The Potential and Hurdles of Targeted Alpha Therapy - Clinical Trials and Beyond.

0.97 MB·English

by  Elgqvist, Jorgen

REVIEWARTICLE
published:14January2014
doi:10.3389/fonc.2013.00324
The potential and hurdles of targeted alpha

therapy – clinical trials and beyond

JörgenElgqvist1,2,3,4*,SofiaFrost5,Jean-PierrePouget1,2,3,4 andPerAlbertsson6

1IRCM,InstitutdeRechercheenCancérologiedeMontpellier,Montpellier,France
2INSERM,U896,Montpellier,France

3UniversitéMontpellier1,Montpellier,France

4InstitutRégionaldeCancérologiedeMontpellier,Montpellier,France
5FredHutchinsonCancerResearchCenter,Seattle,WA,USA
6DepartmentofOncology,UniversityofGothenburg,Gothenburg,Sweden

Editedby: This article presents a general discussion on what has been achieved so far and on the

SørenM.Bentzen,Universityof possible future developments of targeted alpha (α)-particle therapy (TAT). Clinical appli-
MarylandSchoolofMedicine,USA
cations and potential benefits ofTAT are addressed as well as the drawbacks, such as
Reviewedby:
the limited availability of relevant radionuclides. Alpha-particles have a particular advan-
JoelS.Greenberger,Universityof
PittsburghMedicalCenter,USA tageintargetedtherapybecauseoftheirhighpotencyandspecificity.Thesefeaturesare
AnujaJhingran,MDAndersonCancer due to their densely ionizing track structure and short path length.The most important

Center,USA consequence,andthemajordifferencecomparedwiththemorewidelyusedβ−-particle
*Correspondence: emitters,isthatsingletargetedcancercellscanbekilledbyself-irradiationwithα-particles.
JörgenElgqvist,Institutde
Several clinical trials onTAT have been reported, completed, or are on-going: four using
RechercheenCancérologiede
Montpellier,INSERM,U896, 213Bi, two with 211At, two with 225Ac, and one with 212Pb/212Bi. Important and concep-
UniversitéMontpellier1,Montpellier tual proof-of-principle of the therapeutic advantages of α-particle therapy has come from
F-34298,France clinicalstudieswith223Ra-dichloridetherapy,showingclearbenefitsincastration-resistant
e-mail:[email protected]
prostatecancer.

Keywords:targetedalphatherapy,alphaemitters,radionuclidetherapy,dosimetry,ovariancancer,cancer

INTRODUCTION Monoclonal antibodies are so far the most commonly used
Inradioimmunotherapy(RIT),monoclonalantibodies(mAb)are vector (1, 2). Other targeting agents include substrate analogs,
conjugated to radionuclides, which provide a specific internal normallyintheformof peptides(3,4),orligandslikefolicacid
radiotherapy.Theclinicalsuccesssofarhasbeenachievedwiththe (5).ThemAbcanbethewholeimmunoglobulinmoleculeorfrag-
beta(β−)-emitting(electrons)nuclides90Yand131I,conjugated mentslikeF(ab(cid:48))2 orsinglechain,diabodies,etc.Clearanceand
toanti-CD20mAbinfollicularB-cellnon-Hodgkinlymphoma. tumoruptakevarywithsizeandpharmacokineticproperties,and
Thelackofsuccessintheadjuvantsettinginsolidcancer(i.e.,with mAbcannowevenbetailor-made(6).
microscopictumorburden)maybeduetothefactthatemitted A brief introduction to the relatively small number of early
electronsdonotdeposittheirmainenergytothemicro-metastatic stage clinical studies using TAT in a variety of situations will
tumorcellswheretheantibodyhasbound;rather,theenergy(and follow, i.e., in recurrent brain tumor (7–9), recurrent ovarian
itseffects)willbereleasedalongaseveralmillimeterlongelectron cancer(10),humanepidermalgrowthfactorreceptor-2(HER-2)
track,i.e.,inthesurroundinghealthytissue,seeFigure1. positive i.p. cancers (11), myelogenous leukemia (12–16), non-
Thisreviewconcernstargetedalpha(α)-particletherapy(TAT), Hodgkin lymphoma (17), and metastatic melanoma (18, 19).
where α-emitting nuclides are conjugated to a carrier,normally Thereisalsoonerandomizedplacebo-controlledtrialusing223Ra-
an antibody. Alpha-particle decay is the release of a heavy and dichloride (having a high affinity for bone tissue) for sympto-
energetic particle, which deposits its energy in a 70–100µm matic skeletal metastases in prostate cancer, the use of which
long track, i.e., within microscopic tumor cell clusters. Impor- is now approved by the US Food and Drug Administration
tantly, this high linear energy transfer (high-LET) radiation is (FDA)(20).
not dependent on active cell proliferation or oxygenation, and
the resulting DNA damage caused by α-particles is much more HOWCOULDTATBEINTEGRATEDINTHECLINIC?
difficult to repair than that of β−. Thus, highly cytotoxic radi- Today,themultimodaltherapeuticapproachoftenincludeslocal
ation directed to the relevant tumor cell deposits holds the gross-tumor eradication by surgery or external radiotherapy,
promiseofaddingsubstantiallytohithertofailingcurativeadju- togetherwithorfollowedbyregionaladjuvantradiotherapy,and
vant chemotherapy both when administered intraperitoneally eventually systemic adjuvant chemotherapy. The order of these
(i.p.) for ovarian cancer, and as a systemic curative adjuvant interventions may differ. As outlined, TAT is mainly aimed at
treatment for breast, colon, prostate, and other malignancies, microscopic residual disease and is therefore perhaps best used
constituting a “systemic conformal radiotherapy at the cellular after adjuvant chemotherapy, but the timing and situation can
level.” vary. A number of thematic situations where TAT has, or may,
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Elgqvistetal. Targetedalphatherapy

