Selective decrease of donor-reactive Tregs after liver transplantation limits Treg therapy for promoting allograft tolerance in humans

Qizhi Tang; Joey Leung; Yani Peng; Alberto Sanchez-Fueyo; Juan Jose Lozano; Alice Lam; Karim Lee; John R. Greenland; Marc Hellerstein; Mark Fitch; Kelvin W. Li; Jonathan H. Esensten; Amy L. Putnam; Angela Lares; Vinh Nguyen; Weihong Liu; Nancy D. Bridges; Jonah Odim; Anthony J. Demetris; Josh Levitsky; Timucin Taner; Sandy Feng

doi:10.1126/scitranslmed.abo2628

Selective decrease of donor-reactive T_regs after liver transplantation limits T_reg therapy for promoting allograft tolerance in humans

Qizhi Tang^*, Joey Leung, Yani Peng, Alberto Sanchez-Fueyo, Juan Jose Lozano, Alice Lam, Karim Lee, John R. Greenland, Marc Hellerstein, Mark Fitch, Kelvin W. Li, Jonathan H. Esensten, Amy L. Putnam, Angela Lares, Vinh Nguyen, Weihong Liu, Nancy D. Bridges, Jonah Odim, Anthony J. Demetris, Josh LevitskyTimucin Taner, Sandy Feng^*

^*Corresponding author for this work

Medicine, Hepatology Division

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (T_regs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive T_reg (darT_reg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darT_reg infusion, 5 received darT_regs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 10⁶ cells. darT_reg infusion was not associated with adverse events. Two darT_reg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darT_regs. Mechanistic studies revealed generalized T_reg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of T_reg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

Original language	English (US)
Article number	eabo2628
Journal	Science translational medicine
Volume	14
Issue number	669
DOIs	https://doi.org/10.1126/scitranslmed.abo2628
State	Published - Nov 2 2022

Funding

Acknowledgments:W ethankthefollowingindividualsfortheircontributiontothestudy: J.A.Bluestoneforhisadviceduringthedesignofthistrial;T .Sledgeforoverallmanagement andcoordinationoftheclinicaltrial;J.Goldsteinforregulatorysupport;D.Ikle,M.Sever,and K.Spainforstatisticalsupport;S.Blaschka,B.Block,A.Daud,J.G.Hanson,K.Harish,and D.Jakoubekforclinicaltrialadministra tion, conduct,andcoordinationatUCSF ,MayoClinic,and NorthwesternUniversity;L.Acevedo,F .Dekovic,G.Guinti,E.Lama,M.R.Lee,A.S.Leinbach, L. Masiello, B. R. Shy, A. Tam, and J. Xu for support of Treg manufacturing and Treg manufacturing database design and maintenance; J. Du for management of the UCSF Transplantation ResearchLab;F .Vincentiforprovidingpost-kidneytransplantsamples;andA.Shakedfor providingtheA WISH samples.Funding:ThestudyisfundedbyagrantfromNIAID 1U01AI104347(toS.F .andQ.T .). Authorcontributions:Q.T .andS.F .conceptualizedthestudy. N.D.B.andJ.O.providedtrialov ersight. S.F ., T .T ., J.Levitsky,andA.J.D.acquiredclinicaldata. J.H.E.,A.L.P ., A.Lares,K.L.,V .N., andW .L. acquireddarTregmanufacturingdata.J.Leung,A.Lam, andK.L.performedalloreactivefrequencyassays.J.Leungperformedspectralflow.Y .P . performedTCRsequencinganalysis.Y .P ., A.S.-F ., andJ.R.G.performedtheRNA-seq experiment.J.LeungandV .N. isolatedperipheralbloodTregsafterdarTreginfusionfor deuteriumanalyses.M.F .andM.H.quantifieddeuteriuminTregs.S.F ., T .T ., J.Levitsky,andA.J.D. analyzed clinical data. Q.T . and J.H.E. analyzed darTreg manufacturing data. J. Leung, Y .P ., A.S.-F ., J.-J.L.,K.L.,M.F ., M.H.,K.W .L., andQ.T .analyzedmechanisticdata.S.F ., T .T ., andJ.Levitsky interpretedclinicaldata.Q.T .andJ.H.E.interpreteddarTregmanufacturingdata.J.Leung,Y .P ., K.W .L., A.S.-F ., M.H.,andQ.T .interpretedmechanisticdata.Q.T .andS.F .draftedthemanuscript, and all authors participated in the reviewand finalization of the manuscript. Competing interests:Q.T .isaco-founder,shareholder,andscientificadvisorofSonomaBiotherapeutics. Q.T .isaconsultantofeGenesisandQihanBio.Q.T .isacoinventorofthefollowingpatents: “Expansion of alloantigen reactive regulatory T cells” (US9801911B2) and “Regulatory T cells suppressautoimmunity”(US7722862B2).A.L.P .andW .L. arecoinventorsonthepatent“CD127 expressioninverselycorrelateswithFoxP3andsuppressivefunctionofCD4+Tregs” (US9012134B2).S.F .isaconsultantofQuellTherapeuticsandeGenesis.S.F .servesasthechairof DSMBforQuellTherapeutics.A.S.-F .isacofounderandshareholderofQuell Therapeutics. J. Levitsky is an advisor and receives research grant support from Eurofins and Novartis.Theotherauthorsdeclarethattheyhavenocompetinginterests.Dataandmaterials availability:AlldataassociatedwiththisstudyarepresentinthepaperortheSupplementary Materials.RNA-seqdataareavailableinGEO(accessionnumber:GSE208111).ThecelllineK562-hCD40LforgeneratingsBCswasmadeavailabletoQ.T .underamaterialtransferagreement.All requests forother rawandanalyzed dataand materials willbe reviewedby thecorresponding authors to verify whether the request is subject to any intellectual property or confidentiality obligations.Pa tient-r elateddatanotincludedinthepaperweregeneratedaspartofclinical trialsandmaybesubjecttopatientconfidentiality. The study is funded by a grant from NIAID 1U01AI104347 (to S.F. and Q.T.).

