595
`
`STEM CEI.LTRANSPlANTATION FOR RESISTANT I.UPUS. Ann E Traynor,James Schroeder. Robert
`M Rosa, Salim Mujais, Steve Rosen, Suzanne Bowyer, Lawrence jung, Richard Bun Chicago, IL,
`Indianapolis, IN Omaha, NE
`
`Five patients who experienced persistence of aggressive systemic lupus despite cycle(cid:173)
`phosphamide therapy were treated by dose intense immune suppression and autologous hemato(cid:173)
`poietic stem cells. Stem cells were mobilized with cyclophosphamide (2.0 glm2) and granulocyte
`colony stimulating factor (GCSF) 10 ug/kg/day, enriched using CD34 positive selection, ami
`reinfused following immune suppression with cyclophosphamide (200 mg/kg) and anti-thymocyte
`globulin (ATG) 90 mglkg. Results: Median time to an absolute neutrophil count greater than 500/ul
`and non-transfused platelet count greater than 20,OOO/ui in these five transplanted panents were
`day lO and 12 respectively. The first five patients to undergo transplant have now been followed
`for 60-800 days. All are well and without evidence of active lupus. Renal, cardiac, CNS and
`pulmonary functions and all serologic parameters have normalized or markedly improved. No
`patient has received chemotherapy or any immune modulatory agent since transplant other than a
`continuous prednisone taper. Among the four patients who have been followed for over one year,
`the median prednisone dose is 5 mg dally (0-15 mWd). The median SLEOAIscore is I. The first four
`patients have now been followed a median of 18 months (14-27 months) and all are without
`evidence of active lupus. Conclusion: Despite failure of available therapies and serious organ
`dysfunction, each patient is Without active lupus and continues to improve following stem cell
`transplant. Durability of these remissions remains to be determined.
`
`Disclosure: work reported in this abstract was supported by:
`
`598
`
`ACR Minisymposium
`Novel Approaches to Biological Response Modification in
`Rheumatoid Arthritis
`Sunday, November 14,1999,2:15 PM-3:45 PM
`
`rHUlL·lO (TENOVlL) PLUS METJIOTREXATE (MTX) IN ACTIVE RHEUMATOID ARTHRITIS (RA): A
`PHASE 1/11 ~TUDY. Michael E Weinblatt, E William St Clair, Fcrdlnand C Brcedveld, Larry W
`Moreland, Edward C Keystone, Sk-y H Lee, l.owell B Robison, Daniel E Furst, Ken J Bulpitt, Eric M
`Veys, Thomas Haverty, Paul Grim, Janice C Wherry
`
`rHUIl-lO (rIL-lO, TENOVIL) is an anti-inflammatory cytokine which inhibits proinflammatory
`cyroklnes and is effective in animal models of arthritis. Trends towards improvement in RA have
`been seen in early clinical studies of rll-IO alone.
`This study evaluated the effects of adding rIL-IO 10 chronic MTXin patients with active RA.The
`study was a multicenter, randomized, placebo-controlled dose-escalarlng-study of clL-IO (I. 4 or 8
`u: g,tkg qD or 8 or 20 p.g/kg TlW)SC or placebo SC plus MTX (12.'>-25 mg/week PO, SC or 1M) In
`50 pts with active RA treated for 4 weeks along with their stable dose of MTX.
`ACR 20% response criteria was observed in 50% of pts receiving 1i-10 at a dose of 8 1J.g/kg qd,
`50% of patients receiving the 8p.g,tkg llW dose and 63% at 20 p.g/kg TIW dose vs 10% with placebo.
`ACR 50% response criteria was observed in 13% of pIS receiving 11.-10at a dose of 8 Il-g/kg qd, 25%
`of patients receiving the 81l-g/kg TIW dose and 13% at 20 1J.g/kg TIW dose vs 10% With placebo.
`Increases in serum TNF p55 and p75 soluble receptors were seen with rIl-1O therapy.
`tolerated and no antl-Il-In antibodies were found. A dose-dependent
`cll-IO was clinically well
`decrease in platelets and hemoglobin were seen (With the highest doses of rIL-I0, --25% of subjects
`experienced a >40% decrease in platelets or a > 2g/dL decrease in hemoglobin) with rapid full
`recovery following cessation of rU.-IO. 50-70% of subjects treated with 8 or 20 lLg/kg TIW are
`continuing therapy with clL-1Qfor> 12 months in an extension protocol.
