`
`OFFICIAL JOURNAL. OF THE AMERICAN SOCIETY OF TRANSPLANTATION
`AND THE AMERICAN SOCIETY OF TRANSPLANT SURGEONS
`
`‘
`
`AS I s
`
`-
`
`
`
`
`
`
`SUPPLEMENT 1
`
`0 VOL 1
`
`0 2001
`
`
`
`Breckenridge Exhibit 1115
`Luan
`
`Page 1
`
`

`

`
`
`Puma“:
`JOINT SESSION
`
`Abstract# 428
`SIROLIMUS PREVENTS TUMOR PROGRESSION: mTOR
`TARGETING FOR THE INHIBITION OF NEOPLASTIC
`PROGRESSION. Fulung Luan,‘ Mary Maluccio.2 Vijay K. Sharma.‘
`Minoru HojoJ Milagros Lagman.‘ Manikkam Suthanthiran.‘
`’Nep[urology/Transplantation Medicine. New York Presbyterian
`Hospital, Weill Medical College of Cornell University, New York. NY;
`2.S‘urgery. New York Presbyterian Hospital, Weill Medical College of
`Cornell University. New York. NY.
`Post-transplant malignancy is a life-threatening complication. Immunosuppressive
`drug induced impolnnerus in host-immune effector mechanisms are considered to be
`the prime mechanisms. This paradigm has been challenged by the report that
`cyclosporine (CSA) can promote tumor progression independent of its effect on
`the host immune cells and by a cell autonomous mechanism. The universality of
`this mechanism was investigated by exploring the effect of lacrolimus and sirolimus
`on tumor progression. SClD-beige mice that lack functional T—cells. B-cclls and NK
`cells were used as the tumor bearing host. and a renal carcinoma was used as the tumor
`lnoculum. The impact of these two immunosupptessants was diametrically opposite.
`Whereas tacrolimus (4 mg/kg. QOD. SQ) increased the number of pulmonary renal
`cancer metastases (p<0.05). Bonfcrroni p value). slrolimus (4 mg/kg, QOD.SQ)
`prevented pulmonary metastasis (p<0.001). Furthermore. the increase in metastases
`observed with CSA (20 mg/kg/QOD/SQ) was completely prevented by simlimus
`(p<0.001). The dramatic effect of sirolimus was also evident in the immunooompetent
`BALE/c mice. Tacrolimus (p<0.001) us well as CSA (p<0.001) increased the number
`of pulmonary renal cancer cell metastases, and sirolimus (p<0.00l) prevented
`metastases in the BALE/c mice as it did in the SCID-bcige mice. Sirolimus (p<0.01)
`also prevented pulmonary metastasis in the GSA-treated BALE/c mice and in the
`highly malignant intrarenal cancer model. Survival experiments showed prolongation
`following sirolimus treatment of tumor-inoculated SCID~beige mice (p<[].01) or
`BALB/c mice (p<0.01). Studies to explore mechanism for the salutary effects of
`sirolimus showed:
`l) a reversal of the invasive phenotype of renal cancer cells
`(ascertained by scanning electron microscopy): 2) reduction in cell-division
`(determined by flow cytometric analysis of CFSE-loaded cancer cells); and 3)
`promotion of apoptosis (enumerated by flow cytometry). Our studies demonstrate
`that sir-olimus has a diametrically opposite effect to that of calcineurin inhibitors on
`tumor progression. The unlinking of immunosuppression needed for allograft
`protection from mechanisms constraining neoplasia progression opens new avenues
`for the prevention and/or management of post-transplant neoplnsia.
`
`Abstract#429
`AND
`NEORAL”
`WITH
`FTY‘720
`COMBINED
`CORTICOSTEROIDS IS EFFECTIVE AND SAFE IN
`PREVENTION OF ACUTE REJECTION IN RENAL ALLOGRAFT
`RECIPIENTS (INTERIM DATA). Hello Tcdesco.‘ Barry Kahan,2
`Georges Mourad? Yves Vanrcntcrghem,4 losep Grinyo,’ Willem
`Weimar.“ Pascale Pellet,’ Lawrence Chodoff,I Tomasz Sablinski.“
`'HarpitaI do Rim e do Hipertensao. Sao Paulo, Brazil; ”Univ of
`Texas. Houston,- 3I-lopitnl Lapeyronie, Montpellr'er. France: 4U. 2.