FIGURE1|Thefavorablegeometricsituationforα-particlesin anditssub-layer.Theycannotreachtheepithelialcellsoftheintestinal
small-scalemetastases(e.g.,intheadjuvantsetting)isdepictedina lining.Thesituationforβ−particlesontheotherhand,showsthatagreat

scanningelectronmicroscopymicrographofmicro-metastatic dealofitsenergywillbedepositedfarawayfromthebindingsiteand
clustersfromovariancancerontheperitoneallining(mouse).The possiblyintohealthytissueasdemonstratedbythewhitedashedline
rangeoftheα-particlesinred(here~50–70µm),canhardlyreachthe (here~700µm).Consequently,itmayaddtosideeffects.Barequals
surroundingnormalhealthycellsotherthanpossiblythemesothelium 100µm.

be used are shortly discussed, relating both to the route of chemotherapy. Although there is a clear effect on survival, in

administrationand/oraspecificintention. the case of colon cancer, at most, about 30% of patients har-

Intra-cavity administration is a natural starting point for the boring micrometastases are cured (21). Similarly low, or lower,

introduction of TAT in humans. By this approach, the risk of figures for the total efficacy of adjuvant chemotherapy apply

generalsideeffectsof criticalorgans,e.g.,bonemarrow,ismin- for breast and other adjuvant therapies. It is thought that TAT

imized. Similarly, it reduces the risk of unknown toxicity due could be suitable for a boost, or consolidating, therapy after

to unforeseen microscopic accumulation of the radioimmuno- primary surgery and adjuvant chemotherapy. Besides the more
complexelsewhereinthebody.Thisrelatestotheuseofα-particle commonepithelialcancerwhereadjuvantchemotherapyisused,
emitters with relatively short half-life, such as 213Bi (~45min) it has been suggested that malignant melanoma might bene-
and 211At (~7.2h), because most of the radioactive decay will fit from adjuvant TAT. 213Bi-9.2.27,an antibody against human

occur within the specific cavity before the substance is distrib- neural/glialantigen2(NG2),hasbeenadministeredbothintra-

utedthroughoutthebodyviathesystemicandlymphaticsystems. lesionally and i.v. in patients with metastatic melanoma with

Indeed,thishasbeenprovedinrecurrentmalignantgliomasand promisingresults(18,19).Theadjuvantsituationisalsothegoal

for i.p. treatment of ovarian cancer (9–11). In tumor resection in ovarian cancer, with the benefit of using local i.p. admin-
cavities,the anti-tenascin mAb 211At-81C6 was administered to istration (10). In future clinical trials, however, patients who

18patientswithrecurrentbraintumorswithnograde3orhigher would remain disease-free even without such an adjuvant ther-

toxicity,and it was concluded to be a safe treatment with some apymightbeincluded.Itwillthereforebeimportanttoinclude

positiveeffects(9).Withequallylowtoxicity,thesmall11-amino stochastic and long-term risk assessments, such as secondary

acidpeptidesubstanceP(targetingtheneurokinintype-1recep- cancers and/or specific organ dysfunctions, in the therapy jus-
tor)conjugatedto213Bihasbeeneitherinjectedinresidualtumor tification. In these cases, the equivalent absorbed doses in all

orintheresectioncavityofglioblastomamultiforme(7,8). relevantorgansshouldbecalculated,includingaconservativeesti-

The i.p. route of administration was used in nine patients mateoftherelativebiologicaleffectiveness(RBE)fortheemitted
with recurrent ovarian carcinoma using 211At-MX35, an anti- α-particles(22).

bodyagainstsodium-dependentphosphatetransportprotein2b If tumor dissemination is confined to the peritoneum today,

(NaP2b)(10).Thetoxicitywasmild,gradeI–II,andspecifically, extensive cytoreductive surgery with i.p. chemotherapy is sug-
i

therewasnobonemarrowtoxicity.Thiswaslikelyrelatedtothe gested for selected patients, and i.p. TAT may be used as an

factthatonly6%of injectedinitialactivityconcentrationof the additionalboosttherapy.Ananalogouslocaladjuvanttreatment

infused solution could be measured in serum, which peaked at situationwouldbeaftersurgeryforperitonealorpleuralmesothe-
45h.Additionally,212Pbconjugatedtotrastuzumab,ananti-HER- lioma. Other multiple special-case scenarios include, e.g., opti-

2/neu receptor, for patients with HER-2 positive i.p. cancer has mized treatment of neuroendocrine tumors expressing somato-

corroboratedalowsystemicdistribution(11). statinreceptors,usingthesyntheticligandoctreotate(23),which
Adjuvant treatment for large tumor groups, e.g., breast, col- todayaretreatedwithβ−-particlessuchas177Lu,if kidneytoxi-

orectal, and lung cancer, today includes systemically delivered citycouldbeshowntobeless.Inthediffuse-typegastriccancer

