Safety and viral load changes in HIV-1 infected subjects treated with autologous dendritic cell immune therapy following ART discontinuation (CTN #239) Jean-Pierre Routy M.D. McGill University Paris 21 octobre, 29 1
Treatment strategy with DC therapy ART STI Pre-ART set point Set point Viral load Time ART STI Pre-ART set point Viral load DC Immunotherapy Set point Time 2
Results of DC immunotherapy trials in HIV infection Maturat. HIV Ag Route patients Imm.resp Vir resp Authors None Gp 16, Gag, pol IV 6 3 Kundu 1999 IL-1, IL-6, TNFα Monocyt. condition Auto HIV SC 18 18 8 (8%) Lu 24 Auto HIV SC 12 Garcia 25 TNFα IL-1, IL-6, TNF α Gag, Env, Nef Gag, Env, Nef SC 7 2 Ide 26 IV, SC 18 18 No STI Connoly 28 3
Improving HIV DC immunotherapy Limited activity in DC immunotherapy may be explained by: HIV diversity Insufficient co-stimulation and immune potency To overcome these issues: Use autologous vs. consensus antigens CD4L mrna transfection into DC to enhance CD8 response without CD4 help DC administration while patients on ART DC short-lived: Repeat dosing to maintain response 4
Results from Phase 1 DC immunotherapy trial (n=1) Manufactured at Argos Therapeutics Durham, NC, USA DC transfected with amplified autologous HIV Gag, Nef, Rev,Vpr RNAs (Vpr modified) Perfectly matched to each patient s unique viral antigens Safe and well tolerated Induce CTL response without need for CD4 help 5
Phase 1 immunomonitoring results Difference in Frequency of CD8 and CD4 T Cell Proliferation Pre and Post DC Treatment CD8 CD4 6 Routy et al. In press J Clinical Immunol
Study objectives Safety and tolerability Mean time to VL rebound and peak after STI Mean time to best VL response after STI Change in VL after a 12-week STI: Proportion of subjects with CD4 > 35 and: VL < 1 at 3 time points VL < 1 at 3 time points Change in VL compared to pre-art 7
Eligibility criteria At screening visit: First ART regimen for > 12 weeks VL < 5 copies/ml for 12 weeks Pre-ART plasma: Availability of 1.2 ml VL > 15 copies/ml CD4 > 45 cell/μl CD4 nadir > 2 cell/μl No co-infection or autoimmunity 8
Study Design HIV DC immunotherapy Phase 2a N=24 1 clinical centers AGS-4 DC dosing every 4 weeks 8 weeks 12 weeks ART STI STI & Booster Phase 12 weeks If VL< 1 /ml and CD4> 35 9
Patient characteristics (n=24) Total (N = 24) N 24 Mean Age 4.5 Male 24 (1%) White 23 (95.8%) First nation Canadian 1 (4.2%) 1
