9/26/2018 TRIALS, TRIBULATIONS, Tregs ... NO RELEVANT DISCLOSURES + DISCUSSION OF EXPERIMENTAL TOLERANCE INDUCTION PROTOCOLS Sandy Feng, MD, PhD September 20, 2018 PATIENTS WANT TRANSPLANTS WITHOUT IMMUNOSUPPRESSION PATIENTS WANT TRANSPLANTS WITHOUT IMMUNOSUPPRESSION Tolerance Graft survival Allard J et al., Transplantation Direct 2017 Allard J et al., Transplantation Direct 2017 1
9/26/2018 CONCEPTUALLY SIMPLE • Bone marrow/stem cell transplant recipients for hematologic malignancies can accept a kidney from their bone marrow donor without immunosuppression • Create a chimera of recipient and donor Acceptance of donor bone marrow acceptance of Stanford donor kidney CHIMERISM MGH Northwestern BUT DIFFICULT TO ACHIEVE BUT DIFFICULT TO ACHIEVE Chimerism Chimerism Kidney Kidney Rejection Rejection GvHD GvHD Infection Infection Host Host Donor Donor Current approaches to mixed chimerism have not achieved the optimal donor-recipient balance 2
9/26/2018 INTRAHEPATIC TOLERANCE MECHANISMS IMMUNOSUPPRESSION WITHDRAWAL SINGLE CENTER REPORTS OF CLINICAL MANIFESTATIONS OF THE TOLEROGENIC LIVER “TOLERANT” LIVER TRANSPLANT RECIPIENTS Biopsy • Livers are the only organ that is transplanted without Adult or DD vs Time from LT to Tolerant* Center Year N Pediatric LD ISW (yrs) N (%) Pre Post cross-matching. Pittsburgh 95, 97, 07 95 Both DD 8.4 ± 4.7 Y N 18 (19%) Susceptible to antibodies against blood type antigens London/King’s 98, 07 18 Adult DD 7 (5-11) N N 2 (11%) Murcia 03,09 20 Adult DD 3.4 ± 2.2 Y N 8 (40%) But resistant to antibodies against HLA antigens Rome 06, 08, 14 34 Adult DD 5.3 ± 1.7 Y Y 7 (20%) New Orleans 05 18 Adult DD >0.5 per protocol N N 1 (6%) • Recipients of livers, compared to those of other organs, Winnipeg 07 26 Adult DD 4.6 ± 1.8 Y Y 11 (42%) require less immunosuppression. Miami 05, 10 104 Adult DD 4.1 ± 0.3 N N 23 (22%) Pamplona 13 24 Adult DD 9.3 (6-13.3) Y N 15 (63%) • Rejection episodes portend less poorly for future graft 02, 07, Kyoto 115 Pediatric LD >2 per protocol N N 49 (42%) survival. 09, 12 02, 07, Palo Alto 38 Pediatric Both 2.9 ± 3.5 N N 17 (45%) • Liver allografts are less susceptible to chronic injury. 09, 12 Taipei 15 16 Pediatric Both 7.8 ± 5.4 Y Y 5 (31%) Levitsky and Feng, Hum Immunol 2018 3
9/26/2018 INCREASED TIME AFTER TRANSPLANT COMPLETED/ONGOING MULTI-CENTER IMMUNOSUPPRESSION WITHDRAWAL TRIALS Benitez et al., AWISH (ITN030ST) Hepatology, 2013 Tolerant Interval since tx ISW Follow-up (months) Tolerant N (%) (months) (months ) Tolerant Yrs since 1-2y after transplant Benitez N % transplant 41/102 (40%) 131 ± 43* 8.0 ± 4.6* 48.9 ± 7.7* N % 2013 HCV+ 5/30 16.7% 3.0-5.7 3/24 12.5% OPTIMAL NA >50 yrs: 3-6 yrs variable NA Non-immune, non-viral 6/46 13.0% 5.7-10.6 19/50 38.0% <50 yrs: >6 yrs >10.6 19/24 79.2% TOTAL 11/76 14.5% LIFT NA variable NA 101 8.2 119.0 WISP-R Feng 2012 12/20 (60%) (72-124)^ (8.1, 8.8)^ (110.0, 122.1)^ Tolerant (N=12) Non-Tolerant (N=7) iWITH 33 / 88 (38%) >6 years 36-48 wks NA 8.4 (6.0-10.3) yrs 6.1 (4.8-6.2) yrs *Mean ± SD ^Median (IQR) RATIONALE FOR TOLERANCE INDUCTION • Spontaneous tolerance emerges years after transplant. Need to accelerate • Approach must balance risks and benefits. Often prohibitive disease severity Requires strong safety profile REGULATORY • Timing is unpredictable. T CELL THERAPY Living donor transplants uncommon 4