`Gasthuisberg, Leuven, Belgium; 5Hospt'tal Ciudad Sanitaria de Bellvitge.
`Barcelona, Spain; ‘Academirch Ziekenhnis Rotterdam, Rotterdam. The
`Netherlands; 7Novartis Pharma AG, Basel. Switzerland; ”Navarzis
`Pharmaceuticals Corp, East Hanover.
`Fl‘Y720 is a potent immunomodulator with unique effects on lyn'lphocyte hunting.
`Methods: Multicenter, randomized, open—label dose finding study to evaluate safety.
`tolembility and preliminary efficacy of FTY720 vs. mycophenolnte mofctil (MMF)
`with Neoral“ and corticosteroids (CS) in de novo renal transplantation. Adults aged
`.18-65 undergoing primary cadaver or living donor (non-HLA identical) renal
`transplantation, who exhibited good allograft function during the first 12 hours
`post-transplant. were randomized to one of four regimens of F'I'Y'IZO (loading dose
`[LD] on Day I. followed by a once daily maintenance dose). or to MMF 2 gar/day. All
`patients received concurrent Neoral 4- CS per center standard. Induction with
`antilymphocyte antibodies (Ab) or anti-IL-2Rot Ab was not allowed. W. 209
`patients were enrolled. and preliminary efficacy data are available for 159 patients
`who completed at least 30 days on study.
`Trutmcnt‘
`Number (9-) Blurry-confirmed Acute Rejection
`Frvno 1mg LD + 0.25.21; on
`3139 (20.5%)
`Fl'Y'l'lD 2mg H) + 0.5m; QD
`13137 (35.1%)
`W720 4mg LD + LOml QD
`4110 (20.0%)
`mm 4mg LD + 2.5m; QD mi (3.5%)
`MMF 2 gin/day
`5/35 (14.3%)
`5313-41 FTY720 was well tolerated. Episodes of transient bradycnrdia without
`symptoms or sequelac. most of which occurred within first Mb postvtransplnnl. were
`reported in 1 1/124 (8.9%) of FI'Y720~u-eated patients vs. 2.135 (5.7%) ofMMF-treated
`patients. Graft survival is 99% (one graft loss in the MMF group) and patient survival
`is 100%. mm: Preliminary analysis indicates that FTY720 appears to be
`
`PLENARY: JOINT SESSION
`
`effective in the prevention of acute rejection in de novo renal transplant patients
`when used with Neoral and CS. Additional trials are underway to evaluate the role
`of FTY720 in the prevention of acute rejection and graft loss after renal
`transplantation.
`
`Abstract# 430
`ICOS/B7RP-l COSTIMULATION IN ACUTE AND CHRONIC
`ALLOGRAFT REJECTION. Engin Ozkaynak,‘ Wei Gao.‘ Nida
`Shemmeri.‘ Chi Wang,‘ Anthony J. Coyle,‘ Wayne W. Hancock.‘
`‘Millenm'um Pharmaceuticals. Inc, Cambridge. MA.
`In vitro data show activation of primary T cells requires CD28IB7 costimulation but
`effector Tcell functions are CD28/B‘7-independem. In addition, oostimulation blockade
`with Cl‘LA4-Ig or CD 154 rnAb causes prolonged graft survival but chronic rejection
`intervenes. indicating additional costimulatory pathways are active in vivo. We
`present data on the role of inducible oostimulatory molecule (ICOS) and its ligand.
`B7RP-1. in transplantation ('1'x). Serial Nonhems showed that whereas normal heart
`lacked ICOS mRNA. inn-agraft expression was detected by 5d and peaked at rejection
`at 7d in unmodified BALE/c->BL/6 mouse cardiac allograft recipients:
`immunohistology with a blocking rat anti-mICOS mAb (12M!) localized ICOS to
`infiltrating T cells. Therapy with 12M}. but not an isotype-matched. non-blocking
`tat anti-mICOS mAb (15F9). prolonged graft survival (20:1 d vs. 7—8d. respectively.
`p<0.001). and in ongoing studies. a mICOS-lg fusion protein prolonged survival to
`>18d (p<0.01). Molecular assays of 7d grafts showed that compared to controls, anti-
`lCOS mAb suppressed intragraft expression ofIFN-‘y. IL-10 and multiple chemokines
`and their receptors. Mice dented with a subtherapeutic course of CsA rejected their
`allografts by 10d. as did mice treated with IgG/low CsA, whereas allografts in
`recipients heated with anti-ICOS mAb/low CsA are currently >60d post-TX (p<0.001).