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Elgqvistetal. Targetedalphatherapy
subset,TATusing,e.g.,amutatedE-cadherinmAbmayrepresent andinperipherallymphoidtissues.RITwiththelongerrange,low
anoptionfortreatment(24). energyβ−-particle-emittingconjugates(Zevalin®/Bexxar®)isuse-
Palliative treatment can be envisaged for relief of specific fulforthemorebulkylymphomasandareapprovedforfollicular
symptoms from localized disease using the intra-cavity route of B-cellnon-Hodgkinlymphoma,butcomeswithlong-lastingbone
administrationlikemeningeal,pleural,orperitonealcarcinomato- marrowtoxicity(28).ThesafetyandfeasibilityofTATwith213Bi-
sis; the latter is currently being explored (11). Prolongation of lintuzumab(HuM195),ahumanizedanti-CD33mAbthattargets
life was found with i.v. injected 223Ra-dicloride (Xofigo®, for- myeloidleukemiacells,hasbeenestablished(12,14).Importantly,
merlynamedAlpharadin)inaplacebo-controlledphaseIIItrial anti-leukemiceffectswerealsodemonstrated,providingthefirst
forcastration-resistantprostatecancermetastases(20).Although proof-of-conceptinhuman(12).Itissuggestedthatwhenintro-
223Ra-dicloride is not conjugated to a targeting molecule,it can ducingTATdirectlyafterchemotherapy,thecytoreductiveeffect
beconsideredastargetedonthebasisofitsaffinityforbonetis- of thechemotherapycanenhancethepossibilityof asaturation
sue,duetosimilaritiestocalcium.Theotherstudyobjectives,to ofCD33sitesbythetargeteddrug,whichwillincreasethenum-
givesymptomreliefofbonemetastasisandreduceskeletalevents, berofradionuclidesdeliveredtoleukemiacellswithouttheneed
were also fulfilled. Hematological toxicity was surprisingly low foractivityescalation(13).Toevenfurtherenhancetheeffects,the
andagoodtolerabilityistrulyimportantinpalliativetreatment. samemAbisnowbeingconjugatedtotheinvivoα-particlegenera-
Thisdrugisnowalsoinvestigatedforretreatment(25)andusein tor225Ac,whichdecaysinaserieemittingfourα-particles(15),see
combinationtreatmentwithdocetaxel(26)andalsoinosteosar- Figure2.Additionally,anon-goinginvestigationisusingthecom-
coma(27).Atruetargetedtherapy(i.e.,aradionuclideboundto binationof 225Ac-lintuzumabandthecytotoxicdrugcytarabine
a tumor-specific agent) in early stage prostate cancer,with only in older patients with acute myeloid leukemia (AML) (16). The
minimalmetastaticdisease,couldbeusedbeforetheappearance surfacetargetsusedtodayaremostlypresenttoacertaindegree
ofbonemetastasis-relatedsymptoms.Atthetimewhenonlythe onnormalhematologicalcells.Therefore,bonemarrowtoxicityis
prostatespecificantigen(PSA)levelhasstartedtoincrease,after ofconcernandmoremalignantcell-specifictargetsarewarranted.
optimallocalandendocrinetreatment,asapossibleadjunctPSA Regardingmanifestmacroscopicdisease,ashasbeenargued,this
salvagetreatment. situation might not be theoretically optimal for TAT. However,
Systemically dispersed myelo-lymphoproliferative malignancies there are some clinical indications that TAT may actually be of
aremorerapidlyaccessibleforradioconjugatebindingcompared usealsofortreatingmacroscopictumors.Firstly,thereisaninter-
withsolidtumors,whenconsideredasfloatingcellsuspensions. esting phase I trial for manifest stage IV malignant melanoma
However,theydoformextensiveaggregatesinthebonemarrow with promising results, including an objective partial response

FIGURE2|Decaychains.Alpha-particleemittersareinredboxesand shownthreealpha-particleemittersthatarenotmentionedinthetext:
stableisotopesareingreenboxes.Theboxinlightgreentothefar 230U,226Th,and255Fm.Studiesonthefeasibilityofproducing230Uandits
right(251Cf)indicatesthatalthoughtheisotopeisconsideredstablein daughter226Thviaprotonirradiationof231Paaccordingtothe231Pa
medicalapplications(T1/2=898years),itcanstilldecayvia227Acto (p,2n)230Ureactionhavebeenperformed(29).Sofar,thereareno
207Pb(stable).TheT isshowninsideeachbox,andbetweenboxes publisheddataontheuseofthesethreenuclidesforTAT,although
1/2
thetypeofdecay[α,β(−/+),orEC(electroncapture)],withtheprobability 255Fmhasbeenoccasionallymentionedasapotentialcandidatefor

ofeachdecayrouteoccurring(expressedas%).Inthefigurearealso targetedradionuclidetherapy.

