Table Of ContentAUTHOR'SVIEW
OncoImmunology1:5,773–776;August2012;G2012LandesBioscience
Combining targeted therapy
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with immunotherapy (interferon- )
Rational, efficacy in gastrointestinal stromal tumor model
and implications in other malignancies
Lei L. Chen,* Launce Gouw,1 Mahyar Sabripour,2 Wen-Jen Hwu3 and Robert S. Benjamin4
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1DepartmentofInternalMedicine;HuntsmanCancerInstitute;UniversityofUtah;SaltLakeCity,UTUSA;2AgensysInc;SantaMonica,CAUSA;
3DepartmentofMelanomaMedicalOncology;UniversityofTexasMDAndersonCancerCenter;Houston,TXUSA;4DepartmentofSarcomaMedicalOncology; t
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UniversityofTexasMDAndersonCancerCenter;Houston,TXUSA
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Keywords:drug-resistance,interferon-a,immunotherapy,targetedtherapy,imatinib,peginterferona-2b,gastrointestinalstromaltumor ri
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Abbreviations:IM,imatinib;GIST,gastrointestinalstromaltumor;IFN-a,interferon-a;CR,completeresponse;PR,partialresponse;
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PFS, progression-free-survival; mAb, monoclonal antibody
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Imatinib revolutionized gastrointestinal stromal tumor (GIST) treatment but median-progression-free-survival of
unresectable/metastatic disease is , 2 y. B-RAFV600-mutated-melanoma responds to vemurafenib dramatically but o
median-progression-free-survival is , 9 mo. Combining imatinib with immunotherapy (peginterferon a-2b) in GIST D
showed significant induction of antitumor immunity and highly promising clinical outcomes. This strategy warrants
further testinginother malignancies. .
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Imatinib (IM, Gleevec1, Glivec1),1 a drug binding (Fig.1A-C). Although gate- induction of innate and Th1 adaptive
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selective inhibitor of ABL, KIT and keeper mutations in B-RAF can confer cell-mediated immunity (Th1 response).6 c
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PDGFRA/B, represents the first paradigm- vemurafenib-resistance in laboratory Complete remission (CR) + partial
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shift targeted therapy for gastrointestinal models, so far vemurafenib-resistance in response (PR) = 100%; overall survival
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stromal tumor (GIST). Unfortunately, the melanoma manifested mainly receptor- = 100%; one patient died of unrelated B
median-progression-free-survival (PFS) of tyrosine kinase or N-RAS upregulation, illness while in radiographic near-CR;
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unresectablelocallyadvancedandmetastatic or signaling pathway switch to PDFGRB after a median follow-up of 3.9y, five
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GIST is , 2y.2 Vemurafenib (PLX4032/ overexpression.5 of the seven evaluable patients are in
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RG7204) demonstrated response rate of Drug-resistant clones evolve continu- continuing PR/CR with duration .
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52%, and represents a similar paradigm- ously and the poorly-understood resilient doubling the median-genotype-specific-
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shift treatment for B-RAFV600-mutated- cancer stem-cells repopulate continuously; PFS of the Phase III IM-monotherapy
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melanoma,however,theshortmedian-PFS theyrepresentthemainculpritsofrelapse. trial (CALGB150105/SWOGS0033)2
of , 9mo is disappointing.3 Common The vulnerability of developing drug- (Fig.1D, Pts#1, 2, 4, 5, 8); Pt#6 deve- 2
drug-resistant mechanisms include: (1) resistance using monotherapy (Fig.1A–C) loped IM-resistance, but when peginter- 1
Mutation of target evading drug binding, and the nature of these two culprits feron a-2b was re-initiated, a second PR 0
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(2) Upregulation of up- or down-stream prompted us to exploit antitumor immu- was induced, indicative of recall of
signaling molecule(s), (3) Alternative nity to overcome relapse by investigating antitumor immunity.6 ©
pathway(s) bypassing target. The first a new strategy of combining targeted Interferon a(IFNa)isaType 1IFN,a
mechanism dominates IM-resistance in therapy (IM) with immunotherapy (pegin- physiological danger signal (3rd signal)
GIST with missense KIT mutations com- terferona-2b[PegIntron1])inGIST.6 Our and immune modulator.7,8 Peginterferon
monly located in KIT kinase domain4 results show that this combination treat- a-2b and peginterferon a-2a (Pegasys1)
and activation loop. A single amino ment is well tolerated, safe, and induced are two currently available long-acting-
acid replacement (gatekeeper mutations) significant IFNc-producing-CD8+, -CD4+, IFNa. IFNa have been used to treat
is sufficient to alter hydrogen bonds, -NK cell, and robust IFNc-producing- several hematological neoplasia, Kaposi
or hydrophobic support, thus impede tumor-infiltrating-lymphocytes, signifying sarcoma, and viral hepatitis in the past
*Correspondenceto:LeiL.Chen;Email:[email protected]
Submitted:02/15/12;Accepted:02/15/12
http://dx.doi.org/10.4161/onci.19729
www.landesbioscience.com OncoImmunology 773
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Figure1.Forfigurelegend,seepage775.