`In this study ell-IO therapy was well tolerated and safe and trends towards improvement in RA
`activity were seen. For future studies, the rU.-IO doses that maximize the safety and efficacy profile
`are 8 and 20 p.glkg TIW.
`
`Disclosure: work reported In this abstract was supported by:
`Study was funded by Schering-Plough Research Institute. T. Havcrty, PGrint and JWheny are
`employees of SPRI. Drs. Weinblau, St. Clair, Moreland, Keystone and Furst have served as
`consultants to SPIU
`
`596
`
`599
`
`SUCCESSFUL TREATMENT OF REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) BY
`AUTOLOGOUS STEM CELl. TRANSPLANTATION (ASCI) WITH IN VIVO IMMUNOABlATlON AND
`EX VIVO DEPLETION OF MONONUCLEAR CELLS. Falk Hlepe, Oliver Rosen, Andreas Thiel, Gero
`Masscnkcil, Hartmut Radtke, Thomas Haupt, Erika Gromnica-Ihle, Andreas Radbruch, Renate
`Arnold Berlin, Germany
`
`ASCT is a new experimental approach to treat patients with severe refractory autoimmune
`diseases. Various strategies for
`immunosuppression and processing of
`transplants have been
`proposed. Our hypothesis is that effective in vivo lmmunoablatlcn and ex vivo depletion of
`mononuclear cells including autoimmune cells with subsequent ASCT can lead to long-lasting
`remission in severe autoimmune disease. Until now 3 patients with a refractory SlE (2 female, 1
`male, age between 27 and 48 years) have been treated. These patients failed multiple conventional
`therapeutic strategies and had active life-threatening disease at
`the time of transplant, All SLE
`patients exhibited high disease activity with severe organ involvement especially lupus-nephritis
`and positive anti-dsDNA antibodies. Peripheral stem cells were mobilized with cyclophosphamide
`(2 g/sqm) and G-CSF. The transplant was CD34 positive selected by CliniMacs and contained 2.4 to
`7.3 x lOe6 CD34+lkg b.w. and 1.0 to 1.6 x lOe4 C03lkg b.w. The conditioning regimen included
`200 mg/kg cyclophosphamIde and 90 mg,tkg antithymocytc globulin. The patients received
`antibacterial and antiviral prophylaxis. The efficient depletion ofT cells from the transplant did not
`lead to life-threatening infections during the time of lymphopenia. All :} SLE patients with a
`follow-up time of 5, 9 and 13 months after transplant are in clinical and serological remission.
`Antinuclear antibodies, anti-dsDNA antibodies and other autoantibodies (anti·Ro/SS-A, anIH.a/S5-H.
`anti-cardiolipin) are still negative. The activity index ECLAM decreased from 7 to 2, 6 10 2, and 10
`to 2, respectively. An increase of low complement levels to normal values was observed. Moreover,
`the dosage of steroids could be markedly reduced.
`In conclusion, clinical and serological remission in patients with refractory SlE can be achieved
`by successful immunoablation in vivo combined with highly effective purging of the transplant.
`The duration of the remissions is unknown and needs to be studied.
`
`Disclosure: work reported In this abstract was supported by:
`
`A PILOT STUDY OF ISIS 2302, AN ANTISENSE OLIGODEOXYNllCLEOTlDE, IN PATIENTS WITH
`ACTIVE RHEUMATOID ARTHRITIS. Wallcr Maksymowych. Warren Blackburn. Edna Hutchings,
`Lucille Williams, Joseph Tami, Kathleen Wagner, William Shanahan Edmonton, Canada, Blrmlng(cid:173)
`ham, AL, Carlsbad, CA
`
`randomized (3: I;
`Forty-three patients were enrolled in a double-masked,
`ISIS 2302:placebo
`[PBOD, dose-escalation. PBQ.controUed pilot study.
`ISIS 2302 is a 2<J.base phosphorothtoate
`oligodeoxynucleotide (OON)
`thai downregulates human intercellular adhesion molecule I
`(1CAM-I) through an antisense mechanism.
`Patients had to meet criteria for active disease (2:: to swollen joints and other criteria) despite
`adequate NSAID background therapy z approved 2nd line agents z; low dose (SIO mg/djcorttco(cid:173)
`steroids. Patients were administered thirteen 2 hour intravenous infusions over 26 days of ISIS2302
`at doses of 0.5 (10 pIS.), 1.0 (3 pts.) or 2.0 (19 pts.) rug/kg, or normal saline PBO (I I pIS.). and were
`followed for a total of 6 months.