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Elgqvistetal. Targetedalphatherapy
rate of 10 and 40% of patients having stable disease at 8weeks or micrometastases. Consequently, i.p. TAT using specific mAb
(19). A total of 38 patients were treated with the 9.2.27 mAb labeled with α-particle-emitting radionuclides, with the higher
(againsthumanmelanomachondroitinsulfateproteoglycan)con- LET and shorter path length than β−-particles, could be more
jugatedto213Bi.Secondly,preliminaryreportsof aphaseIdose effective.AphaseIstudyhasusedthemAbMX35F(ab(cid:48))2 frag-
escalationtrialwith213Bi-labeledanti-CD20againstrelapsedor mentslabeledwith211At,thatwasadministeredasi.p.infusionto
refractorynon-Hodgkinlymphomapreliminaryshowednoacute patients with relapsed ovarian cancer but after having achieved
orextramedullarytoxicityintworespondersoutof ninetreated a complete macroscopic response on second-line chemother-
patients (17). These results are even more promising consider- apy (10). The tolerability was very good and it was concluded
ingtheshorthalf-lifeof213Bi(~45min),sinceamorelong-lived that this treatment could achieve therapeutic absorbed doses in
nuclidewouldlikelyhavebeenabletopenetratethetumormasses microscopictumornoduleswithoutcausinganyradiation-related
better, with possibly even better therapeutic effects. Thus, it is toxicity(10).
arguedthatifpenetrationisoptimizedandhighenoughactivityis
deliveredtoyieldhomogenouscurativedoses,alsotumorsinthe RADIONUCLIDES
sizerangeof5–10mmcanbeeradicated,ashasbeenshownexper- Some important physical characteristics of relevant α-particle
imentally(30).Thispotentialcouldevenbefurtherenhancedwith emitters are presented below, with reference to studies on their
theuseofpre-targetingstrategies(seeseparatesection). therapeuticapplications.SeeFigure2foraschematicofthedif-
ferentdecaypathways.Importantly,asitisnotpossibletodirectly
THEOVARIANCANCEREXAMPLE measuretheαdecayinvivo,evenasmallamountofaccompanying
TheovariancancerexampleaimstouseRITasalocallyinjected γ-radiation will enable scintigraphic evaluation for pharmaco-
adjuvanttherapy.Unfortunately,epithelialovariancancer(EOC) kinetic and dosimetric studies to be performed. All α-particle
mortality has not decreased during the last decades, despite a emitterswithaserialdecaythatincludesα-particledaughterscan
decline in incidence and treatment intensification. Diagnosis is presentproblems,asthedaughterswilldetachfromthetargeting
commonlymadeatanadvancedstagewithwidespreadperitoneal vectorduetotheelevatedrecoilenergy(upto200keV).Suchfree
dissemination; 70–75% of the patients are diagnosed at more nuclidescanthendiffuseaway,leadingtountargetedirradiation
advanced stages i.e.,>stage I. Standard therapy for stage II and ofnormaltissues.Usingmicrodosimetry,theenergydepositedin
higherconstitutessurgerywithcytoreductiveintent(i.e.,removal thetargetcouldbereducedby50%,ashasbeencalculatedforthe
ofasmuchaspossibleofthemacroscopictumorsfromtheperi- 211Atα-particle-emittingdaughter210Po,withaT1/2of0.5s(41).
toneal surface including bilateral salpingo-oophorectomy), sup- Actinium-225 (225Ac)hasaT1/2 of10days,causingtheemis-
plementedbyi.v.chemotherapy,andsometimesi.p.chemotherapy sionoffourα-particlesinaserialdecay.Thedecayisaccompanied
(31). To enhance survival, trials have assessed the use of whole byγ-radiation.Thisnuclidecanhavegreattherapeuticpotential
abdominalormoving-stripexternal-beamradiotherapy(EBRT) whenradiochemistrycanproducestablebindingto225Acandits
(32),or non-specific i.p. radiotherapy with colloid preparations daughters.Thisnuclideisavailableasaconsequenceofproducing
of 198Au or 32P as adjuvant therapies (33, 34). However, the 233Uviathenuclearreaction232Th(n,γ)233Th(β−)233Pa(β−)
results of these studies have not justified their routine use and 233Ufornuclearenergyandnuclearweaponspurposesdecadesago
long-term toxicity in normal tissues is a major concern. How- (Figure2).Thepossibilityofproducing225Acbyuseofacyclotron
ever,even when cytoreductive surgery and chemotherapy result viathe226Ra(p,2n)225Acisnowalsoinvestigated(42).225Acis
in complete remission at second-look laparotomy and normal- currentlytestedintwoclinicalstudieswhereitisconjugatedtothe
izationoftheserummarkercancerantigen125(CA-125),about anti-CD33mAbHuM195(15,16).
70%ofpatientswithstageIIIovariancancerwillrelapse.Recur- Radium-223 (223Ra) has a T1/2 of 11.4days and emits four
renceisoftencharacterizedbygradualdevelopmentofascitesand α- and two β−-particles in the decay chain as well as γ-rays,
chemotherapy-resistanttumorcells,growingasperitonealmicro- until the stable isotope 207Pb is obtained. This nuclide can be
scopiccelldeposits,eventuallyleadingtointestinaladhesionsand producedbyneutronactivationof 226Rabythenuclearreaction
