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201é i FI}H'RE OF MEDICINE

THE

CANCER
DEFENSE
Enhancing the body's own immune
system is leading to promising results
in the battle against malignancy

By Karen Weintraub

A new generation of treatments that boost the immune sys-
tem's ability to fight and contml malignant cells indefinitely
have achieved remarkable rtsults over the past frveyears.
Tlpr¡sands of peoph whh aggressive and advanced lung
and skin oncer¡, as well as rarious kinds of lzukemia and
lymphoma, have been treated-a¡d many of them have
seenringly been cured.
lmastigaton are developing new reginrens and combina-
tions of treatnrents that nray prove safer and more efrective
úan cunent approaches in the nextfewyears.

lllLstl'atbn hlt Dantul Haizhejg April 2O16, Scicn Li l¡c^m(rlican.com {,3

+. .{"" * -¡ * + -!" + i I + + + + + + f + +" -j" + + + + + + + + + + + +
+
i ++++ + *'.i. + + + ++ ++ ++ +' +" ++ + * ++ ++ ++ + + ++
{- ++"++ + + +++ ++-r-+ + *++ + ++ + +++-i- + ++ ++ + +
,i + +.+" + + + ++ 4- +'i-+ + + + + + + + + + + +. + + + +.+ +. + + +
IT MICHELLE
BoY E R har,receivedherdiagno.
sis of adl'anced and aggressive skin ca¡icer in 201O instead of
2013, she u'ould aimost certainly be dead by now. Melanoma, the
most lethal form of skin malignancy, had spread from a mole on
her back to her lungs. and she knew her prognosis was grim. But
beginning in May 2O13, the 29-year-old Seattie resident sf¿rted ¿
series of revoluür,nary treatments-some of which ñrst became
available in 20)1-that prompted trer immune system to identiS.
attack and shrink the tumors. Although Boyer still has cancer
and the immune-boosting dru&s have taken a toll on her borly,
she is grateful to be alive and hopes that either her current
eourse of therapy or the next one will evenhrally give her the
kind of miraculous results that other patients have talked about
on the Internet.'At this point, this is my iife," she says. "People
think it would be really hard to stay positive, but because to me it
seems nonlal, it's not as much efftrrt ¿r-s yilu would think."
Karen Koehlel 59, a retired specia) eclucation teacher from
Park Ridge, N.J., may irave won the immunotherapy jackpot on
her first try. She has apparently been cured of a dif{erent kind of
cancer-in her case leukemia-after a single infusion, in early
2015, with some of her own immune cel1s that had been geneti-
caLly ailered to figl.rt her malignatlcy rnore qqgressiveiy. The treat-
menf which lasted a couple of horus,landed her in intensive care
for several days because her rewed-up immune Wstem shifted so
f¿r into overdrive. This setback was followed by weeks in a regn-
lar hospital bed. But rvithin a month after her treatment, scans
showed no signs of cancer aryvrhere inherbody.
Boyer and Koehler are two of the thousands of cancer patients
who hav-e unclergone various kinds of immunotherapy over the
past five yeals. Their experiences illustrate both the prcmise a.nd
the challenges of this fundament¿lly ne$'approach to treating
cancer-one that, instearl of dousing the body with toxic chemi-
cais or radiation from the outside to kill cancer cells, energizes the
complex and highly interactive cells and molecular signals of its
defense network-c to do tlre job from the inside. 'fhe results so far
have been encóuraging; immunotherapy is quicHy becoming a
pillar-aiong with surgery, radiation and chemotherapy*of treat-
ment for some cancers.
In clinicai trials of a neq'immunotherapy for a highly aggres-
sive fornr of leukemi4 90 percent of patients rinderwent a com-
plete remission: doctors coulil lind no evidence of their disease
an¡vhere in their borlies. Alüough some may eventually suffer a
return of their cancer, for many ot¡ers the response appears to
be a permanent cure. In other trials, more than half of patients
rvith advanced melanoma wl-ro received immunotherapy can
now count their life expectency in years instead of months. Im-
munotherapy, says Ga-ry Gilliiand, president and director of the
Fred Hutchinson Cancer Research Center in Seattle, "is truly par-
¿digm shifting in our approach to treating cancer."
tl{, Scir:ntifir Amer'lcan, ?o1(i
^irril
Karen Weimnub is a lreelance heakh
and science joumalist who writes regularly
for 5TAT (www.sutnews.com), USA loday
and the New York llm¿r, arilong others.
These are, admittedly, still early days. Increasing life expec-
tancy to a few yearc for some cancers still means that patients
die of the disease. So scienüsts continue to e&eriment with rlif-
ferent ways to urüeash ¿nd boost the immune response, includ-
ing vaccines, viruses, genetically engineered cells and pills [see
bo*es orz pages 46 aú 5O]. They are also beginning to combin€
these approaches to see if they can help more patients, perhaps
with felver s:ide effects. But there is no longer any doubt that
physicians can tap the immune system to beat cancer at ieast
some of the time- "[We are at] the end of the beginningi' of the
immunotherapy story says Eric Rubin, vice president of global
clinical oncology for Merck Research Laboratories.
LIQUID SUCCE5S
rHE DRlarv of fighting cancer with the immune system d¿tes
back at least 125 years to William Coley of New York City, ¿ phy-
sician who injected some of his cancer patients with bacteria in
an effort to jump-.start their body's natural healing powers. Co1-
ey's approach was taken up by a few other doctors initially. But
it gradually fell out of favor after his death in 1936. to be re-
placed by advances in chemotherapy and later hormone and an-
tibody treatments, which showecl more consistent results on a
larger number of patients.
The iciea of boosüng the immune system. however, has never
entircly lost its appeal, prornoted in part by the Cancer Resea¡ch
Institute, a Neq'York City*based philanthropy started in 1953 by
Coley's claughter. In recent decades. as nrolecular biology has en-
ha¡ced researchers'understanding of the inrmune system, ho&'it
worlc; and when it fails, cancer investigators ha\€ restocked fheir
arsenal with more potent immunoiogical weapons.
Among the most attraLtive targets for those weapons hal.e
been cancers of the circul¿rtory and lymphatic systems. such as
leukemia and l¡rmphoma. These diseases occur when various
kinds of progenitor celis called stem ceils, rnüich normaily give
rise to red antl white blood celis (among other tissues). inste¿d
mutate ancl gror.r- uncontrollably, crowding out health)¡ cells and
robbing the body of their r.'ital functions. Many of these so-called
liquid tumors form when sonrething goes wrong with a part of
the immune system called B ceils. Norm¿lly B cells generate an-
tibodies against b¿cteria and viruses. (B cells also help to cooF
dinate various other immune responses. along with another
group of cells callecl Tcells.) Butwhen B cells become ca¡ceIous,
they de,stroy the body from the inside out.
In the late 20th century i¡lyestigators deveioped the biological
equivaleni of a guided missile that attached ilqelf to a B cell pro-
tein (CD20) founcl on the surface of these cells at a specific. 1at€
staé*e of their eústenee. Dubbed rituximab, this so-called mono-
clonai antillody signaled the T cells to do someüing lhey do not
usually do: attack ancl destoy these older, CD20-bearjng B cells.
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201é
TI}HJRE
-OF
MEDICINI