Treatment emergent AEs Treatment Emergent Adverse Event Total (N = 24) Subjects with Treatment Emergent AE grade 3 Subjects with Treatment Emergent AE grade <3 Gastrointestinal symptoms Diarrhea Other Constitutional and administrative site symptoms Fatigue Influenza like illness Injection site erythema Injection site induration Injection site pain Clinical laboratory changes Rheumatoid factor > 2 Neurological symptoms Headache Other No HIV-related events observed 24 14 7 7 23 9 7 18 15 7 1 1 9 4 5 11
Viral load dynamics at 12 weeks post STI (n=16) Mean time to: Weeks Viral rebound (>5) 4.5 Peak VL 7.9 VL and CD4 Changes Mean Change of VL from pre ART 1.13Log ( 8%) (N=13 responders) Mean CD4 at screening 663 (366 123) Best VL response (13/16 with reduced VL) 1.1* Mean CD4 at STI start 644 (383 995) CD4 at 12 weeks of STI 521 (243 935) *4 weeks after last dose; Consistent with requirement for continued monthly dosing in the presence of viremia 12
Changes in VL after 12 weeks of STI 1.47.5 ** *.3 * * * * * *.7 11 5 11 8 11 3 11 9 11 2 25 3 11 11 25 1 24 2 24 1 21 2 23 1 22 2 23 2 2 1 22 1.5.41.12.17.28.63.62.71 1.98 1.14 1.34 1.5 1.5 2 1.7-5.1 *Protective HLA allele (B27, B57, or B51) *Susceptibility HLA allele (B45 or B35) 13 ΔLOG (Pre-ART compared to 12 Weeks of STI)
14 12 1 8 6 4 2 Patient 11-5: boosting strategy 12 weeks ART 38 weeks ART 5 45 Pre-ART VL 4 35 3 25 2 15 1 5 CD4 Counts Wk (Dose) Wk2 Wk4 (Dose) Wk6 Wk8 (Dose) Wk1 Wk12 (Dose) Wk14 (Int) Wk16 (Dose) Wk18 Wk2 (Dose) Wk22 Wk24 Wk26 Wk28 (Dose) Wk3 Wk32 Wk34 Wk36 Wk38 Wk4 (Dose) Wk42 Wk44 Wk46 Wk48 Wk5 Wk52 Wk54 Wk56 Wk58 Wk6 Wk62 Wk64 Viral Load (Copies/mL) CD4 nadir = 1 7 DC administered i.d. Patient ID HLA-A HLA-B HLA-Bw HLA-Cw DQB1 DRB1 AGS-4-1-11-5 11 81 6, 6 71 21, 32 31, 44 14
Patient 11-2: VL rebound 12 weeks 14 12 ART ART 16 weeks Pre-ART VL 3 25 1 8 6 4 2 2 15 1 5 Wk (Dose) Wk2 Wk4 (Dose) Wk6 Wk8 (Dose) Wk1 Wk12 (Dose) Wk14 (Int) Wk16 (Dose) Wk18 Wk2 (Dose) Wk22 Wk24 Wk26 Wk28 (Dose) Wk3 Wk32 Wk34 Wk36 Wk38 Wk4 Wk42 Wk44 Wk46 Wk48 Wk5 Wk52 Wk64 CD4 Count Viral Load (Copies/mL) CD4 nadir = 1 7 DC administered i.d. Patient ID HLA-A HLA-B HLA-Bw HLA-Cw DQB1 DRB1 AGS-4-1-11-2 O111, 111 O81,3511 6,6 O4171 O53,63 131,14BCAD 15
6 5 4 3 2 1 Patient 11-8: CD4 T cells decrease 12 weeks ART 16 weeks ART 2 Pre-ART VL 18 16 14 12 1 8 6 4 2 CD4 Counts Wk (Dose) Wk2 Wk4 (Dose) Wk6 Wk8 (Dose) Wk1 Wk12 (Dose) Wk14 Wk16 Wk17 (Int) Wk19 (Dose) Wk21 Wk24 (Dose) Wk26 Wk27 Wk28 Wk29 Wk32 Wk33 Wk35 Wk37 Wk39 Wk41 Wk43 Wk45 Wk47 Wk49 Wk51 Wk53 Wk55 Viral Load (Copies/mL) CD4 nadir = 1 7 DC administered i.d. Patient ID HLA-A HLA-B HLA-Bw HLA-Cw DQB1 DRB1 AGS-4-1-11-8 11, 21 811, 5811 4, 6 32, 71 21 31 16