bowelobstruction. 226Ra (n, γ) 227Ra (β−) 227Ac (Figure 2). 223Ra is an alkaline
Chemotherapyinjectedi.p.intheabdominalcavitycanresult earth metal ion and similarly to calcium ions,it accumulates in
in both a reduction in recurrences and a decrease in mortal- thebone.Tothisaim,223Ra-dichloridewasdevelopedandisnow
ity,although at the cost of increased normal tissue toxicity (35, FDA-approvedforbonemetastasesincastration-resistantprostate
36). The advantage of i.p. administration compared with i.v. cancer(20).
injection for localizing radiolabeled mAb to microscopic peri- Bismuth-213 (213Bi) decays with a T1/2 of 45.6min to 209Bi
toneal tumor disease was shown in earlier studies, both in ani- (stable),duringwhichitemitsoneα-particleandanaccompanied
mal models and in patients (37, 38). Therefore, local treat- 440keVγ-radiation.Thisnuclidecanbeobtainedbyelutionof
ment with the β−-particle-emitting radioconjugate 90Y-HFMG the225Ac/213Bigenerator,therebymakingavailabilityanddisper-
(human milk fat globule-1, a mAb toward MUC-1) was inves- siontoclinicalcenterspossible.Thegeneratorisproducedbythe
tigatedinalargerandomizedcontrolledphaseIIItrial,butover- OakRidgeNationalLaboratoryintheUSAandbytheInstitute
all survival did not improve, although a slight decrease in local for Transuranium Elements in Karlsruhe,Europe. Although the
intraperitoneal recurrence was observed (39, 40). This negative drawbackofitsshorthalf-timeputshighdemandonthelogistics
result might be in part explained by the delivery of a too low for radiochemistry and treatment, 213Bi has still been the most
absorbeddosefromtheemittedβ−-particlestosingletumorcells usedTATnuclideinclinicaltrialssofar(12–14,17–19).
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Bismuth-212 (212Bi)hasaT1/2 of 60.6minandemitsoneα- therapies (22), e.g., urine, blood, and peritoneal fluids in the
and one β−-particle. High energy (2.6MeV) γ-rays are emitted case of i.p. treatment (10). All α-particle emitters used so far
in the decay; therefore, patients must be treated using special in clinical studies (211At,213Bi,223Ra,212Bi,and 225Ac) emit γ-
radiationprotectionroutines.Thisnuclideisavailableasacon- photons,characteristicX-ray,orbremsstrahlungradiation.Using
sequenceof producing233Uviathenuclearreaction232Th(n,γ) the γ-camera makes quantification of biodistribution possible.
233Th (β−) 233Pa (β−) 233U (n,2n) 232U for nuclear energy and The spatial resolution of such images is, however, fairly low.
nuclearweaponpurposesdecadesago(Figure2).Thelaststepin Also, the injected activity is much lower than in a diagnostic
which232Uwasproducedviathe(n,2n)reactionwasanunwanted setting, generally resulting in a poor signal-to-noise ratio. For
sidereactionduringtheproductionof233U(Figure2).However, similarreasons,3-Dimensionalsingle-photonemissioncomput-
theparentnuclideof212Biistheβ−-emitter212Pb,havingaT1/2 erizedtomography(SPECT)imagingof theactivitydistribution
of 10.6h. The chelator TCMC is used with 212Pb and functions in patients is time-consuming. The accuracy could be increased
asaninvivo nanogeneratorfortheα-particleemitter212Bi.The usingco-registrationtechniqueswithcomputedtomography(CT)
University of Alabama (USA) has started a clinical trial to eval- images(49).
uate 212Pb-TCMC-trastuzumab toxicity levels and anti-tumor Obviously, the absorbed dose in tumors and normal tissues
efficacyinpatientswithHER-2positivecancersintheabdominal need to be estimated from preclinical studies before initiating
cavity(11). treatment studies. However, clinical quantification with the γ-
Astatine-211(211At)decayswithaT1/2 of 7.2handemitsan cameracanonlygiveanestimateoftheuptakeoftheradiophar-
α-particle in both of the two possible decay routs to the stable maceutical in whole organs and in macroscopic tumors, while
nuclide 207Bi. Scintigraphy and standard dosimetry are possible quantificationof theabsorbeddoseinsmallercompartmentsin
duetotheaccompanyingγ-radiation.Thelimitedavailabilityis organs or microscopic tumors is hardly achievable. In TAT, the
currentlyamainobstacleforawideruseofthisnuclide,asitcan targeted tumors are often too small to be detected and,at best,
onlybecyclotronproduced(43).Ithasbeenusedinclinicaltri- indirectmethodscanbeusedforestimatingtheabsorbeddose.
als,locally administered in surgical resection cavities and i.p. as Withregardtonormaltissueprotection,incertaincases,block-
previouslydiscussed(9,10). ing agents can be used. For example, both astatine and iodine
belong to the halogen elements and pre-treatment with potas-
DOSIMETRY sium perchlorate can effectively prevent uptake of free 211At in
Dosimetrywasoriginallydevelopedforradiationprotection(44) cells expressing the sodium-iodine symporter (NIS),e.g.,in the
anddiagnosticimaging(45),butisnowalsoneededforoptimiza- thyroid(10).