`A role for ICOS in chronic rejection was also assessed; allografts were perforated in
`conjunction with CD154 mAh (250 pg. 1.17. at Tx) plus anti-ICOS or control [gG
`therapy (500 ttg/d. bid. i.p., for 14 d). and were harvested at 30d post-Tit. Scoring of
`elastin.stained allografts [>6lgroup) showed IgG-treated controls had severe Tx
`arteriosclerosis (4.4 i 0.6. mean 1: SD) whereas vessels were largely normal post-
`ICOS mAb (0.2 10.1. p<0.001). and the myocatdium was well preserved. In summary.
`we show that (i) ICOS is involved in acute rejection; (ii) targeting lCOS/B'lRP-l
`interactions prolongs allograft survival and suppresses intt'agraft cytokine expression
`and T cell activation; (iii) the beneficial effects of blocking ICOS/B7RP-l
`costimulution are not impaired by concomitant CSA therapy; and (iv) ICOS-dependent
`costimulation plays a key role in the development of Tx arteriosclerosis, including
`after interruption of CD4OICD154 signaling. Hence, our data demonstrate for the first
`time a key role of the ICOS/BTRPJ pathway in acute and chronic alloresponses.
`
`Abstract# 431
`TWO-YEAR INSULIN INDEPENDENCE AND METABOLIC
`FOLLOW-UP AFTER ISLET-ALONE TRANSPLANTATION IN
`AUTOIMMUNE DIABETES. A. MJ. Shapiro.‘ E. A. Ryan,l R. V.
`Rajotte,‘ G. S. Korbutt.‘ T. Kin.I K. O'Kelly.‘ G. L. Wamock.‘ D. L.
`Bigam.‘ N. M. Kneteman.‘ l. R.'1'. Lakey.‘ 'Surgery, University of
`Alberta, Edmonton, AB, Canada.
`Purpose: To evaluate longer-term outcomes of islet-alone transplantation in
`autoimmune diabetes.
`Methods: 15 consecutive patients with longstanding Type 1 diabetes underwent
`islet-alone transplantation with ABO~compatiblc cadaveric islets infused
`intraportally by percutaneous access. Steroid-free immunusupprcssion consisted of
`daclizumab induction with maintenance sirolimus and low-dose lacrolimus.
`Results: Median follow-up is 17.6 months [first 7 patients) and 8.5 months overall.
`with the longest patient remaining off insulin for 21 months currently. All patients
`have sustained insulin production (C—peptide meal: mean 1.99 :t 0.2 pie. rising to
`3.90 10.7 ng/ml at 90 min). 12/15 patients are free ofinsulin currently (4 have normal
`glucose tolerance). 7115 have a stable form of type 11 diabetes controlled with oral
`hypoglycemic agents and occasional low doses of insulin (<10 units/day). and 1/15
`awaits a second islet infusion. All patients have required more than one pancreas
`donor (mean islet mass 11,437 Elkg). There have been no episodes of CMV infection
`(mismatches in 8/15 cases). There have been no cases ofI’l'LD, malignancy or serious
`infection to date. Mean serum creatinine was unchanged pro-transplant vs current
`(1.1 pro vs 1.1 mgldl). although 2 patients with inadequate pro-transplant clearance
`had post-transplant elevation which has improved by withdrawal of tacrolimus and
`replacement with mycophenolate.
`Mean HbAlC was completely canceled by islet transplant (mean 8.9% pre vs 5.6%
`(3 mo). 5.7% (6 mo) and5.6% (12 mo)). IVG’I‘T data indicate that acute insulin response
`(AIRg) was consistently maintained for up to 12 months of available follow-up, with
`no evidence of deterioration in function over time (no acute rejection and no
`autoimmune recln'tence). The increment in Ale was more marked after the subsequent
`transplant than after the first (0.12 10.1 initial vs 2.42i0.6 mU/ml subsequent. p<0.0l).
`suggesting that the initial transplant may have facilitated engraftment of the
`subsequent graft.
`'
`Conclusions: Sustained long-term independence from insulin can be achieved with
`low risk in patients undergoing islet-alone transplantation using a steroid-free
`immunosuppressive protocol.
`
`243
`
`Breckenridge Exhibit
`
`1115
`Luan
`
`Page2
`
`