'9

\ú

MICHFLLE BOYER leamed in 2013 that she had adr¡¿nced skin cancer. After six courses of immuno-
therapy, she is still not cured but is living longer than her doctors initially thought possible.

Phlbgreplr blt A t¿nilt.llutie !l:!s¿!m ott Ap¡il 2016, Scicnlilic^rn{rfi c:rn.ctim {,5
 ;'i r.'!'
''; -: J. i r.. i.. .r _t "t. r
,.i. .i. -1, .i

- i. I

The problem *'as that CD20 is not a cancer-specific m¿rker. with lhe T cell-targeling AIDS ürls tragicaliy clemonstrates.)
Ilappears on normal B cells as q,'ell as dangerous ones. So the A¡lcl after ther rlrug rvore off, most patíents evenluaily starteci
drug killed both heall.hy and cancetc¡us B cells. TL Lurns oul, making B ceils on their onn again from the stockpile of sterr
howevet, that most people can live without B cells. (The same is cells in their bone m¿rrow. Clinical trials in the 1990s demon-
not true of T cells, as the de¿th of millions of people infected strated that the combination of chenr.¡therapy and rituximab
wa-s partícularly effective against B cell-
based cancers^
Koehler's leukemia originated rlith
AVACCINE FOR CANCER? nutated B cells, but rituximab rnacle her
Targeting cancer cells using their own DNA vety sick and secmed only partiall¡r eff'cc'
could help eliminate tumors and prevent recunences tive. so she stopped taking it. In adtlition.
tests indicated her cancer u'oukl resist
By Beatnz M. Carrena and Elaíne R. Mardis standard chemotherapy. Because her nta-
lignancy was rapidly getting rvorse, her
doctors suggested an experimental im-
nrune treatment custom-designed to
fight her fbrm olleukemia. She agr:eed.
,:, . .. :-. .': The goal of the new treatment 14as to
it.'. .:i.... .