tionofthetherapeuticsituationusingradiopharmaceuticals.The Inthecaseof i.p.TATforovariancancer,acontrolγ-camera
basicconceptsofdosimetryarepresentedintwoMedicalInternal imageoftheabdominalregionwitharadioactive-traceranalogto
RadiationDose(MIRD)publications(46,47). assure free distribution of the fluids is important. The radioac-
α-Particle dosimetry takes into account a number of differ- tive flow out of the abdominal cavity can also be determined
ent parameters,particularly the short path length of α-particles usingaradioactive-traceranalog,bymonitoringtheactivitycon-
in tissue (~100µm) and the inhomogeneous distribution of α- centration in blood over time (10). Pharmacokinetic data show
radiopharmaceuticalsintumorsandtissues.Thus,predictingthe that the variation in the absorbed dose in bone marrow can be
biological effect based on mean absorbed dose in a tumor or around20%(10).Ifthebonemarrowisthedose-limitingorgan,
organmightbemisleadinginsomecircumstances.Thehigh-LET its absorbed dose then determines the maximal tolerated activ-
(~100keV/µm)andvaryingLET(withamaximumattheBragg ity (MTA),and a radioactive-tracer analog study will be crucial
peak)alongtheα-particletrackarealsoparametersthathaveto for estimating the patient-specific MTA. However, for i.p. TAT,
betakenintoaccountwhenperformingα-particledosimetry. noeffectonthehematopoiesiswasrecorded(10).Instead,other
TheRBEofα-particlesrangesfrom3to7,i.e.,α-particleirradi- organsmightdeterminetheMTA,possiblytheperitoneum;there-
ationis3–7timesmoretherapeuticallyeffective,ortoxic,perunit fore,theactivityconcentrationintheperitonealfluidiscrucialto
ofabsorbeddosethanphotonsorelectrons(47).InTATclinical calculate.
studies,anRBEoffivehasbeenappliedtoestimatetheequivalent α-Particle dosimetry on the cell level should be used when
absorbed doses (10,14,48). The weighting factor applied when macrodosimetry cannot explain the results of an experiment or
estimatingtheeffective(orequivalent)absorbeddose(expressed whenitaddsvaluetothemacrodosimetricmethod(50).Forα-
inSv,Sievert)isrelatedtothestochasticeffectsofradiation,e.g., particles,thebiologicaleffectofjustasingleionizationeventcould
cancerinduction.Afactorof 20iscommonlyrecommendedfor be so large that the calculation of the mean absorbed dose in a
thestochasticeffectsofα-particlesthatshouldhowevernotbeused tumorasawholecanbeverymisleading.
whenpredictingthetherapeuticefficacyortoxicityinpatientswho Hence,thereisaneedformicrodosimetrywhenthestatistical
receiveTATtreatment.Indeed,thisweightingfactorwasconserv- variationof thedepositedradiationisnotminimalinthetarget
ativelyderivedforradiationprotectionandwasnevermeantfor suchasacancercellnucleus.Theconceptualframeworkofmicro-
estimatingthedeterministiceffectsrelevanttotherapy(47).Also, dosimetrythattakesintoaccountthestochasticnatureofenergy
theclinicalexperiencewithα-particlesissparse,andthereforethe depositsinsmallmicroscopictargetswasproposedalmost60years
tolerancetoabsorbeddosesinhumanshasyettobedetermined. ago(51),andtheInternationalCommissiononRadiationUnits
α-Particledosimetryintheclinic requirepharmacokineticdata and Measurements (ICRU) report No. 36 from 1983 defined all
similar to those that are required for conventional β–-particle themicrodosimetricconcepts.Calculationsandexperimentshave
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Elgqvistetal. Targetedalphatherapy
shownthatasfewasfivehigh-LETα-particletraversalsthrough PRIT regimens, all based on the same essential principle, have
thecellnucleusareenoughtokillacell,whereas10,000–20,000 been proposed since the pre-targeting concept was proposed
low-LET β–-particles are needed to achieve the same biological by Goodwin et al. in 1988 (80). In the first step, a targeting
effect(52–54). immunoconjugate (pre-targeting molecule) is administered and
Importantly, microdosimetry should be considered for non- sufficienttimeisallowedforitslocalizationattumor-associated
targeted but critical tissues, even if it receives a very low mean antigen sites. As the pre-targeting molecule does not carry any
absorbeddose(47). cytotoxic substance, normal tissues are not affected by lengthy
circulation times during the distribution phase. Then,unbound
THEBIOLOGYINTARGETEDαTHERAPY immunoconjugatemoleculescanberemovedfromthecirculation
Thewayhigh-LETradiationlikeα-particlesinteractwithbiolog- using a clearing agent, before injecting the radiolabeled vector
icalmatterhasbeendescribedearlier(53,55–60).Theyproduce (effector molecule). The effector molecule is a small molecule
denseionizationsalongalineartrackandgeneratelocallymultiple designed to rapidly diffuse into tumors and cancer cell clus-
damagesitesinsensitivetargetslikeDNA.Theselesions,produced ters,whereitwillspecificallybindtotheantigen-associatedpre-