9/26/2018 Tregs ARE AT THE CENTER OF Tregs ARE AT THE CENTER OF IMMUNE HOMEOSTASIS AND TOLERANCE IMMUNE HOMEOSTASIS AND TOLERANCE General Immune General Immune Homeostasis IL-15 Homeostasis IL-15 TNF- IL-6 TNF- IL-6 thymic Treg thymic Treg IL-1 IL-1 Activated Acti vated T reg Allergy & Asthma Allergy & Asthma T reg Macrophage IL-23 Macrophage IL-23 AutoAb AutoAb IL-12 Autoimmune Disease Autoimmune Disease IL-12 Ag Ag IFN- IFN- Inflammatory Bowel Disease Inflammatory Bowel Disease MHC/pep MHC/pep TCR TCR naive naive T eff T eff T cell Graft versus Host Disease Graft versus Host Disease T cell B cell/DC Bcell/DC CD3 CD3 Organ Transplantation Organ Transplantation T GF- T GF- IL -10 IL -10 Local Regulation T reg peripheral Treg Local Regulation T reg peripheral Treg A SIMPLIFIED CONCEPT OF TOLERANCE GROWING EVIDENCE THAT Tregs TREG:TEFF BALANCE ARE POTENTIAL THERAPEUTICS • Tregs have efficacy to prevent GvHD • Treg therapy for GvHD does not appear to inhibit anti-tumor responses • Donor-specific Treg therapy does not appear to inhibit responses to viral pathogens or vaccines in mouse models Treg Teff • Can Treg therapy be applied to reduce or eliminate non-specific immunosuppression in humans? Self tolerance Immune protection Induced tolerance 5
9/26/2018 UCSF CLINICAL Treg CELL THERAPY PROGRAM Products Clinical trials Clinical Treg team T1D/I Co-Directors TILT T1D/II Qizhi Tang and Jonathan Esensten PolyTreg T1D Advisor Jeff Bluestone CB-T1D IsletTx Regulatory Jingying Xu, Ashley Leinbach Skin QA cSLE Pemphigus CBTregs Flory Dekovic, Lizzy Lama, disease Alice Tam DART Manufacturing TASK1 Amy Putnam, Angela Lares Kidney Tx ONE Study Safety TRIALS IN Mike Lee, Vinh Nguyen, Mixed arTreg Karim Lee, Joey Leung deLTa chimerism QC Subclinical KIDNEY Weihong Liu, Alyssa Mullenix TASK LITTMUS ARTEMIS Liver Tx Inflammation completed ongoing planning UCSF POLYCLONAL Treg PRODUCTION Expansion 5 10 4 10 #1: Polyclonal #2: Polyclonal Harvest; 3 CD25 10 -CD3/28 beads CD3/28 Beads Release assays 0 3 4 5 0 10 10 10 CD127 ONE Study Safety TRIALS IN Release criteria parameters CD4 CD8 FOXP3 Subclinical KIDNEY criteria >95% <5% >60% TASK Inflammation Putnam et al., Diabetes 2009; FDA Master File 17507 6
9/26/2018 TASK PILOT UCSF POLYCLONAL Treg EXPANSION TregA DOPTIVE THERAPY FOR S UBCLINCAL INFLAMMATION IN K IDNEY TRANSPLANTATION expansion yield identity/purity – FOXP3 Subclinical inflammation in 2048 1.5×10 10 6m protocol biopsy 1024 1.3×10 10 Fold expansion Total Treg produced 512 1.0×10 10 256 • Re-biopsy in 7.5×10 9 128 14d 5.0×10 9 64 • PolyTreg 400+/-100 million n=15 Infused Tregs in 32 2.5×10 9 circulation 16 • Biomarkers 0.0 PolyTreg Potency Putnam et al., Diabetes 2009; FDA Master File 17507 Chandran et al., AJT 2017 TASK PILOT TASK PILOT BIOPSIES TregA DOPTIVE THERAPY FOR S UBCLINCAL INFLAMMATION IN K IDNEY TRANSPLANTATION Tregs Baseline 2 weeks 6 months Subclinical inflammation in 337.2 126.1 CD45+ cells/mm 2 18.9 6m protocol biopsy Pt 1 • Re-biopsy in 14d PolyTreg 400+/-100 million n=15 • Infused Tregs in Urine biomarkers circulation Cxcl9 Cxcl10 • Biomarkers Normalized Cxcl9 conc. (pg/ml) Normalized Cxcl10 conc. (pg/ml) 469.1 303.5 74.9 400 250 Pt 2 200 300 150 200 Pt 1 Pt2 Pt3 100 100 50 Age 62 58 46 0 0 g g g g e e Membranous r e r e r r T T T T - - - - e s t r e s t ESRD cause ? Hypertensive GS FSGS P r o P o P P glomerulonephritis 278.0 454.4 514.0 Pt 3 Immunosuppression Basiliximab; Tac, MMF, prednisone 6 month bx i1, t1, ti2 i0, t1, ti1 i1, t1, ti1 PolyTreg dose 320 x10 6 318.9 x 10 6 363.8 x10 6 Chandran et al., AJT 2017 Chandran et al., AJT 2017 7
9/26/2018 PK OF INFUSED POLYCLONAL Tregs 59.8% 60 %Enrichment 40 20 0.0% 0 Macallan, et. al, Nat. Prot. 2009 unlabled Labeled T1D 002-015 % Deuterium enrichment 8 T1D 007-103 in circulating Tregs T1D 002-017 6 TASK002 TASK003 TRIALS IN deLTa Safety 4 TASK004 2 ARTEMIS Minimization LIVER 0 LiTTMUS Tolerance 0 7 14 21 28 Day Post Infusion Chandran et al., AJT 2017 HOKKAIDO TRIAL: DONOR-SPECIFIC Treg PRODUCTION Lymphocytes aCD80 mAb aCD86 mAb Donor Irradiate Frozen until Co-culture use 2 weeks Cultured LDLT 1-to-4 wks cells before LT Infusion TRIALS IN deLTa Safety Recipient ARTEMIS Minimization LIVER Day -1 Day 0 Day +13 LiTTMUS Tolerance Todo et al. Hepatology 2016 8
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