`By Paulus 20% criteria, responses were similar in the ISIS 2302 and PB0-treated patients over the
`first 3 months, but differentiated thereafter, with the greatest response observed in the 0.5 mglkg
`patients. Over Months <Ul, the proportion of patients achieving Paulus 20% responses averaged
`37%. 33%, 18% and 10% for the 0.5, 1.0,2.0 rug/kg and PBO groups, respectively. Transient Paulus
`50% responses, occurring sometime between Days 60-180, were observed in 10%,33%,21%, and
`0% of patients in the 0.5, 1.0,2.0 mg/kg, and PHO groups, respectively. Administration of ISIS 2302
`was well tolerated. The only apparent drug-related adverse effect was an annctpated, transient (24
`hours post dose). and dose-related increase in aPlT (-7 seconds at 2 mglkg), due to inhibition of
`lntrinslc tenase complex activity, a class effect of phosphorothioate DONs.
`Although these results suggest that ISIS 2302 is effective and well
`tolerated in the treatment of
`rheumatoid arthritis, the delayed response suggests that chronic dosing may be more effective. The
`development of second generation antisense chemistries targeting IeAM-I may allow for chronic
`Or-d) dosing.
`
`Dlsdosure: work reported In this abstract was su pported bY'
`Study sponsored by Isis Pharmaceuticals, Carlsbad, CA, 92008
`
`597
`
`600
`
`HIGH·IJOSI'.IMMIiNOABUTIVt: CYCUJI'UtlSI'HAMln,E 1:'11 ~1.1:'. M 1'('I.n. A JooC's. R Bmdsk}·l\;tlllm"rr. MU
`
`HI¢t-tk""C' .mo1tlltn~bl~llvt' C}·t·I"f'hru;f'h~mi...C'(111)1(;:200 mWkIO wilhout seem cell .....s.".l.lr n:&uh~ in oJulOtble...... mpktC' rrmisaiu/U in lhe: rrtiljurity
`of pll .....ith ;apLi)li" ;anemi;a;anoJmher rdlOtt-lUry ~llloimmulIl:' w>Cil.'I(');. Stern rcll
`rescue Is nut n«c).'\;IIY. bCl.";Iu>c c:.Ifly seem "db:.lre re)I~I;aOl It!
`IIDie. IIIJIe: lIc1lvel':'ltrn: .":.IlTlC' lIlN: "f CYloun u-'lCd10 hoot' marrow lr:.to"pl~OI"I.onpll'(l"~r:.tlkm reg1mens. hUI :I\·uld.. Ih... prtlbh:m or1T·lnfusion
`or:tuturnltl~'e Irmph'''1tC'S With M...m-i.·C'IIIT.....'UC,'. WC'h:....e rull<>Wt-d II pts wilh Sl.t :titer 1101(;. Mdhods: II :iLE pili .....rfil c-.OlY 10 oth.:r rcWmelil
`underwent HUIe. Completc" n:-mj~ion II lIdin.:d:t.~ no lIbcax: itlth·jty. on phy~lulOldc or 0<1preoJnbounC" anll"" ImmunuMJpprcMlvt IhC"rapy. Panl;tl
`~l"'m>c Is dclintll ill. mUll lIJIoC"">C ~n.vlly. nn ph)'slllk'ldl' or no prrnnJ"unl:' ~nll nn ImmllnlJ!l'ullpll' ....d\·C'!IO.
`seuow up
`(mlhs)
`
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`
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`PL·E
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`LT
`BU
`
`Indication
`Skin
`Killnq·
`SkinIP)·Ol.I. (ianj::.)
`Kidnt,·
`Kidney
`eNS. Hl:'n1C."
`Sidn. Kklnc)'
`Kidney
`CNS
`c~s. Pulm 1m.!
`KilJncy
`
`1'tIethUII't"ulo;o. Cl:'lIrtpl
`("~IICo;oPI
`
`«J1cr~t. C)'clo~flOtin
`
`Cc'lIcepl
`cellcePI
`lmur~n
`
`100ur.m.ql",,~n
`
`Ct'tmun
`
`11II1Ir~n
`
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`C)1Uun. ("..elkepl
`
`t,~.\
`
`.~.~;
`
`417
`2.81
`7.9.\
`2j6.~
`10).7:1
`1U1;\
`0.'"