.lijril!*;-:: clestro], ¿11 of Koehler's B cells, as ritux-

'rt.-;::i:':i:i ;.iltl ¡iirj! !a) ir¡cjliii!:1, rr,j :r;-.",¿:i :ii:,¡itij t'..,r,r1, ',i. " -. .:
imab would, but with tlvo key differences.
l.;i';rr-;i.¡ij i.; ii'rir:i: a"ilil;ri.l iliiililitj:r"
A tlifferent prt;tein (CDlfl) on the B cells
"ji¡*:¡t; i:¡¡ii,l JtJt í.:i.rr.iÉi1.:ri-i it :rr-'j."i:.i:iljr:1cj ::i:t¡i-ttr;.iie;j trt'ill.j'..r :j. . r.: ¡j., . -li ,.
. ,- was the objec*il'e. And rather than using
iii.'l;rlt ii'r:ili<el¡.jt':¡llll::ir-tlr¡:,¡r'ii::::..l]l.fí11-i.iir*¡r; 11..!t::iÍ.,'-j. ''
iir-:i:n,., :¡..ri,:1.'ltii¡ ¡t :-l:i,.::.li:'iitu.l ¡"--.ali:niit
an added drug to paint a target on that
rl rlc i.:,r,.-j_tr i:i,,1 :i:!:i tili it¡r: i:;'' ,-.:ri.
protein for T cell.s that were alread-v in
i. ' J'. .. , ¡ r....,'. j'. 1.',- 1. .'
i:,ril:; [:,'i,¡r¡ i¡¡-:l:+¡ ,,'¡tr]:ir';t: .:,:iii:rl.¡.. r':: liijt:r,r!;.¡ii! ;;t:ij i-tai:¡,r¡'t. :rt.:r1 1.".,,,'¡ l;1:ir¡¡j
Koehlers body. doctors took a more di-
r,{ rect approach. They rernoved some ofher
l:+i.:.,r:l,lr ii:+1 l;riit'¡¿.,:t.i ii:¡:.lf|:1ii,..¡i.i:'i'f:ilarrr iü iii{lii fii. i:'i'rii:iir:, iii':si.;ii1,-.'-
- I i ii:";'ir::l
T cells ¿ncl genetically engineered them
il3 iI r I t.i.; l -. .,: ¡ l. |;-',,'¡i ¡¡ -- .¡r- ¡¡ !-¡1¡¡ 1 ¡,.
to attac'k CIf19 autonlatic¿lly, without
¡

ait,i:i-rrxii_},, it->.zt:;.::t:',i. i.,rii iilii*t i;:¡:i irr;'r;r;1,;ej ¿Jr irt.'iIL: ;i, i:r, ;.:11-
any prompting.
Bmtriz M. Caneno is ir:iir:. !1',¡'r :¡,'* i;;ii,.li;ü :.1.: ;il¡: tr:;i i'i jil:;-:li*:, i::r. ::,ili.;r..:i rii J i;¡;i iitriil*
Investigators call these turbocharged
olrnedicine¿tWashingtoll i.i:i;i:.::1,:li;:irel--j":i.iir:¡:iir:ailt'. 1;i..:tj,r..:,i.r.!jl!!!i:ii.j ir.rirü¡,¡i-:,i.:iji:;i!:
cells chimeric antigen receptor T cells. or
Univer srtv irr St- Louis.
ir'""n]úrjono"r, " : ' -i: 'f i ' r: :
CAR-'l-. lihey display some of the charac-
l"crislics oI both Tcclls ¿nil lJ ccüs in much
ertE.andLouiseF.Dunn ',r;11.¡¡;ji;¡r.'¡.iil;:; !.ir{li.Oi:i,./'irrl;t:iir.t:\i:.i,'j:rt,,,..:,.; .' ,,iii-¡
the same way that ancient mythological
Distinguished Professorof rtli':ii::t i:lli:ii:ci¡i:;.,tli;irit¡,r lL::r';1.-'1tr i,irtieilr. ¡.::r' i'-i¡-ir.--:,. i.,l::ri:ri :,::;*,1
Medicinearldm-dircao¡ : - . :-: creatures ca-lled chin-reras were supposed
, : .i
o{theMcDonnellGenonre rír(_rr:,: to be m¿de up of diflerent anim¿ls. CAR-T
i ¡i.ii_l-i:*ci¡i:^r::ri.i,;!+.uilirii: i.:É:jjjr i;:,.r i:,¡i.r¡.¡t.;l1.i1,:11 ,¡,.i!l 1¡¡.r¡
lnstiLüte ¿tWdsnipqtllF therapy is sti1l experinental, butthe Food
Unrver\fy tn 5L Louls. and Drug Administraüon is expected to
S",hCr"ar"arlMr¿¡ ii¡i,¡,:'iii¡l',:;ti:" i:i:;¡:l lr.r í:at\[:1íirit:.1ij:i.iii.1.r1{:r i r-i:]i r*,:l:.:'cl:tr¡ ..:',-: consider approving the treatment for gen-
studyhowhumanirnnru- r;:¿llii L"¡lli:*t ::':iil i:*.lt'i;:i: iii¡;:i,,:.,:;'.,1.;i;¡-. lri::.)i):iiiii! ii,¡ ::lr:!;,¡-i..-..,ir¡:.
eral use someüme rt€xt y¿¿¡.
nologyand cancergenom 1..i1:.i ',,i::1f ,,.,',1 l'i¡:ii riri¡: ,,l.li:,ir;.:iii .¡;lil-l iil-,::¡r r;t'.-.i;,rr;;t:ii,:.r
iCSrfrayimprOvethempieS í:,il:iltiii:, ..1.t; !ai: i,iili-:.r i;: -ii:¡*¡,i,1, lrat ri;t,.:|:i :rit.!irir a,ti.,._r!ii,:;,::ji:l:liti: ]'he CDIg-i.argeting CAlt-T cells muiti-
direcledatcancer' ;','',t',.,,,irr,,, ii:;tt ,v¡i:l¡ i:li.1¡i;l-,,:,¡¡::t: i.)¡.jilaj.tt':: ¡.,ii1{- ri,{.riti:t-¡l¡t,,
p1iet1 so quickly inside Koehler's body th¿t

