i mo ft h i ss t u d ywast ot a r g e t p r i m a r ytumor( T a b l eI m i c r o m e t a s t a s e s, t h u s a v o i d i n g t h e p r o b l e m o fp o o r r o u p p e n e t r a t i o ni n t ol a r g et u m o rm a s s e s . Th巴 tr巴ated g show巴d as i g n i f i c a n t l yi m p r o v e ds u r v i v a l( 3 8 ,3 9 ) .S i m i l a r l y , t h e r a d i o l a b e l l e d r e c o m b i n a n t a n t i B c e l l a n t i b o d i e s , r i t u x i m a bo re p r a t u z u m a b , etcリ showed p r o m i s ea g a i n s t lymphomasr e s i s t a n tt oc o n v e n t i o n a lt h e r a p y( 4 0 ,4 1) ,a n dt h e r e c o m b i n a n ta n t i H E R 2 MAb, t r a s t u z u m a b (Herc巴ptin) c o m b i n e dw i t hch巴motherapy prolong巴d th巴 median t i m et o t h eprogr巴ssion o fb r e a s tc a n c e rcomparedt oc h e m o t h e r a p y I )( 4 1 ) . a l o n e( T a b l eI I na d d i t i o n ,i ts e e m sl i k e l yt h a tn e i t h e rNK・LAK n o rT ｭ nt u m o r s,a n dt h i smayc o n t r i b u t et o LAKc e l l sl o c a l i z ew巴II i

K u r o k ie ta l :S i g n i f i c a n c eo fT u m o r A s s o c i a t e dAntig巴ns i nt h eD i a g n o s i sa n dTh巴rapy o fC a n c e r T a b l eI V .Majors t r a t e g i e so fg e n et h e r a p yf o rc a n c e randt h e i rtumort a r g e t i n gappro町hes. 1 .D i r e c tgen巴 therapy ( d i r e c tk i l l i n go ft u m o rc巴lls b yg e n ep r o d u c t so rt h e i rs e c o n d a r yp r o d u c t s )

*,

1 )S u i c i d eg e n e s: HSY北且， CD, i N O S ,e t c . 2 )T u m o rs u p p r e s s o rg e n e s ;p 5 3, MTSl, e t c . 3 )A n t i s e n s eo l i g o n u c l e o t i d i e sa g a i n s to n c o g e n e s :K-ras,bc/-2,e t c . 4 )A n t i a n g i o g e n i cg e n e s :angiostatin，巴ndostatin, e t c . T u m o rt a r g e t i n gu s i n ga n t i T I As c F vc h i m e r i ce n v e l o o eg e n e(Retrovector）ゐ T u m o rt a r g e t i n gu s i n gb i s o e c i f i ca n t i b o d vt oa d e n o v i r u sf i b e ra n dTAA( A d e n o v e c t o r ) 主旦盟旦E並rgeting u s i n gTAAo r o m o t e r / e n h a n c e rg e n e• ホ弓

事’、

u m o rc e l l sb yg e n e t r a n s f e r r e di m m u n o c y t e s, e t c . ) 2 .I n d i r e c tg e n et h e r a p y( i n d i r e c tkilli旬。f t 1 )G e n et r a n s f e ri n t oi m m u n o c y t e s( i m m u n o g e n et h e r a p y ) IFN－α， TGF－~ ， etc. a .C y t o k i n eg e n e s: T N F ,I F N y, I L 2, I L 4 , I L 6, • transfect i n t oC T L s b .C h i m e r i ci m m u n er e c e p t o rg e n e s :a n t i T A As c F v / F c R yo ra n t i T A AscFv/CD3~ • transfect i n t oC T L s(tumort a r g e t i n go fC T L sv i achim巴ricimmune I巴cetors) c . T u m o r a s s o c i a t e da n t i g e ng e n e s :MART-1, etc. • transfect i n t oDCs C A M 1, L F A 3, etc. • transfect i n t oDCso rf i b r o b l a s t s d .C o s t i m u l a t o rg e n e s :B7,I etc. • transfect i n t of i b r o b l a s t s e . MHCg e n e s :HLAc l a s sI , r a n s f e ri n t ot u m o rc e l l s 2 )G巴ne t e t c . a .C y t o k i n eg e n e s :I F N y, I L 2, I L 4, TNF , G C S F ,GM-CSF, c . C o s t i m u l a t o rgen巴s: B7,ICA孔11 , L F A 3 ,e t c . d .MHCg e n e s :HLAc l a s s, Ie t c . 3 )DNAv a c c i n a t i o nb yi . m .o rs . c .i n j e c t i o n :TAAg e n e s( C E A ,MUC-1, e t c . ) 4 )D r u g r e s i s t a n c eg e n et r a n s f e r: MDRl, MGMT, etc. • transfect i n t oh e m a t o p o i e t i cs t emc e l l s 1A b b r e v i a t i o n su s e d :H S V t k ,h e r p e ss i m p l e xv i r u st h y m i d i n ek i n a s e ;C D ,c y t o s i n ed e am i n as e ;i N O S ,i n d u c i b l en i t r i co x i d es y n t h a s e ;MART-1, m e l a n o m aa n t i g e nr e c o g n i z e db yTc e l l s1 ;I C A M 1 ,i n t e r c e l l u l a ra d h e s i o nm o le cu l e 1;LFA3 ,l y m p h o c y t ef u n c t i o n a s s o c i t e da n t i g e n 3 ;G C S F , g r a n u l o c y t ec o l o n y s t i m u l a t i n gf a c t o r ;M U C 1 ,t u m o r a s s o c i a t e dm u c i n1 ;MDRl,m u l t i d r u gr e s is t a n c e1 ;MGMT,0 6 m e t h y l g u a n i n eDNA ~ethyltransferase. F o rd e s c r i p t i o n so ft h eo t h e ra b b r e v i a t i o n s, s e eT a b l e sIa n dI I I . 会 The u n d e r l i n e dw o r d sdenot巴 the t u m o rt a r g e t i n ga p p r o a c h e s .