`':U7
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`
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`(:umpICI ... RC"fl\"~~!nn
`Nllnc
`Nulle'
`Sonc
`Complele- Rcmi:\.lliom
`Potni:tlResponsc
`C.llmplclt'R...mlssiun
`NunC"
`C;umpltlrKo;oml,,-,,-Io'n
`Pulm tUN.(;om. Rem.
`N'lIle
`
`Exampk of Rc:rut.I Compldc Rnn-Lulon for CK (" = pn!'.HDlC)
`
`tl/l·II'.m"
`11/191'»1
`1I11l19'J
`4/lW99
`
`Urine proldn (X)
`1."'"
`lfl,H
`1.427
`1l,4'Jj
`
`PtTdnl-.one (rna)
`<.
`
`"IU,
`
`ConclU5lon: 11U1(;Ciln leal.! 1(1,Jur...ble, "(lmplele ro:mi»ioo ur SU; In pl~ who hotve r...i1eo allmher Immunm\lJlprn~i1'("Ihcr~pie•• IncludJnK
`mnl1lhl)'IV l·)·duphn,plumJ<k:. ~"'Urpbwllh rcn~lluI1U" rcr"'t-Iul)' 10 JJInther Ihcr~plc"1'C'''l'''Imlnl. 111CR'hit\·t" hccn nn Cil"l"'ou(lnknllny IU(~IIt·.
`HOlt: offeB 3n 311...m:t1l\·t' 10 u ...m t·tlll\'S(·ut' in refr:II:lory 10 Su: pIs ~I 1/3 Ihe COSI(If Slem cell tr:U\spl;m13Iion.
`
`D....cbure work I"C"'ponniln Ihb atKlrac1 wa~ !>uppont'd by:
`
`RESULTSFROM THE FIRST HUMAN CLINICAl. TRIAL OF GENE TlIERAPY FOR ARTHRITIS. C H
`Evans, P 1>Robbins, S C Ghivlzzani, J H Herndon, M C Wasko, M Tomaino, T A Muzwnlgro, H I
`Georgescu, E Elders, T WhiteSide, S C Watkins, R Kang Pittsburgh, PA
`
`PURPOSE To determine whether it is possible to transfer safely Il-IRa cDNA 10 the joints of
`patients with RA, and to express that DNA Intraarticulurly.
`MEllIODS Nine postmenopausal women were recrulted to the study. Eligibility criteria included
`the need for total joint replacement surgery of the Mep joints 2·5 and surgery on at least one other
`joint. Autologous synovium was recovered at the time of the latter surgery and used as a source of
`synovial fibroblasts. which were then expanded in culture. Cultures were divided in two. One was
`stably transduced with a retrovirus carrying the Il-IRa cDNA and the other remained as an
`untransduced, control cell population.
`Cells were tested for a variety of advcnuuous agents prior to tnjecuon into the Mer joInts
`destined for surgical replacement. In a double blinded fashion, two joints received transduced cells
`and two received control cells. Patients were treated in a dose escalation manner. one week after
`gene transfer, the Mel> joints were surgically removed and the retrieved tissues analyzed for
`evidence of successful gene transfer and gene expression.
`RESULTS All patients completed the protocol unproblematically and no adverse events were
`nOled. All synovia recovered from joints receiving the tnlOsgene showed evidence of gene
`expression by both RT-PCR and by EUSA measurement of IL-IRa in media conditioned by l1Ie
`retrieved tissues_ It
`\Vas also possible to confirm this conclusion by III sf", hybridil.3tion.
`Interestingly, several joints receiving (he control cells also gave positive RT-PCR and protein signals.
`TIle results of rigorous control experiments suggest that these are not false positives.
`CONCLUSIONS It is possible to tiJnsfer genes to human rheumatOid joints and to express them
`intraarticuIarly. The first p:ltient received her genes nearly Ihrce )'ears ago and neither she, nor any
`other participant, has experienced adverse events related to Ihe gene transfer protocol. TIle
`dcteclion of transgene expression in control joints adjacent to Ihose receiving the gene remains an
`It may suggest
`unexplained observation.
`the existence of communication channels lx-tween
`adjacent, severely diseased joints, or the ability of injected cells to migrate interarticularly.
`Supponcd by NIH grdnl RO I AR43623
`
`Disclosure: work reportcd In this abstract was supported by:
`
`5170
`
`MEDAC Exhibit 2005
`ANTARES v. MEDAC
`IPR2014-01091
`Page 00001