!,,'i; ,,taii:, r::ii:¡it:.:,:,.trÉ.; the single bag ofnlocliflecl cells that she re-
iaji;t1.:!í1Í;: ii.-;1] ,:i:f::¡::,i-:i:jija1..t.: iiiiarj
ceived ou F'ebmary 10, 2015, knocked out
Llii¡ .:,:;l¡t¡.:"i i:+I j:¡. all her E cells. Unlike other patients, how-
i:',j,liia-¡i::!-,i1
evcr, her body seems to have lbrgotten
how lo make health-rr B cells" Fortunatell',
there is a work-around: er'ery month she
ri, gets an houfs-long infusiorr cfartifici¿l an-
;,, -, . :, ,:..
'. :.. .'. .. . , ' - .. -:' .
tibodies, caileci gamma globulin. to help
protect her against infection. The infu-
sions are a time-consuming hassle, she
...'-'¡il',Íiar',ji;i;¡jr:irjti:riii.l-tr¡;,i.-!,.!:/.;: says, but "it's not chemo, so I'11 take it."
l,:ii¡i:l',1:;J,l'-.'Cl-j.i.;:¡l 1l;ili,.:1::ii: :rtri:.r¡l-,1.- '.
CAR-T therapy did hit Koehler with
something that can be worse than cire-
..-.,,-',".., mo's nausea-a storn called c¡tokine re-
ii:+:::l¡,:;i::,Jii-;:'':;;i.llt¡-t.,,f i1¡:; :.1,,.:rlit.r.;i¡i::lt;il.riSi¡itiiliriSlr"liii:-iiÍr:t{tr.
lease syndrome. This reaction occurs
n4reii rnany more T cells than usu.al ¿re
actiyateil at once-tri8gering a flocr1 of

¡16 Scicntilic Ar¡rcricln, AI]r-il 2(]1(i


KAF{EN KOEI{LÉR remains free o{ cancer a year after receiving an infusion of her own
immune cells, which had been genetically engineered to er:adicate her leukemia,
chemical signais. called c¡tokines, that the immnne system uses
to comnunicate. 'l'he result can be a life-threatening fienzy of
activil,ri in which immune cel1s destroy heaithy tissues, causing
multiorgan failure.
For Koehler, the storm came en hard and f'ast. She felt terri-
bl¿: within an hour of receiving helr own alterr:d'l cell.s. By that
night she was in intensive ca.re where she remained lbr eight
days-half of that time she was in a coma and totally unrespon-
sir,'e. She has no nremory of what transpired then but can recall
the hallucinations of a few days late¡ *'hen she asked nurses for
lrelp packing lunch for a pair of f¿rmous golfers. Koehler has
been adtlictetl to golf since 1999, when she took it up as a way to
nreet nren, includingthe man who later became her husbanrl.
I3y the time Koehler got out of the hospital in early March
2015, she was incredibly weak but rebounding fast. A bone mar-
row test shorved no evidence of cancer, and three weeks after
that she w¿n b¿ck on the golf course with her husband. 'Ihe cyto-
kine stonn w¿t-s lerrible, but unlike themo, the etfects subsicied
within a few weeks ¿nd did not cause her to lose her hair. For-
tunately, given that cytokine storn-ts are fairly common q'ith
?hútoÍIruph ba,1rtll like rt
CAR-Tce1i treatmenls, pllsici¿ns have be-
gun to learn just how far to push patients
like Koehler to get the greatest beneht
rvithout risking thcir lives.
CAR-T ceLi ther¿py ntust be custoln-
designecl anti produced for each patienl
Manuf¿rcturing them for all the leukemia
and l¡rmphoma patients who might want
them g'ill be a cl'rallenge, a^s weil as ex-
traordinarily expensiw-although it is too
soon to knolv exactly how much CARjIb
will cost because tirey have been used only
in acarlemic research so far. Robert Preti,
founder of PCI a CIAR{' manufarturer, is
workirlg to improve the procluction prcl-
cess; he believes thesc ¿rre mainly engi-
needng issues th¿rt will be soived with a
few more years of ha¡d r,l'ork.
The other major challenge facing
C.A,R-1'treatmenl is translating its success
from lirlniri cancers to solitl tumors-the
kind that forms lumps in the breast. pros-
t¿tc, lung, skin and other tissues. One
silrmbling block is that CAR-T cells have a
hard Lime leaving the bloodslream i,o {ind
a solici ilrmor', explains Ira Nfellman, rvho
is vice president of c¿mcer immunology at
Genentech. In the blood. the liquid tumor
ce1ls a¡e relatilely ea^sy to locate. Even 201ó
FI$IJRE
more crucial, whereas CAR-Ts can elimi -0t
n¿te 1l cells in blootl ¿md ly'rnph ca¡cers.
there is no comptrable cell in solid tumors MEDICINI
that palients can live s'ithout.
SOLID STATE
soLID TUl.roR-s pose other difiiculties for
immunt. tl:eatnents. They are often sur- -
rounded by a matrix of con¡ective antl
other tissues. which blocks cells from en-
tering the malignant mass. In addition, the internal pressure of
a solic{ tunror is ffiically hig'her than its surroundings, rüich
tends to flush out the chemic¿l signals that the lmmrrne system
uses to flag aberr¿nt cells-not to mention nan¡..- drugs.
Let these tunrors havc shonm some I'u1nerabi1ir"v. In 2011 the
Foa approrerl a monoclon¿l antibody called ipilimtunab to treirt
atlvanced cases of nelanoma. Unlike traditional therapy ipili-
mumab is not ciesigned to kill tumors direc.t).v; rather it reieases
the biologica.i brakes th¿t some cancers are able to clamp on the
immune system. freeing the body's clefenses to do a better job.
Melanoma has a nasty habit of clefrauding immune system
cells. The clumps of cancer cells have an assorfment of mal-
formerl proteins on the suri¿ce, rvhich T cells are supposed to
spot. swaml around and destroy before the aberrant growth has
a chance to get any bigger. But every now ancl tiren ¿r na,scent tu-
mor develops ¿ way to senrf out chemical signals thirt tell the
T cells that all is n'ell and to stand Llorvn their att¿ck.
Irr efiect, the c¿ncer ce1ls har/e hii¿cked a noL'mal feature of
the immune systeru: a safety mechanism that tamps down üe
body's ranipaging defense cells before they stan dam¿rging
{pril 2016, S¡irn [ilir,\merican.cr¡¡i 4r7
 N EW CANCBR'I'RAATMITNTS