t h ep o o rr e s u l t so ft h eabove-mention巴d, n o n s p e c i f i cLAK c e l lt h e r a p y( 2 4 ) .Too v e r c o m et h i s ,b i s p e c i f i cMAbsh a v e b e e nu s e d( 4 2 ) .I nt h e s e,o n ea n t i b o d yi sd i r e c t e da g a i n s ta TAAa n dt h eo t h e ra g a i n s ts u r f a c em a r k e r sone f f e c t o rc e l l s , s u c ha sCD16onNKc e l l sa n dCD3onT c e l l s( T a b l eI I I ) nt h e o r y ,t h e s ea n t i b o d i e ss h o u l dh e l pt ol o c a l i z et h e ( 4 3 ) .I LAKc e l l sont h etumorviat h e i ra n t i T AAa c t i v i t y. CTLs i n d u c e db y tumor a n t i g e n p u l s e d DCs, o rF l u ｭ s e n s i t i z e d CTLs p u l s e d w i t h t u m o r s p e c i f i c Ab / HLA c o m p l e x e sh a v ea l s ob e e nu s e da sp a s s i v ei m m u n o t h e r a p yf o r c a n c e r( T a b l eI I I )( 4 4, 4 5 ) . a b l eIVs u m m a r i z e st h e 2 . Cancergenetherapyand TAAs. T m司 or s t r a t e g i e so fg e n et h e r a p yf o rc a n c e r,w h i c hc a nb e l a r g e l yc a t e g o r i z e di n t oe i t h e rd i r e c to ri n d i r e c tg e n et h e r a p y , a n da l s oi n c l u d e st h e i rt u m o rt a r g e t i n ga p p r o a c h e s( 4 6 ) . Directgenet h e r a p y .D i r e c tg e n et h e r a p yf o rc a n c e ri n v o l v e s

t h ei n s e r t i o no fag e n ei n t otumorc e l l sf o rd i r e c tk i l l i n go r

s u p p r e s s i o no fa b n o r m a lg r o w t hb yg e n ep r o d u c t so rt h e i r e n e su s e df o rt h i s s e c o n d a r yp r o d u c t s (Tabl巴 IV). The g s t r a t e g ya r es u i c i d eg e n e s ,f u n c t i o n i n g tumor s u p p r e s s o r g e n e s , a n t i s e n s e g e n e s a g a i n s t known o n c o g e n e s , o r a n t i a n g i o g e n i cg e n e s( T a b l eI V )( 4 6 ) . Am a j o rcommonp r o b l e mw i t ht h e s es t r a t e g i e s,h o w e v e r , i st h el a c ko ft u m o rs p e c i f i c i t yo fv i r a lv e c t o r su s e df o rg e n e t r a n s f e r( 4 7 ) . Most c l i n i c a lt r i a l sf o rg e n et h e r a p yh a v e a d o p t e dr e t r o v i r a lv e c t o r so r i g i n a t i n gf r o mm u r i n el e u k e m i a v i r u st ot r a n s f e rs p e c i f i cg e n e si n t ot a r g e tc e l l s .Toe s t a b l i s h g e n et h e r a p ya saf e a s i b l et r e a t m e n to fc a n c e r ,moree m p h a s i s i sr e q u i r e di nd e v e l o p i n go p t i m a lg e n ed e l i v e r ys y s t e m sw i t h g r e a t e rtumort i s s u es p e c i f i c i t y .Oneo ft h ee f f o r t so ft i s s u e ｭ s p e c i f i ct a r g e t i n gi sb a s e donatt巴mpts t oengine巴r th巴 normal r e t r o v i r a le n v e l o p ep r o t e i n .R e c e n ta d v a n c e si nt h eg e n e t i c 巴ngineering f i e l dp r o v i d eac o n c e p tf o rt a r g e tc e l ls p e c i f i c i t y b yc h a n g i n gｷ t h et r o p i s mo ft h en o r m a le n v e l o p er e t r o v i r a l r e c e p t o r b i n d i n g domain w i t h al i g a n do ra ns c F vt h a t 民cognizes asp民ific c e l lsu 巾ce r e c e p t o ro rTAA( T a b l eI V )