ASJC Scopus subject areas

General Medicine

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10.1126/scitranslmed.abo2628

Cite this

Tang, Q., Leung, J., Peng, Y., Sanchez-Fueyo, A., Lozano, J. J., Lam, A., Lee, K., Greenland, J. R., Hellerstein, M., Fitch, M., Li, K. W., Esensten, J. H., Putnam, A. L., Lares, A., Nguyen, V., Liu, W., Bridges, N. D., Odim, J., Demetris, A. J., ... Feng, S. (2022). Selective decrease of donor-reactive T_regs after liver transplantation limits T_reg therapy for promoting allograft tolerance in humans. Science translational medicine, 14(669), Article eabo2628. https://doi.org/10.1126/scitranslmed.abo2628

@article{6889a5f0eba345f6bdf02518155d3eb3,

title = "Selective decrease of donor-reactive Tregs after liver transplantation limits Treg therapy for promoting allograft tolerance in humans",

abstract = "Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.",

author = "Qizhi Tang and Joey Leung and Yani Peng and Alberto Sanchez-Fueyo and Lozano, {Juan Jose} and Alice Lam and Karim Lee and Greenland, {John R.} and Marc Hellerstein and Mark Fitch and Li, {Kelvin W.} and Esensten, {Jonathan H.} and Putnam, {Amy L.} and Angela Lares and Vinh Nguyen and Weihong Liu and Bridges, {Nancy D.} and Jonah Odim and Demetris, {Anthony J.} and Josh Levitsky and Timucin Taner and Sandy Feng",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = nov,

day = "2",

doi = "10.1126/scitranslmed.abo2628",

language = "English (US)",

volume = "14",

journal = "Science translational medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

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Tang, Q, Leung, J, Peng, Y, Sanchez-Fueyo, A, Lozano, JJ, Lam, A, Lee, K, Greenland, JR, Hellerstein, M, Fitch, M, Li, KW, Esensten, JH, Putnam, AL, Lares, A, Nguyen, V, Liu, W, Bridges, ND, Odim, J, Demetris, AJ, Levitsky, J, Taner, T & Feng, S 2022, 'Selective decrease of donor-reactive T_regs after liver transplantation limits T_reg therapy for promoting allograft tolerance in humans', Science translational medicine, vol. 14, no. 669, eabo2628. https://doi.org/10.1126/scitranslmed.abo2628

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T1 - Selective decrease of donor-reactive Tregs after liver transplantation limits Treg therapy for promoting allograft tolerance in humans

AU - Tang, Qizhi

AU - Leung, Joey

AU - Peng, Yani

AU - Sanchez-Fueyo, Alberto

AU - Lozano, Juan Jose

AU - Lam, Alice

AU - Lee, Karim

AU - Greenland, John R.

AU - Hellerstein, Marc

AU - Fitch, Mark

AU - Li, Kelvin W.

AU - Esensten, Jonathan H.

AU - Putnam, Amy L.

AU - Lares, Angela

AU - Nguyen, Vinh

AU - Liu, Weihong

AU - Bridges, Nancy D.

AU - Odim, Jonah

AU - Demetris, Anthony J.

AU - Levitsky, Josh

AU - Taner, Timucin

AU - Feng, Sandy

PY - 2022/11/2

Y1 - 2022/11/2

N2 - Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

AB - Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

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