TH RIE IMMUNE STRATEGIES Hsw is

irnmunotherapy
Surgery, radiatian and chenlotherapy have iong sen'ed changing th€ trcatment
of solid tunnors?
as the staneJanC treatmenis agüinst c:ncer. Sut clinkal trials
Cancen of the skin, lungs and other üssues
over the paet ír\e yeañ have shown th:t supercharging the are called solid turnon because they form
Normal
checkpoim
i:odyi imrnune celis-whieh evclv¡:d ro frgirt har-rnful bac' a mass that creat€s its own protectitte
detator
teria and viruses, a¡nonq ather th!ngs*offers a pcwerfui environmenL Checkpoint inhibiton
protein
new additiot¡ tt) the nrix by helping the cells tc frnd help to disrupt this envircnmenl
eliminafng advanced skin tumon
and destroy tuivr*ils. Tli*: appnraches shown Tumor pr0te¡n

herre are being tested ¡lone ¡:r !n cc¡rrbi-

for one in five patients
that quieu -
in clinical trials. Tcells _
n¿tiün wiih $tiler trcalrñetrt5"

Cllrerrkpoi nt I rrlribi I ors Many cancer ells hide from the

Left unchedted, immune responses .,\i immune system by disPlaYinq
ri;
can be so powerful that they will I
speciñc proteins that tell nearlry
;rn\s
1

destroy heah*ry tissue. Thus, T cells not to advance to the next

specialized immune cells called stage ol activaüon and, essentially,
Tcells must pass serealbioloqical
chec*poinrs before achíeüng full AS .-Tumor to leave the tumor alone.

strength. Cancer cells often act on

these checkpoints in a way that Anificial
prevenls the immune system fmm antibody
attacking the tumor, New drugs-
called checkpoint inhibiton- Researchen mmpare the genetic
disable the cancer cells'immune- blueprints of malignant and
dampening signals, allowing the The drugs consist of artifrcial Cancer- heahhy cells, looking for
immune system to do hsiob. antibod¡es selected to disable specifc information about antigens that
the bnkes that tumor cells put
on the immunesystem.
/\ t.
antioen are{ound only on the cancercells
These anügens are added to the
Cancer cell
. .;-'. y'- )1 I I

dendritk cells, which absorb them.

_i:
ti :.,
sr-,,.
ri:
:l
'1...::¡ *
The no¡ mature denddtic cells

l)r¡nd ri{.ir: {icl I lirctirre are then reinjected.