4 2 6 1

ANTICANCERRESEARCH2 2 :4 2 5 5 4 2 6 4( 2 0 0 2 ) ( 4 8 5 0 ) .R e c o m b i n a n ta d e n o v i r a lv e c t o r sa r ea l s oa t t r a c t i v ei n r ec a p a b l e t h ec o n t e x to fc a n c e rg e n et h e r a p ybecaus巴 they a t i l i t yo f o fd e l i v e r i n gg e n e st oaw i d ev a r i e t yo ftissu巴s. Theu a d e n o v i r u s e si sl i m i t e db yt h e i rl a c ko fs p e c i f i c i t yandb yt h e a b s e n c eo ft h er e c e p t o r ( s )f o rt h e s ev i r u s e sonmanytumor c e l l s .R e d i r e c t i n ga d e n o v i r a lv e c t o r st ot u m o r s p e c i f i ct a r g e t s c a nb e achiev巴d b yu s i n gb i s p e c i f i cc o n j u g a t e sw h i c ha r e p r o d u c e db yt h ec h e m i c a ll i n k a g eo fa na n t i a d e n o v i r u s a n t i b o d y and a na n t i r omot巴r g e n e s ,a sw e l la se n h a n c e r addition ’ several TAAp g e n e s ,h a v ea l s ob e e nu s e df o rt u m o r s p e c i f i cgen 巴 delivery w i t hr e t r o v i r a lv e c t o r so rad巴noviral v e c t o r s( T a b l eI V )( 5 2 , 5 3 ) ,a l t h o u g ht h ee x p r e s s i o nl e v e lo ftumor叩ecific promot巴rs s u c ha sCEAp r o m o t e ri sg e n e r a l l yl o w( 5 3 ). I n d i r e c tg e n et h e r a p y .I n d i r e c tg e n e th巴rapy i n v o l v e st h e h a tm o d i f i e so rstimulat口 immunocytes i n s e r t i o no fag巴ne t t ob emoree f f e c t i v ea g a i n s ttumorc e l l s( T a b l eI V ) .R e c e n t k n o w l e d g et h a tT c e l l r e c o g n i z e d peptid巴巴pitopes a r e p r e s e n t e db yHLAm o l e c u l e s,andt h a ti n d u c t i o no fimmune r e s p o n s e si sd e p e n d e n t on c o s t i m u l i ,h a sl e dt ot h e d e v e l o p m e n to fmorer a t i o n a ls t r a t e g i e s( 2 4 ) .T h e r e f o r e ,t h e gen巴s us巴d f o rt h i ss t r a t e g ya r ec y t o k i n eg巴nes, TAAg e n e s, c o s t i m u l a t o r ym o l e c u l eg e n e s ,o rHLAc l a s sIg e n e s ,w h i c h a r eo f t e ni n s e r t e di n t otumorc e l l sa s¥ V e i la si m m u n o c y t e s ( T a b l eI V )( 4 6 ) .H o w e v e r ,t h etumora c c u m u l a t i o np r o p e r t y o fCTLsa c t i v a t e db yc y t o k i n eg e n et r a n s f e ri sa l s ou n c l e a r, l i k et h ec a s eo fLAKc e l l s .A n o v e lmethodf o rs o l v i n gt h i s p r o b l e mi st h es p e c i f i cr e d i r e c t i n go fCTLst otumorc e l l s t h r o u g hc h i m e r i cimmuner e c e p t o r s( C I R s )w i t ha n t i T A A s p e c i f i c i t y . R e c o m b i n a n t CIRs e n c o m p a s s a n t i T A A a n t i b o d i e sf u s e dt ot h es i g n a l i n gd o m a i n so fe i t h e rt h eFc r e c e p t o r( F c R )o rT c e l lr e c e p t o r (TCR) ( 5 4 ) . CTLs e x p r e s s i n ga n t i T A As c F v / F c R yo ra n t i T A A scFv/CD3~ r e c e p t o r sr e c a p i t u l a t et h ec y t o p a t h i ce f f e c t sm e d i a t e db y TCRo rFcRa n da l l o wt h et a r g e t i n go ft u m o rc e l l si na n HLA-independent manner ( T a b l eI V )( 5 4 ) . With t h i s t e c h n o l o g y,l a r g e numberso fCTLsw i t hr巴directed t a r g e t Sp巴cifi則y h a v eb e e ng e n e r a t e d( 5 4 ) .T h i sstrat巳gy mayl e a dt o anewa p p r o a c hf o rt h ea d o p t i v eimmunoth巴rapy o fTAAｭ p o s i t i v et u m o r si n humans,e s p e c i a l l yi nc o m b i n a t i o nw i t h c y t o k i n eg e n et h e r a p y . T r a n s f e c t i o no ft h eg e n e sf o rc y t o k i n e s ,c o s t i m u l a t o r so r HLAc l a s sIm o l e c u l e si n t ot u m o rc e l l sh a sa l s ob e e nshown t og r e a t l yi n c r e a s et h e i ri m m u n o g e n i c i t yi na n i m a lt u m o r p r o t e c t i o ne x p e r i m e n t s( T a b l eI V )( 2 4 ,5 5 ) .Simila均， DNA c o n s t r u c t sc o d i n gf o rTAAsandc o s t i m u l ic a na l s ob eus巴d d i r e c t l yi na n i m a lm o d e l sa n d / o ri nhumanc l i n i c a lt r i a l st o i . m . )o rs u b c u t a n e o u s( s . c . ) immunize b yi n t r a m u s c u l a r( i n j e c t i o n ,a v o i d i n gt h ep r o b l e m so fg e n e t i cr e s t r i c t i o n i n h e r e n ti nu s i n gtumorc e l l st h e m s e l v e s( T a b l eI V )( 5 6 ,5 7 ) . T h i smethodi so f t e nc a l l e dDNAv a c c i n a t i o n .W h i l ea l lt h e s e m e t h o d sc a np r o t e c ta n i m a l sa g a i n s ts u b s e q u e n t tumor c h a l l e n g e , t h e y a r e much l e s s succ巴ssful i n t r e a t i n g e s t a b l i s h e dt u m o r sandt h e r ei sl i t t l ee v i d e n c et h a tsp巴cific