774 OncoImmunology Volume1Issue5
Figure1(Seeoppositepage).IMbindingtoactivatedKIT(toppanel)andremissiondurationpost-combinationtreatmentwithIMpluspeginterferon
a-2binGIST6(lowerpanel).(A-B),3DribbondiagramofIMbindingtoactivatedKIT.Red,IM;green,activationloop;greendottedline,hydrogenbonds;
gold,keyaminoacids.IMformscriticalhydrogenbondstoneighboringaminoacidsThr670,Cys673,Glu640andAsp810.Val654isinakeyposition
supportingthecorrectalignmentofthekeyhydrogenbondsofIMtoThr670andAsp810(DFGmotif).Therearetwoadditionalcriticalhydrogenbonds,
onebetweenArg796andTyr823(activationloop),anotheronebetweenArg796andAsp792(A).Anyaminoacidsubstitutioninthesekeypositionscan
disruptthecriticalconformationandimpedeIMbinding.Twosuchexamples,missensemutationVal654AlaandTyr823Aspareshown(B)Val654Ala
resultedinlossofhydrophobicsupportofIM,andmissensemutationTyr823AspresultedinlossofhydrogenbondswithArg796.(C)2Dbinding
interactionsofIMwithneighboringaminoacids,hydrogenbondsareshowasgreen(H-bondinteractionwithaminoacidmainchain)andblue(H-bond
interactionwithaminoacidsidechain)arrows.Pistackinginteractionsareshownasorangelines.Residuesinvolvedinhydrogen-bond,chargeorpolar
interactionsareshownaspinkcircles.ResiduesinvolvedinvanderWaalsinteractionsareshownasgreencircles.(D)Remissiondurationpost-
combinationtreatmentaftermedianfollow-upof3.9y(4.6–3.5y,calculatedasof02/15/2012),fivepatientsareincontinuingPR/CR(Pts#1,2,4,5,8),
muchimprovedcomparingtothemedian-genotype-specific-PFSofPhaseIIIS0033IMmonotherapytrial(yellowbars).Pt#3presentedwithStageIV
aggressiveGISTharboringKITexon11deletion,extensivelivermetastasis,mitoticfigure$40/highpowerfield,hadswiftexcellentresponseachieving
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PRwithin8weeks,butprogressedwithPFSslightlylongerthantwoyears.Pt#6developedIM-resistance,andre-initiationofpeginterferona-2bresulted e
insecondPR.Pt#6progressedagainwhileoffalltreatment,andcombinationtreatmentofsunitinibpluspeginterferona-2bresultedinstabledisease t
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(B,lastcolumn).