Dendritic cells normally parolthe

body lmkinq for bits of pnrteins called .t:
.
ant¡qens that look unfamiliar.Thry Researchen ext¡act hmhhy cells"
presentthe ofending anügens to cancer cells and immature .¡,ri
other immune defenders, known as dendritic cellsfrom a paüenu
CD4+ and CD8+ Tcells. The Tcells
:l
then auack ány other cells that bear
úe targeted anügen. By chocsing
amigens iound on cancer cells but
:
i'i
tt

.."r
--..t

lmmature
not on heahhy ones and mixing I

dendriüccell
the antigens with a pat¡ent's own jj
dendritic cells outside the body,
researchers create a kind of vaccine i," Clinicians extract T ells frcm
a patient and infect them whh
thatwill s¿ek out and destroythose Tu*6¡ *r .r Vi*, a benign virus carrying genetic
same cancer cells {or l¡eañ to come, I
I informarion (RNA) that allows
I
tie T cells to generate a surface
t
RNA receptorthat will recognize a
specifrc antigen on the cancer cdl.
I

{lAlUl'('llls i:- -.
Chimaic antigen receptor {CAR) T
d,r'-
cells combine auributes of wotypes
of immune defenders: Tcells and B
,jl"
cells. Molecules called recepton found
on a CAR-T cell looh like a hybrid of
*l
- ''': '
receptoa on B cells and T cells The Patient'sTcell --**; a-.
CAR protein allorc this unusual cell ,\)- Lhlmencanugen
to both latch onto select antigens and r"\:! receptor{CAR}
destroy any cells that bear the target l::
ant¡gen. This mishmash eliminates
intermediate steps rypically taken
by B and Tcells, making CAR-Í cells
vhtually unstoppable.
 Could intestlnal
bacteria boct the
effectiveness of
i.l immune trcatments?
.,'i::1i
,¿, r(: Studies in mice suggest that the prcsénce
l' : i.j of specific baaerial species in the intestine (pan
.rr:l
of the body's so-called microbiomei may boost
the immune s)¡steml abilityto slorthe grorth
of certain types of tumorrAlso, checkpoim Ll
''::,
'. !' inhibiton do a better job of eliminating l
cancer in rodems úrat harbor ...,:$'
these bacteria.
Artifiehl
antilod{UÉ1(, ' 'r : , .,,' r'"" ri'.:::ri"'
m/l,ll€fftul

By prsventing umor cells from

interaaing with the dre*poim
system forT cells, checkp,oim
inhibitor lree the T cells to attack
a tumorwiü newfound vigor.

oí'
{
Tumorcdls
t,t:,.'1iü

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i .':::i;: ::\...."

20fó
rt {t Rt
0r
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4¡
cD8+Tcdl *
Mawre/

TcdlswithCAR
mol€Iilleson
theirsurfrce

/"r,ri','',;:*".. \
.r@:
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CAR-Tells
How are

\ #,i$fl;'r changing the trcatment

cf liquid tumors?
liquid tumors are cancen (such as
lym$r,omas and leukenias)dratfurm in tle
bhod and lym$atic q6tern. CAR-T cells travd
easily in úe Hcod,where these ma$gnam
cells are oftenfo$d,wiping un erery
trace d€ancer in as mary as 90
percemofpatíefitsstudiedwith,i
anaggressivehukrnia. ..,,'tt'

Illwtrati.rn bg Shi.wka N- Aoh¿ April 2016, Scicnlific^mcrican.com {*9

healthy tissue. Nlore speciflcaliy-, liris sai'ety mecha¡rsm consists celis have more mutations, so his immune rystem nay have neecl-
of a series of checkpoints, or gate\r'ays, that either rally defense just it singlc nudgc to rclcasc thc T cclls lhal wcrc alrcady
ce1

cells Lo ¿Llack or Lurn Lhem ofl. rlepending on which chemical there. In some patients, in contr¿st, lhe T cells may riever hal/e
signals are present. (lf the checkpoints ever got stnck in the made it into the tumor and so there rvas nothing there to un-
"o¡ren" positi<ln, the ensuing immune reaction i¡,'ould likely kill a block. In other patients, the T c.tls seem l.r be in the right place,
person faster than any malignant grouth could.) By producing but the drug still does not work-perhaps because multiple steps
proteins that, block the checkpoint system, cancer cells prevent need to lre urrjamrred. A 2015 stridy in the Nae Engla'ntl Jounrul
the immune system from el'er ramping up to fight r¡f{ c¿ncer. oJ Illedicine shorved th¿t more melanorna patients did better
Blocking that false signal with ipilimumab or other so-calle{i whern given hvo checkpoint inhil¡itors instead of one.
checkpoint inhibitors reawakens the immune celis, allowing Still, doctors are not good at predicting who will respond to
them once again to zero in cin their targels. which checkpoint inhibitor or combination of treatments, and so
Ipilitnumab soon proved effe$ive in lung cancer a^s well as Boyer and patients like her have to heep experimenting with dif-
melanoma, and phannaceutical compani€s beg¿n developing ferent therapies- Tr¡day.itist more than 20 percent of advanced
other drugs that used the same strate&v. Fbrmer LT.S. president melanoma paüents ln clinica.l trials get a complete lesponse frorl
Jimmy Carter, 91, whose melanoma had spread to his brain, took checkpoint inhibitors. with slightly more than half having some
one such drug, pembrolizumab, and he announced late in 2015 res¡ronse. To confuse matters even more, some tumors that appear
that the drug harl cleared all his tumors. to atffact tt'rv Tcells still respuntl tu checkpoint inhibitrrrs, wltere*
ISoye¡ on a similar regimen rvith a similar disease. has not as the drug.s sometimes have no effecl on other tunlors that con-
fared ¿u rvell. And that is a puzde. Some rese¿Lrchers speculate tain lots ofTcells-suggesting the cancer is playing other tiicks.
that Carter's advance<l age may have helperi him. Older cancer Thir.t has matle picking an effective solicl tumor treatment