4262

a c t i v ei m m u n i z a t i o nh a sb e e ne f f e c t i v es of a ri nhumans, m o s t p r o b a b l yduet ot h eHLAl o s s e sontumorc e l l sm e n t i o n e d a b o v e( 2 9 ) . o s e l i m i t i n gf a c t o ri nc a n c e r M y e l o s u p p r e s s i o ni sam司 or d chemoth巴rapy. T he i n t r o d u c t i o n o f a n t i c a n c e r d r u g ｭ r e s i s t a n c eg e n e si n t oh e m a t o p o i e t i cs t e mc e l l so fc a n c e r p a t i e n t sh a sb e e np r o p o s e dt oo v e r c o m et h i sl i m i t a t i o n( 5 8 ) . A l t h o u g ht h i sc a n c e rgen巴 therapy i ssomewhatd i f f e r e n tf r o m o t h e rt h e r a p i e sb a s e donat u m o r c e l lk i l l i n gmechanism,t h i s s t r a t e g yi sa l s oi n c l u d e di nt h ei n d i r e c tg e n et h e r a p yg r o u p ( T a b l eI V ). R e f e r e n c e s u m o rI m m u n o l o g y; 1G r o e nT P :T u m o r a s s o c i a t e da nt i g e n s . In:T M e c h a n i s m s ,D i a g n o s i s, T h e r a p y( D e nO t t e rW a n dRu即日berg E J , e d s ) .A m s t e r d a m ,E l s e v i e r, 1 9 8 7 ,p p .1 3 2 7 . 2G h o s eTa n dB l a i rA H :A n t i b o d y l i n k e dcytoto氾c a g e n t si nth巴 t r e a t m e n to fc a n c e r :c u r r e n ts t a t u sa n df u t u rep r o s p e c t s .JN a t l 1 :6 5 76 7 6, 1 9 7 8 . C a n c e rI n s t6 3DeV r i e sJ E,Y s s e lH a n dS p i t sH :T u m o r a s s o c i a t e da n t i g e n s l o n e s .I n :T u m o r d e t e c t e db yh u m a nc y t o t o x i cTl y m p h o c y t e（口L) c n d Immuno l og y ;M e c h a n i s m s,D i a g n o s i s,T h e r a p y( D e nO t t e rW a Ru 附1b巴rg E J, e d s ) .A m s t e r d a m, E l s e v i e r, 1 98 7, p p .2 94 2 . 4G o l dPa n dF r e e d m a nS O :D e m o n s t r a t i o no ft u m o rs p e c i f i ca n t i g e n s i nh u m a nc o l o n i cc a r c i n o m a t ab yi m m u n o l o g i c a lt o l e r a n c ea n d a b s o r p t i o nt巴chniques. JE x pMed121:4 3 94 6 2, 1 9 6 5 . 5Z a r e m b aS ,B a r z a g aE, Z h uM, S o a r esN, Ts a n gKYa n dS c h l o mJ : I de n t i f i ca i t o no fan 巴nhancer a g o n i s tc y t o t o x i cTl y m p h o c y t epeptid巴 f r o mh u m a nc a r c i n o e m b r y o n i cantig巴n C a n c e rR es5 7 :4 5 7 0 4 5 7 7 , 1 9 9 7 6B a s tRCJ r ,R a v d i nP ,H a y e sD F ,B a t e sS , F r i t s c h eHJ r , J e s s u pJM, K e m e n yN ,L o c k e rGY, M e n n e lRGa n dSom巴rfield MR:2 0 0 0 u p d a t eo fr e c o m m e n d a t i o n sf o rt h eu seo ft u m o rm a r k e r si nb r e a s t a ndc o l o r e c t a lc a n c e r :c l i n i c a lp r a c t i c eg u i d e l i n e so ft h eA m e r i c a n S o c i e t yo fC l i n i c a lO n c o l o g y .JC l i nO n c o l1 9 :1 8 6 5 1 8 7 8 ,2 0 0 1 . 7S e l lS :C a n c e rm a r k e r so ft h e1 9 9 0 s.C o m p a r i s o no ft h en e w g e n e r a t i o no fm a r k e r sd e f i n e db ym o n o c l o n a la nt i b o d ie sa n d o n c o g e n ep r o b e st op r o t o t y p i cm a r k e r s .C l i nL a bMed10.・ 1-37 , 1 9 9 0 . 8S c h w a r t zMK：・ Current s t a t u so ft u m o u rmark巴rs. S c a n dJC l i nL a b I n v es t 5 5 :5 1 4, 1 9 9 5 . 9K o p r e s k iM S ,B e n k oFAa n dG o c k eC D :C i r c u l a t i n gRNAa sat u m o r m a r k e r :d e t e c t i o no f5 T 4mRNAi nb r e a s ta n dl u n gc a n c e rp a t i e n t s er u m .AnnNewY o r kA c a dS c i945.・ 172-178, 2 0 0 1 . 1 0S r e e k u m a rA ,N y a t iMK ,V a r a m b a l l yS ,B a r r e t t eTR,G h o s hD, Lawrenc巴 TS a n dC h i n n a i y a nAM:P r o f i l i n go fc a n c e rc e l l su s i ng p r o t e i nm i c r o a r r a y s :d i s c o v e r yo fn o v e lr a d i a t i o n r e g u l a t e dp r o t e i ns . Cane巴r R e s6 1 :7 5 8 5 -7 5 9 3 .2 0 0 1 . 1 1G h o s s e i nRAa n dR o s a iJ :P o l y m e r a s ec h a i nr e a c t i o ni nt h ed e t e c t i o n o fm i c r o m e t as t as e sa n dc i r c u l a t i n gt u m o rc e l l s .C a n c e r78.・ 10-16, 1 9 9 6 . 1 2B o c k m a n nB ,G r i l lHJa n dG i e s i n gM :M o l e c u l a rc h a r a c t e r i z a t i o no f m i n i m a lr es id ua lc a n c e rc e l l si np a t i e n t sw i t hs o l i dt u m o r s .B i o m o l E n g17.・ 95-111, 2 0 0 1 . 1 3L o p e z F e r r e rA,d e B o l osC,B a r r a n c oC ,G a r r i d o M,I s e r nJ , C a r l s t e d tI ,R e i s CA,T o r r a d o Ja n dR e a lF X :R o l eo f f u c o s y l t r a n s f e r a s e si nt h ea s s o c i a t i o nb e t w e e na p o m u c i na n dL e w i s antigen 巴xpression i nn o r m a la n dm a l i g n a n tg a s t r i ce p i t h e l i u m .G u t 4 7 :3 4 9 3 5 6, 2 0 0 0.