incloseproximitytoeachother,arepoorlyrepairable,thusmaking targetingmolecules.Thefastclearanceofunboundeffectormol-
α-particleshighlydeleterious(61,62).WhileconventionalEBRTis ecules improves the tumor-to-normal tissue ratios of absorbed
characterizedbyhighabsorbeddosesdeliveredinaveryshorttime dose compared with directly labeled immunoconjugates. With
in a homogenous way,TAT and radionuclide therapy in general pre-targeting, no trade-off needs to be made between efficient
arecharacterizedbyalowabsorbeddoserate,protractedexposure, targeting/penetration/tumor residence time and protection of
andheterogeneousenergydeposit(63). dose-limitingnormaltissues.
In EBRT, physical events predominate in the final outcome Efficient interaction between the pre-targeting molecule and
of the therapy, and most of the effects can be correlated to theeffectormoleculehasbeenachievedusingahandfuloftech-
theabsorbeddoseaccordingtoalinear,linear-quadratic,orsig- niques, particularly those based on streptavidin-biotin (81) or
moidrelationship.Conversely,physicalcharacteristicsoftargeted bispecificantibodies(82).Oftheradionuclideswithpotentialuse
radionuclidetherapycanofferthecellstheopportunitytorepair inTAT,someappearmoresuitablethanotherswhenfactorssuch
someoftheirsublethallesions(64–67).NuclearDNAplaysacen- as availability and daughter nuclides are taken into account, in
tral role in response to targeted radionuclide therapy,but other addition to chelation and conjugation chemistry. In particular,
cellular sub-compartments including the mitochondria and cell twopromisingcandidatesforefficienttherapyemerge:211Atand
membrane might also be strongly involved in situations of het- 213Bi. However, they both have short T1/2 (7.2h and 45.6min,
erogeneousenergydeposits(68–74).Therefore,thebiologyofthe respectively), which put high demands on the distribution of
irradiated tissue and its interaction with its environment might radiolabeledvectorstoensurefavorableabsorbeddoseratios.This
play an even more pronounced role in targeted radionuclide issuecouldbeovercomebyusingapre-targetingstrategy,thereby
therapy than EBRT, and bystander and abscopal effects involv- increasingthetherapeuticpotentialoftheseshort-livedα-particle
ing activation of signaling pathways and the immune system emitters.
should probably be investigated more accurately (75–77). The Several preclinical studies have shown the benefits of pre-
consequencesarethattheabsorbeddose-effectmightbemoredif- targetedαtherapy(PTAT),mainlyinhematologicalcancers,such
ficulttoestablishandradiation-inducedbiologicaleffectsmight asAML(83),non-Hodgkinlymphoma(84),anaplasticlargecell
beobservedintissuesfarbeyondthephysicalpathlengthof the lymphoma (85), and adult T-cell leukemia (85). PTAT for dis-
α-particles. seminatedovariancarcinomawasevaluatedinonestudyinwhich
211At-PRIT(1.5MBq)and211At-RIT(0.9MBq)werecomparedin
PRE-TARGETEDαTHERAPY amousemodelofi.p.TAT(86).Theadministeredactivitieswere
All targeted therapies rely on the ability of the vector to find its based on the previously estimated MTAs for the two regimens
targetandtoallowtheassociatedcytotoxicagenttodeliverthecell- and resulted in equal tumor-free fractions (TFF; 0.45) 8weeks
killingeffect.Advancesingeneticengineeringhaveledtothedevel- afterirradiation;however,themicetreatedwith211At-PRIThad
opmentofmanymoleculesthatcanberadiolabeledandusedfor smaller tumors and lower ascites incidence. This indicates that
RIT.However,despitethegrowingnumberofdesignedantibody pre-targetingcanimprovetheoutcomealsoofi.p.TAT,although
fragmentsandfusionproteins,treatmentsareoftenhamperedby thegreatestgainofPTATisgenerallyconsideredtobeinsystemic
lessthanoptimalpharmacokinetics.Thekeyliesinfindingabal- treatments.
ancebetweentumorradiationuptakeandremovalofcirculating
radioactivity. Rapid clearance of unbound radioimmunoconju- SUMMARYANDFUTUREPERSPECTIVES
gatesisessentialforlimitingtheabsorbeddosetonormalorgans, Radioimmunotherapy with short-ranged, high-efficiency α-
butatooshortaretentiontimeinbloodwillresultinatooshort particles is a very attractive and promising treatment strategy.
targetingtime,andthusinthedeliveryofatoolowabsorbeddose α-Particleshaveanadvantageintargetedtherapybecauseoftheir
tomalignantcells. exceptionally high cell-killing ability. Therefore, different from
Thispharmacokineticchallengecanbehandledbyseparating RIT with β–-particles, α-particle emitters labeled to a targeting
physically and temporally the targeting phase from the delivery vectorcandirectlykillsinglecancercells(byself-irradiation).Sev-
of the ionizing radiation, an approach generally referred to as eralcompletedoron-goingclinicaltrialsusingTAThaveshown
pre-targetedradioimmunotherapy(PRIT)(78,79).Anumberof its feasibility for treating disseminated and/or micro-metastatic