_,,. ,,í. ...¡.,, iSi..il.]:r !:il]¡:l-{iil lf i: i :

GERM WARFARE l:1 i-i:rlaill, ll.iJi ii* iJeiiÉi;i j:i j jl iiir;lr.li:¡i -:i li:: la irúrl1j i: r::j:.:li.
:'t, .-:r r,.::..; .., :.- il.:ii:l.¡l l.¡]l : r:üer-- iil:!:,
Some types of intestinal 'i..-.7,
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By Maria-Luísa Alegre
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;-l'r;,i ri l-i ; ii i i.:1 ;i i;i::-' !:i:r ad l :r:i:.1:j ¿ : i :,¡l : i ¿,i :-
andThamas F.Gajewski
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Maria-luisa Alegrr .i i . :, : - r.......
(:iirqll;e,1{lt;firl ir:;:ii ;1ii¡ííli rtiliit.:¡l is a profesor in tire :¡ 41*i il r,ilii¡-i i-'r i;.l ii: rl.1;'.^.,t'rii i:ii r"ltI. t,.::r; : r ii-
,..:,,1.. r,., . ,, i ........- dEartment of medicire at i'.¡'ü:l::ii-r i:i:raiiar;r'::t ji::'¡Ji:ir.tti;.:iri¡:r.: i¡';i.r's l,l'
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the Univenitv of Chicago.
ll i¡il't j
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Thomas [, Gajewski
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is a professor in lhe
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depanments o{ pdrology
iiti!r+1-illrfir ir¡'ilt*ii¡ r-;':il.¡ i-tl iii: a¡d of medicine atthe !!ijiir iil bi:rrlli tilat ilr,:-iL;ll:i':.
irl'¡rt'¡¡.iilz'r 1¡r'1iir'i:-¡

:bi* t¡ r-ligr-¡*r-:.r li1ci.]tlrli jl ji: Univenity of Chicago. i¿::l;. Li;:!, i,:i¡ji.tg:- ;i;..ii.Jiir;ii':!.iIi r.il*r;tg¡r¡;.

an animation thatshovn knv selected immunetreatments wuk at ScientiñcAmerican.covnápr20'ló/immunothe*'apy