Kurokie ta l :S i g n i f i c a n c eofTumor-Associat巴d Antigensi nt h eDiagnosisandTherapyofCancer

1 4ZammatteoN, LockmanL, B r a s s e u rF, D e P l a e nE ,L u r q u i nC, L o b e r t PE , HamelsS ,BoonTa n dRemadeJ :DNAm i c r o a r r a yt om o n i t o rt h e l i nChem4 8 :2 5 3 4 ,2 0 0 2 e x p r e s s i o no fMAGE-Agen巴s. C 1 5V e r h a a r L a n g e r e i sMJ,ZonnenbergBA,d e K l e r kJMa n dB l i j h a m 6 :3 GH:R a d i o i m m u n o d i a g n o s i sandt h e r a p y .C a n c e rT r e a tRev2 1 0 ,2 0 0 0 . 1 6Buchsbaum DJ:E x p e r i m e n t a la p p r o a c h e st oi n c r e a s er a d i o l a b e l e d S u p p l . ) :5 7 2 9 s 5 7 3 2 s , a n t i b o d yl o c a l i z a t i o ni nt u m o r s .C a n c e rR e s55 ( 1 9 9 5 . 1 7P a r kCH: Ther o l eo fr a d i o i s o t o p e si nr a d i a t i o no n c o l o g y . Semin Oncol2 4 :6 3 96 5 4,1 9 9 7 . 1 8T a k e n o s h i t aS, HashizumeT, AsaoT ,NakamuraJ , KatohR, O r i u c h i ta l . . N , Ootake H, I n o u e T, Watanabe N and Endo K e I m m u n o s c i n t i g r a p h yu s i n g9 9 m T c l a b e l e d anti-CEA m o n o c l o n a l 5 :4 7 1 a n t i b o d yf o rp a t i e n t sw i t hc o l o r e c t a lc a n c e r .Anticanc巴r Res1 4 7 5,1 9 9 5 . 1 9Czuczman MS: CHOP p l u sr i t u x i m a b chemoimmunotherapy o f S u p p l .1 4 ) :8 8 9 6 ,1 9 9 9 . i n d o l e n tB c e l llymphoma.SeminOncol26( z o l sRF:C u r r e n ts t a t u so f 2 0BoenteMP,YehK,HoganW MandO s t a g i n gl a p a r o t o m yi nc o l o r e c t a lando v a r i a nc a n c e r .C a n c e rT r e a t Res82.・ 337-357, 1 9 9 6 . 2 1Duska LR,Hamblin MR, M i l l e rJ L , Hasan T :C o m b i n a t i o n photoimmunotherapyandc i s p l a t i n :e f f e c t sonhumano v a r i a nc a n c e r e xviνo JN a t lC a n c e rI n s t9 1 :1 5 5 7 1 5 6 3,1 9 9 9 . 22Ab巴 H, K u r o k i M, T a c h i b a n a K,L iT ,A w a s t h i A,Ueno A , MatsumotoH,I m a k i i r eT,YamauchiY ,YamadaH, A r i y o s h i, A and K u r o k i Ma: Tar g e t e ds o n o d y n a m i ct h e r a p yo fc a n c e ru s i n ga p h o t o s e n s i t i z e rc o n j u g a t e dw i t ha n t i b o d ya g a i n s tc a r c i n o e m b r y o n i c 5 7 5 1 5 8 0 ,2 0 0 2. a n t i g e n .A n t i c a n c e rRes22:1 2 3ChangAE ,G e i g e rJD,SondakVKa n dShu S :A d o p t i v ec巴llular t h e r a p yo fm a l i g n a n c y .ArchS u r128.