FrontiersinOncology|RadiationOncology January2014|Volume3|Article324|6
Elgqvistetal. Targetedalphatherapy
malignancieswithoutsignificantorinsurmountableproblemsof with213Bi-DOTA-[Thi8,Met(O2)11]-substanceP:apilottrial.EurJNuclMed
toxicity.Althoughthedefinitionof micrometastasesisvague,in MolImaging(2010)37(7):1335–44.doi:10.1007/s00259-010-1385-5
clinicaloncologyoccultmetastases(i.e.,notdetectedbyroutinely 8.KneifelS,CordierD,GoodS,IonescuMC,GhaffariA,HoferS,etal.Local
targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-
usedimagingprocedures)mightinvolvesingletumorcellsupto tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p. Clin
clustersofbillionsofcells.Therefore,acocktailofbothα-andβ–- CancerRes(2006)12(12):3843–50.doi:10.1158/1078-0432.CCR-05-2820
emittingradioconjugatesmightbemoreeffectiveinsomecases. 9.ZalutskyMR,ReardonDA,AkabaniG,ColemanRE,FriedmanAH,Friedman
ThepossibilityofTATasapotentialcurativetreatmentincludes HS,etal.Clinicalexperiencewithalpha-particleemitting211At:treatmentof
its use as a local boost after initial treatment (e.g.,i.p. in EOC), recurrentbraintumorpatientswith211At-labeledchimericantitenascinmono-
clonalantibody81C6.JNuclMed(2008)49(1):30–8.doi:10.2967/jnumed.107.
or perhaps as i.v. systemic adjuvant treatment, both targeting 046938
micro-metastaticdisease.Asystemicapproachmayindeedbeof 10.AnderssonH,CederkrantzE,BackT,DivgiC,ElgqvistJ,HimmelmanJ,etal.
particular interest in patients with EOC that includes retroperi- Intraperitonealalpha-particleradioimmunotherapyofovariancancerpatients:
tonealvascularizedmetastases,e.g.,inthelymphnodes.Fraction- pharmacokineticsanddosimetryof(211)At-MX35F(ab’)2–aphaseIstudy.
JNuclMed(2009)50(7):1153–60.doi:10.2967/jnumed.109.062604
atedRITisanotherpotentiallyinterestingregimentoimprovethe
11.MeredithRF,TorgueJ,AzureMT,ShenS,SaddekniS,BanagaE,etal.Pharma-
therapeuticindex,thusresultinginreducednormalorgantoxicity cokineticsandimagingof(212)Pb-TCMC-Trastuzumabafterintraperitoneal
whilemaintainingthetherapeuticefficacy(87).Radionuclidesthat administrationinovariancancerpatients.CancerBiotherRadiopharm(2014)
emitAugerelectronscouldofferanalternativeapproachcompared 29(1):12–7.doi:10.1089/cbr.2013.1531
withthenuclidesdescribedinthisarticle,reviewedelsewhere(88). 12.Jurcic JG,Larson SM,Sgouros G,McDevitt MR,Finn RD,Divgi CR,etal.
Augerelectronsareenergeticallyveryweak(<<1keV)andhave Targetedalphaparticleimmunotherapyformyeloidleukemia.Blood (2002)
100(4):1233–9.
apathlengthintissuethatisfarshorterthanthatofα-particles. 13.Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Taskar N, Divgi CR,
However,toeffectivelydamageDNAmolecules,theAugeremitter PanageasKS,etal.Sequentialcytarabineandalpha-particleimmunotherapy
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The therapeutic outcome of TAT is influenced by a number cerRes(2010)16(21):5303–11.doi:10.1158/1078-0432.ccr-10-0382
14.SgourosG,BallangrudAM,JurcicJG,McDevittMR,HummJL,ErdiYE,etal.
of crucial issues that all need to be handled,e.g.,the specificity Pharmacokineticsanddosimetryofanalpha-particleemitterlabeledantibody:
oftheantibody/targetingconstruct;thelevelofantigenicexpres- 213Bi-HuM195 (anti-CD33) in patients with leukemia. J Nucl Med (1999)
siononthetumorcells;thepotentiallossofimmunoreactivityof 40(11):1935–46.
theantibody/targetingconstruct;theamountof unlabeledanti- 15.MemorialSloanKetteringCancerC,NationalCancerInstitute,ActiniumPhar-
body/targetingconstructafterinjection;theexistenceofdiffusion maceuticals.TargetedAtomicNano-Generators(Actinium-225-LabeledHuman-
ized Anti-CD33 Monoclonal Antibody HuM195) in Patients With Advanced
barriers that hinder the penetration of the antibody/targeting MyeloidMalignancies.U.S.NationalInstitutesofHealth(2014).
construct into the tumors; the choice of radionuclide (half-life 16.M.D.AndersonCancerCenter,ActiniumPharmaceuticals.LowDoseCytara-
and path length); too low specific radioactivity; and for the i.p. bineandLintuzumab-Ac225inOlderPatients.U.S.NationalInstitutesofHealth
situation,anyextraperitoneallocationoftumorcells. (2015).
17.HeegerS,MoldenhauerG,EgererG,WeschH,MartinS,NikulaT,etal.,edi-
A major issue that may hamper wide implementation in the
tors.AlpharadioimmunotherapyofB-lineagenon-Hodgkin’slymphomausing
clinicandthatneedstobesimultaneouslyaddressedistheavail- 213Bi-labeledanti-CD19-andanti-CD20-CHX-A”-DTPAconjugates.Proceed-
abilityofsuitableα-particleemittersatareasonablecost(43,89). ingsofthe225thACSNationalMeeting,DivisionofNuclearChemistry&Tech-
Otherwise,TATwillremainjustapotentiallyeffectivetreatment, nology;2003 March 23–27;New Orleans,LA,USA. (2003).Available from:
oraveryrarelyimplementedoption.Finally,aftersafetyissuesand http://oasys2.confex.com/acs/225nm/techprogram/P613172.HTM
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