for a particular inclividual a matter of trial anil erro¡ as Boyert
experience illustrates. TWo yeam after surgery to remove the
cancerous mole from her back. she learned üat the melanoma
had returned and u'as spreading throughout her lungs and
chest. Because the growths 'rvere now too large to be cut r¡ut,
Boyer agreed with her physicians to take part in a clinica.l trial
at the beginning of 2013 that would inject her with high doses
of interleukin-2 (IL-z), one of dozens c¡f difJ'erent chemical sig-
nals that heip to boost the immune system's abili[y to fight can-
cer. At frrst tire tlrug seemed to stop the growth 0f Boyert tu-
mors, but after three months, scans showed that the cancer was
onthe move again.
Boyer opted for a second clinical trial, this time pairing üe
recently approved checkpoint inhibitor ipilimumab with stiil an-
other immune-signaling molecule lmown as IL-21. Within a few
weelc^ lroweve¡ the side effefts of the IL-21 treaünent (nausea,
tliarrhea and unbearable pain) had become so disabiing that
Boyer had to $top getting the injections, although she continued
receiving the ipiiimumab. By the end of 2013 some of the ca¡cer-
ous spots had started to expand, and so her medica-l team optetl
for radiation to try to li.mit the growth. By spring of the foilowing
year a few of these hrmors were smaller, but new ones had ap-
peared on her heacl and in her breast.
Surgery dispatched the lump in her breast, and ilvo other im-
mune-boostíng therapies seemed tcl hold the rest of her tumors
in check for a whüe. By January 2015, however, it became clear
that she needed another plan ofaction-new spots had begun to
grow in her brain, breast and abrlomen. A month later she en-
tered a clinical trial, which combined yet another checkpoint in-
hibitor with a drrg that is supposed to slow tumor growth. As
this article went to press, Boyer's cancerous spots remain stable.
and some of themhave even shrunk alittle.
There is no denying that so many treatments have battered
Boyer's body. She spends her nights and many ofher days in a
plush loveseat to rest her back. She goes to work as a structural
engineer most mornings r.¡n the weeks she has offfrom her sixth
and current round of treatment. Otherwise she entertains her-
self by playing üdeo ¡;ames-Ca-Il of Duty is lrer favoúte. All roid.
however'. slr.e does not regtet tr:fing six differentimmunotherapy
regimens so far. "It seens to me that some of these treatments
maybe slowed down the grofih a little bit," she says. One of her
doctors, Boyer remembers, "said part of the game for melanoma
wa,s not necessariiy finding the right tre¿tment now, trut keeping
yourself alive long enough until they flnd üe right teatment."
And so she is and so far accepts her current qua]iw of life.
LOOKING AHE.AD
BECAUSE soyr,n and other patients are living long enough to feel
some contentment. Genentecht Mellman is excited. For immu-
notherapy, possibilities have be$rn to turn into actual results in
patients, he says. Investigators no longer worry about whether
their research wiil eventually help someone; now they can
spend their ürne making effective treatments better. "We need
to find the boundaries and iimita¡ions ancl Iigure out ho\ / to get
around them." l\{ellman says, but "this is an incredibly inspiring
and thrilling way t0 do science."
Flventually the process of selecting an immune treatnent
tvill become more logical, he believes. A patient with a solid tu-
mOr might flrst have the tumor biopsied to look for the presence
++++++ "{- -i-'F + + + + + + + + + + + * + + + + + -f. + + + + + .i
+ + + + + +. 4' n" {- + + + + + + + + + + f + .i + + + + + + + + -t- r,+.
+ ++ +++ ++ +. ++ ++ "t-+ + + +++ + +++ ++.++ + ++ ++"
+ ++ * + + + + "i-+ + + + ++" ++ f + +.f, + ++ + + +++ ++ ++
of T cells.If enough T cells were in the tumor, the persorr would
tikely be given a single clreckpoint inhibitor or may'be several in-
hibitors. (At present. the rrDA has approved three cheekpoint in-
hibitors, but more than a dozen others are under development)
If the tumor has not already attracted ma¡y Tceils, doctors may
try various other techniques to both drive the immune cells in
and call the immune system's attention to the abnormal gro'lvt¡
before opening the checkpoints.
Researchers are also considering hotv to use standard cancer
care, including radiation and chemotherapy, to boost the im-
nune response. Killing a number of tumor cel1s with lower dos-
es of chemotherapy or radiaüon should release lots ofcellular
debris ftom the tumor. thereby alerting the imniune systen to
send Tceils to whatever ¿bnormal growth rcmains. (Gefting the
balance right may be tricky because too mueh ehemotherapy
and radiation have ¿lso been showri to suppress parts of the im-
mune system.) 1hen, the addition of a checkpoint inhibitor
might be ¿ble to effectively frght the wcakenerl c¿ricer befbre it
has a chance to recover. But scientists have only just begun to
test slrch hy'potheses.
Finally. as more and more immunotherapies are approved by
the FDA, they present ar entirelv clifferen[, nonmedica] chai-
lenge: price. Combining therapies raises the cost t¡f nüat a¡e al-
ready quite erpensive treatments. The global market for oncolo-
gy drugs is now approaching $100 billion a year. according to
IMS Health, a meclical data company, but rlrug firm executives
acknowledge that insurers and the public will not be willing or
T
able to indefinitely cornbine clrugs that can run 5150,000 or
more per patient. 'fhey are looking at manut'acturing improve- 201é
menls, lower doses and shorter treatment times, among other TI}H'RE
approaches, to lorver the eventual cost oftreatment. OF
Flven today's curative therapies are far from perfect. Koehler MEDICINI
stiil has some lingering effects from her tlea-.hrient. She tires
mtlre easil.ru th¿n she used to. If she goes to lunch with frientls,
she might not have the energy'to take a hike later r,r'ith her hus-
band. "The toughest paft now is how far do I push myself," she
says. But Koehler is able to enjoy tlte retirement she took when -
hcr lirsl Lhcrapy did not work" Shc golfs, hikcs or snowshocs
when the weather permits. Inspired by the therapy dogs that
visited her during her hospitai stay. she brings her own goltlen
retrieve¡ CJ, to the local hig'h schooi to help relieve exam stress
among students there. Cancer doctors believe immunotherapy
will soon allow them to give many more patients similar oppor-
tunities to enjoy a new lease on iife. il
¡IORE fO EXPTORE
ChimricAmigen RmprorDesign, Michelsadelain etal.
The Basic Prlnciples of
inGncer Dismvuy,Yd. 3, No. 4 pages 3,88-398; April 2013. hup://cancerdiscwery.
aacrixrnalsorg/contentl3/4/38&fu lLpdf
2Ot5 Guidance on Cancr lmmundherapy Developnrentin Early-Phase
Oinical Sn¡die* Gt¡idarrce kreloprnent Revie¡vCo¡nminee et al.in €aner
Sciarcq Vó|.10é, No.12, pages lTól-17ñ; December2015. http://onfinelibrary.wiby.
comdoi/101'tllltasl2&9edf
Advans in lmnunehenpybr Melanoma. Jason M. Redman etal. in
BMCl,fudrcrne, Artide No.8; fubruary ó,201ó. htrp//bmcmedicine.
Vd^ 14,
biomedcer¡tral.cománkles/'10í8óls129ló-01ó-0571 {
FROM OUN ARCHIVTS
Gncer! Off Switd¡. Jedd D. Wolchok; l4ay 2014.
scientilicámerican,rcmlmaqazi ne/se
Aprii 2Of6, ScjcnülicAmr:r'ic¿¡.cr;m 5I