・ 1281-1290, 1 9 9 3 . 2 4R o i t tI , B r o s t o f fJandMaleD:Immunology , 5 t he d , .London, Mosby I n t e r n a t i o n a lL t d , .1 9 9 8, p p .2 8 0 2 8 3 . 2 5Tan JK and Ho VC: Pool巴d a n a l y s i so ft h ee f f i c a c yo fb a c i l l e Calmette司Guerin ( BCG)immunotherapyi nm a l i g n a n tmelanoma.J 9 9 3 . DermatolS u r gO n c o l19.・ 985・990, 1 ,J a c o b s e nM,K巴mp D,ZhaoW,Zhao 2 6BrandauS,Riemensb巴rger J X,JochamD,R a t l i f fT-LandB o h l eA・ NK c e l l sa r ee s s e n t i a lf o r 2 :6 9 7 7 0 2, 2 0 0 1 e f f e c t i v eBCGi m m u n o t h e r a p y .I n tJCanc巴r 9 2 7HippJD,HippJ A ,L y d a yB Wa n dMinevBR:C a n c e rv a c c i n e s :a n updat巴. I nV i v o1 4 :5 7 1 5 8 5, 2 0 0 0 . 2 8H i s h i iM,K u r n i c kJT,R a m i r e z M o n t a g u tTa n dP a n d o l f iF :S t u d i e s o ft h emechanismo fc y t o l y s i sb yt u m o u r i n f i l t r a t i n gl y m p h o c y t e s .C l i n 8 8 3 9 4 ,1 9 9 9 . ExpImmunol116:3 r o s s r o a di ntumor 2 9A l g a r r aI ,C a b r e r aT a n dG a r r i d oF :Th巴 HLA c 0 0 0 . i m m u n o l o g y .HumImmunol61.・ 65-73 , 2 3 0P a r m i a n iG,R i v o l t i n iL ,A n d r e o l-GandC a r r a b b aM：匂tokines m 0 0 0. c a n c e rt h e r a p y .ImmunolL e t t74：・ 41-44, 2 3 1R i b e i r oRC,R i l lD,RobersonPK ,FurmanWL,P r a t tCB,B r e n n e r n dP u iCH:C o n t i n u o u si n f u s i o no fi n t e r l e u k i n 2i n M,C r i s tW Ma c h i l d r e nw i t hr e f r a c t o r ym a l i g n a n c i e s. C a n c e r72.・ 623-628, 1 9 9 3 . 3 2S t o c c h iLa n dN e l s o nH:D i a g n o s t i ca n dt h e r a p e u t i ca p p l i c a t i o n so f m o n o c l o n a la n t i b o d i e si nc o l o r e c t a lc a n c e r .D i sColonRectum41 ・ 2 3 2 2 5 0,1 9 9 8 . 3 3P e n i c h e tMLandM o r r i s o nS L :A n t i b o d y c y t o k i n ef u s i o np r o t e i n sf o r 4 8 :9 1 1 0 1 ,2 0 0 1 . t h et h e r a p yo fc a n c e r .JImmunolMethods2 3 4L i a oS ,KharePD,ArakawaF ,K u r o k i M,H i r o s eY ,F u j i m u r aS, Tomita Y and K u r o k i Ma: T a r g e t i n go f LAK a c t i v i t yt o CEAｭ e x p r e s s i n gtumorc e l l sw i t hananti-CEAs c F v / I L 2f u s i o np r o t e i n. 0 0 1 . A n t i c a n c e rRes21 ：・ 1673-1680, 2