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50 years and have demonstrated good outnumberedbytumorcells(approximately highly promising clinical outcome6 t
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tolerability and safety. A minimum of ten 108.5 tumorcells/cm3).Our highly promis- (Fig.1D), and we plan to incorporate
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steps are required to develop anti- ingclinicaloutcome(Fig.1D)testifiesthat theinsightsgainedintofuturelargertrials. d
tumor immunity: (1) immunogenic IFNa successfully modulates steps 2–10 We believe this mew strategy may benefit
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tumor kill;9,10 (2) triggering innate anti- toward antitumor response during com- large number of different subtypes of o
tumor immunity; (3) initiating adaptive binationtreatment.6Monoclonalantibodies cancer patients. Currently, many malig- n
antitumor response in the presence of (mAb) against cytotoxic T-lymphocyte- nancies have encouraging suitable “tar-
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1st (tumor-specific antigens), 2nd (co- associated antigen 4 (CTLA-4) (e.g., geted” drugs to achieve simultaneous
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stimulation), and 3rd (danger) signals; ipilimumab) can modulate step 4, and PR/CR and antitumor immunity if com-
(4) tumor-antigen capture and processing mAb against programmed cell death 1 binedwithimmunotherapy(peginterferon .
by dendritic cells (DCs) with differenti- pathway(PD-L1/PD-1)(e.g.,MDX-1105) a). The short PFS of vemurafenib-treated e
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ation toward Th1 response (not T regu- canmodulatesteps8and10,andrepresent B-RAFV600-mutated-melanoma3 may be
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latory response); (5) cross-priming by promising immune modulators to enhance improved by combination with peginter-
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DCs in the context of MHC-I and co- CTL functions, but their adverse effects feron a (immunotherapy) and warrant a
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stimulatory molecules to subsets of naive remains unknown contrasting the 5 years’ trial. Another example is to combine c
T-lymphocytes resulting in generation experience with IFNa. oxaliplatin10 (or irinotecan) with peginter- s
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of tumor-specific T-lymphocytes, clonal Effective, non-marrow suppressive, feron a for colorectal cancer with one
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expansion and differentiation in lymphoid minimally toxic treatment modalities con- precaution―careful dosing of chemo- B
organs; (6) effector T-lymphocytes traf- stitute “targeted therapy” in the broad therapeutic agents to avoid leukopenia,
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ficking to tumor sites; (7) cytokines sense,whichincludestargetedsmallmole- whichisdetrimentaltoDCdifferentiation
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production, especially IFNc, by effector cule inhibitors, hormone receptor agonist/ toward Th1 response. Some other very
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T-lymphocytesupontumorantigenrecog- antagonists, and monoclonal antibodies. encouraging examples to combine with
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nition, overcoming the suppressive tumor Advances in tumor biology undoubtedly peginterferon a (immunotherapy) and
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microenvironment;(8)effectorphasecon- will lead to discovery of more effective warrant testing include leuprolide and
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sisting of effector functions of CD4+ T- targeted therapeutic agents in the future, or bicalutamide for prostate cancer,
lymphocytes and CD8+ T-lymphocytes but drug-resistance and early relapse will tamoxifen or aromatase inhibitors for 2
(CTLs)―killing of tumor cells; (9) undoubtedly maintain recurrent themes ER+PR+ breast cancer, lapatinib for 1
0
Differentiation into CD4+- and CD8+- using monotherapy. We combined pegin- ER+HER2+ breast cancer, trastuzumab
memory T-lymphocytes; (10) apoptosis of terferon a-2b (an immune modulator and for HER2+ breast cancer, erlotinib or 2
©
tumor-antigen-activated T-lymphocytes to a danger signal) with IM (non-marrow crizotinib for non-small cell lung cancers
achieve homeostasis and minimize auto- suppressive and effective in tumor killing harboringEGFRmutationsorEML4-ALK
immune disease. Steps 4 and 5 require . to provide 1st and 2nd signals) in GIST fusion gene respectively, and radiation
two weeks, and steps 8 may take . 6mo model,demonstratedsignificantinduction therapy for radio-sensitive tumors (i.e.,
because CTLs are usually overwhelmingly of innate and Th1 response along with seminomas, Ewing sarcoma, lymphoma).
www.landesbioscience.com OncoImmunology 775
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