3 5UenoA,ArakawaF , Abe H, MatsumotoH,KudoT,Asano R, Tsumoto K,Kumagai I ,K u r o k iM a n dK u r o k i Ma.:T c e l l immunoth巴rapy f o rhumanM K 1 e x p r e s s i n gt u m o r su s i n gaf u s i o n p r o t e i no ft h es u p e r a n t i g e n SEA and a n t i M K 1s c F va n t i b o d y . 0 0 2 . A n t i c a n c e rRes22.・ 1769-1776 , 2 3 6MatsumotoH,L i a oS,ArakawaF,UenoA,Abe H,A w a s t h iA , K u r o k iM a n dK u r o k iMa:T a r g e t i n go fi n t e r l e u k i n 2t ohumanMK1e x p r e s s i n gc a r c i n o m ab yf u s i o nw i t has i n g l e c h a i nFvo fa n t i M K 1 0 0 1 2 0 0 8, 2 0 0 2 . a n t i b o d y .A n t i c a n c e rRes22:2 3 7Tomizuka K ,S h i n o h a r a T;Y o s h i d a H,Uejima H,Ohguma A , Tanaka S,S a t o K,Oshimura M and I s h i d aI : Double t r a n s f t w o i n d i v i d u a l human chromosomic m i c e : maint巴nance o chromosome f r a g m e n t sc o n t a i n i n gl gh e a v ya n d kappa l o c i and 7 : e x p r e s s i o no ff u l l yhumana n t i b o d i e s .P r o cN a t lAcadS c iUSA9 7 2 2 7 2 7, 2 0 0 0 . 3 8A b i c h tA andL o c h m u l l e rH:T e c h n o l o g ye v a l u a t i o n :edr巴colomab , C e n t o c o rI n c .C u r rOpinMolTher2.・ 593-600, 2 0 0 0 . 3 9YipD,S t r i c k l a n dAH,K a r a p e t i sC S ,HawkinsCAandHarperPG: Immunomodulationt h e r a p yi nc o l o r e c t a lc a r c i n o m a.CancerT r e a t 6 9 1 9 0, 2 0 0 0 . Rev26:1 o rlymphoma.C u r rOncolRep2 :1 5 7 4 0McLaughlinP :Bioth巴rapy f 1 6 2, 2 0 0 0 . r i l l o L o p e zA J :A n t i b o d y t a r g e t e d 4 1White CA,Weav巴r RL and G 2 :1 2 5 immunotherapyf o rt r e a t m e n to fm a l i g n a n c y .AnnuRevMed5 1 4 5, 2 0 0 1 . 42Kuwahara M,K u r o k i Ma,Arakawa F , Senba T , Matsuoka Y, HideshimaT ,Y a m a s h i t aY andKandaH:A mouse / humanc h i m e r i c b i s p e c i f i ca n t i b o d yr e a c t i v ew i t h humanc a r c i n o e m b r y o n i ca n t i g e n ｭ 6 :2 6 6 1 e x p r e s s i n gc e l l sa n dhumanT l y m p h o c y t e s .A n t i c a n c e rRes1 2 6 6 7, 1 9 9 6 . 4 3T a l a cR andN e l s o nH:C u r r e n tp e r s p e c t i v e so fb i s p e c i f i ca n t i b o d y ｭ 4 :1 7 5 1 8 1, b a s e di m m u n o t h e r a p y .JB i o lR e g u lHomeostA g e n t s1 2 0 0 0 . Inv i t r o 4 4T s a iV,KawashimaI ,KeoghE ,D a l yK ,S e t t eA andC e l i sE: i m m u n i z a t i o n a n d e x p a n s i o n o f a n t i g e n s p e c i f i c c y t o t o x i c T l y m p h o c y t e sf o ra d o p t i v e immunotherapy u s i n g peptide-puls巴d d e n d r i t i cc e l l s .C r i tRevlmmunol18.・ 65-75 , 1 9 9 8 . 4 5R o b e r t B,G u i l l a u m e P,L u e s c h e rI , DouceyM-A,C e r o t t i n iJ C, RomeroPa n dMachJ P :R e d i r e c t i n ga n t i v i r a lCTLa g a i n s tc a n c e r fmonomericMHCc l a s sI v i r a lp e p t i d e c e l l sb ys u r f a c etarg巴ting o :p .2, 2 0 0 1 . c o n j u g a t e dt oa n t i b o d yf r a g m e n t s .CancerImmunity1 4 6K u r o k iMa, ArakawaF, KhareP D ,K u r o k iM, L i a oS ,MatsumotoH, fcanc巴r g e n e AbeH andl m a k i i r eT:S p e c i f i ct a r g e t i n gstrategi巴s o th巴rapy u s i n gas i n g l e c h a i nv a r i a b l ef r a g m e n t( s c F v )w i t h ah i g h 0 :4 0 6 7 4 0 7 1, 2 0 0 0 . a f f i n i t yf o rCEA.A n t i c a n c e rRes2 Ja ndC h a p l i nD J :T a r g e t i n g 4 7DachsGU,D o u g h e r t yGJ,S t r a t f o r dI :3 1 3 3 2 5,1 9 9 7 . g e n et h e r a p yt oc a n c e r :ar巴view. OncolRes9 4 8R u s s e l lS J,HawkinsREandW i n t e rG :R e t r o v i r a lv e c t o r sd i s p l a y i n g 0 8 1 1 0 8 5, f u n c t i o n a la n t i b o d yf r a g m e n t s .N u c l e i cA c i d s Res 21:1 1 9 9 3 . 4 9Somia NV, Zoppe M and Verma IM: G e n e r a t i o no ft a r g e t e d yu s i n gs i n g l e c h a i nv a r i a b l e fragm巴nt: a n r e t r o v i r a l v巴ctors b nv i v og e n ed e l i v e r y .P r o cN a t lAcadS c iUSA92.・ 7570a p p r o a c ht oi 7 5 7 4 ,1 9 9 5 . 5 0KharePD,L i a oS,K u r o k iM,H i r o s eY ,ArakawaF ,NakamuraK, Tomita Y a n d K u r o k i Ma: S p e c i f i c a l y t a r g e t e d k i l l i n g o f carcinoembryo凶c ant伊n (CEA）ー巴xpressi時 c e l l sb y ar e t r o v e c t o r d i s p l a y i n gs i n g l ec h a i nv a r i a b l ef r a g m e n t e d( s c F v )a n t i b o d yt oCEA andc a r r y i n gi n d u c i b l en i t r i coxid巴 synthas巴（ iNOS) g e n e .C a n c e rRes 6 1 :3 7 0 3 7 5 ,2 0 0 1 .

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ANTICANCERRESEARCH2 2 :42554264(2002) 6R o s sH M ,WeberLW,WangS ,P i s k u nG ,D y a l lR ,SongP,T a k e c h i 5 1HaismaH J ,G r i l lJ ,C u r i e lDT ,HoogelandS ,v a nBeusechemV W , S Y ,N i k o l i c Z u g i cJ ,HoughtonANa ndLewisJ J :P r i m i n gf o rT c e l l ｭ P i n e d o H M and G e r r i t s e n WR: T a r g e t i n go fa d e n o v i r a lv e c t o r s m e d i a t e d r句ection o t h r o u g hab i s p e c i f i cs in g l ec h a i na n t i b o d y .C a n c e rGeneTh e r7 :9 0 1 fe s t a b l i s h e dt u m o r sb yc u t a n e ous DNA 9 0 4 ,2 0 0 0 . immuniz at i o n .Cl i nCanc巴r Re s3 :2 1 9 121 9 6 ,1 9 9 7 . 5 2M a w a t a r iF ,T s u r u t aS ,I d oA ,UekiT ,NakaoK, KatoY, TamaokiT, S7H o r i gH,Le eD S ,C o n k r i g h tW,Di v i t oJ ,Has s o nH,LaM a r eM, I s h i i N and Nakata K: R e t r o v i r u s m e d i a t e dg e n et h e r a p yf o r R i v e r aA, P a r kD,T i n eJ ,G u i t oK ,TsangKW, SchlomJ and h e p a t o c e l l u l a rc a r c i n o m a :s e l e c t i v e and e n h a n c e ds u i c i d eg e n e KaufmanHL:Ph a s eIc l i n i c a lt r i a lo far e c o m b i n a n tc a n a r y p o x v i r u s e x p r e s s i o nr e g u l a t e db yhumana l p h a f e t o p r o t e i ne n h a n c e rd i r e c t l y (ALY AC)v a c c i nee x p r e s s i n ghumanc a r c i noembry on i ca nt i g e na nd l i n k e dt oi t spromot巴r. C t h eB 7 . 1c os t i m u l a t o r ym o l e c u l e .C a n c e rImmunolImmuno t h e r49: a n c e rGeneTher5 :3 0 13 0 6 ,1 9 9 8 . 5 3UedaK,I w a ha sh i M,Nakamori M,Nakamura M, Matsuura I , S 0 4 S 1 4, 2 0 0 0. SCowanKH ,Mos c o wJ A ,HuangH,Z u j e w s kiJ A ,O'Shaughn巴ssy J , Ya ma u e H and Tanimura H: C a r c i n o e m b r y o n i ca n t i g e n s p e c i f i c S S o r r e n t i n oB ,Hine sK,C a r t e rC ,S c h n e i d e rE ,C u s a c kG,ChangYN, s ui c i de g e n et h e r a p yo fc y t o s i n ed e a m i n a s e /5 f l u o r o c y t o s i ne ,P a s t a nIandN i e n h u i sA:P a c l i t a x e lc h e m o t h e r a p y GottesmanM M e n h a n c e db yt h ec r e / l o x Ps y s t e mi nt h eo r t h o t o p i cg a s t r i cc a r c i n o m a 1 :6 1 5 8 6 1 6 2 ,2 0 0 1 . a f t e ra u t o l o g o u ss t e m c e l lt r a n s p i a nt a t i o n and e n g r a f t m e n to f m o d e l .C a n c e rRe s6 5 4P a t e l SD,Moskalenko M, S m i t h D, Maske B,F i n e r M H and h e m a t o p o i e t i cc e l l st r a n s d u c e dw i t h ar e t r o v i r u sc o n t a i n i n gt h e McA1thurJ G :I m p a c to fc h i m e r i cimmun er e c e p t o re x t r a c e l l u l a r m山idrug r e s i s t a n c e compl巴mentary DNA (MDRl) i nm e t a s t a t ic :4 1 2 4 1 9,1 9 9 9 . br巴ast c a n c e rp a t i e nt s . C l i nC a n c e rRe s5 :1 61 9 1 6 2 8 ,1 9 9 9. p r o t e i nd o m a i n sonTc e l lf u n c t i o n .GeneTher6 ,KingD MandSheehy S SA l b e r t i n iM REmlerCA,S c h e l lK,TansKJ MJ:Duale x p r e s s i o no fhuma nl e u k o c y t ea n t i g e nm o l e c u l e sa ndt h e R e c e i v e dJ u n e1 2 ,2 0 0 2 B 7 lc o s t i mu l a t o r ym o l e c u l e(CDSO)onhuma nmelanomac e l l sa f t e r 2 , 2 0 0 2 A c c e p t e d S e p t e m b e r particl巴ーmediated g e n et r a n s f e r .C a n c e rGeneTh e r3 :1 9 2 2 0 1,1 9 9 6.

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