Patient 22-2: 12 weeks 1 14 ART 22+ weeks 9 8 12 7 6 5 4 3 1 8 6 4 2 1 2 Wk (Dose) Wk2 Wk4 (Dose) Wk6 Wk8 (Dose) Wk1 Wk12 (Dose) Wk14 (Int) Wk16 (Dose) Wk18 Wk2 (Dose) Wk22 Wk24 Wk26 Wk28 (Retest) Wk3 (Retest) Wk32 (Dose) Wk34 Wk36 CD4 Count Viral Load (Copies/mL) CD4 nadir Pre-ART VL = 1 7 DC administered i.d. Patient ID HLA-A HLA-B HLA-Bw HLA-Cw DQB1 DRB1 AGS-4-1-22-2 61, 31 811, 41 6,6 34, 72 32 41, 44 17
Patient 11-9: 12 weeks 8 ART 42 weeks 25 7 6 5 4 3 2 1 2 15 1 5 Wk (Dose) Wk2 Wk4 (Dose) Wk6 Wk8 (Dose) Wk1 Wk12 (Dose) Wk14 (Int) Wk16 (Dose) Wk18 Wk2 (Dose) Wk22 Wk24 Wk26 Wk28 (Dose) Wk3 Wk32 Wk34 Wk36 Wk38 Wk4 (Dose) Wk42 Wk44 Wk46 Wk48 Wk5 Wk52 Wk54 Wk56 CD4 Count Viral Load (Copies/mL) CD4 nadir Pre-ART VL = 1 7 DC administered i.d. Patient ID HLA-A HLA-B HLA-Bw HLA-Cw DQB1 DRB1 AGS-4-1-11-9 261, 3331 451, 5811 4, 6 32, 621 22, 31 71, 111 18
Patient 11-11: 12 weeks 9 ART ART 25 24 weeks 16+ weeks 8 7 Pre-ART VL 2 6 5 4 3 2 15 1 5 1 Wk (Dose) Wk2 Wk4 (Dose) Wk6 Wk8 (Dose) Wk1 Wk12 (Dose) Wk14 (Int) Wk16 (Dose) Wk18 Wk21 (Dose) Wk23 Wk24 Wk26 Wk29 (Dose) Wk32 Wk34 Wk36 Wk38 Wk4 (ART Wk42 (ART Wk44 Wk45 Wk48 Wk5 Wk52 Wk54 Wk56 Wk58 CD4 Count Viral Load (Copies/mL) CD4 nadir = 1 7 DC administered i.d. Patient ID HLA-A HLA-B HLA-Bw HLA-Cw DQB1 DRB1 AGS-4-1-11-11 11, 21 81, 353 6, 6 41, 71 21, 31 31, 114 19
Patient 23-2: 12 weeks 8 ART 2+ weeks 14 7 Pre-ART VL 12 6 5 4 3 2 1 8 6 4 1 2 Wk (Dose) Wk2 Wk4 (Dose) Wk6 Wk8 (Dose) Wk1 Wk12 (Dose) Wk14 (Int) Wk16 (Dose) Wk18 Wk2 (Dose) Wk22 Wk24 Wk26 Wk28 (Dose) Wk3 Wk32 Wk34 CD4 Count Viral Load (Copies/mL) CD4 nadir = 1 7 DC administered i.d. Patient ID HLA-A HLA-B HLA-Bw HLA-Cw DQB1 DRB1 AGS-4-1-23-2 31, 32 1811, 443 4, 6 51, 161 21, 22 31, 71 2
Conclusions DC immunotherapy is safe and well tolerated during both ART and STI Demonstrated feasibility in multicenter setting During 12-week STI: 5/16 subjects had VL < 1 at 3 time points 9/16 subjects had VL <1 at 3 time points Need to optimize DC dosing frequency Based on these interim data we are planning a phase 2b randomized placebo-controlled multicenter clinical trial 21
Acknowledgements Université de Montréal Yassine-Diab B Yegorov O Sekaly RP McGill University Boulassel MR Clinical investigators: Jacobson J Angel J Baril JG Gill J Loutfy M Raclis A Smaill F Tremblay C Vezina S Walmsley S National Immune Monitoring Laboratory (NIML), Montréal: Landry C Coutsinos Z Gagnon D Caroline Benoît-Hébert Argos Therapeutics, Durham, NC Healey D Tcherepanova I Chew T Jain R Nicolette C This study has been funded by NIAID, NIH, (No NO1-A1-619), CANVAC-1C and CTN-CIHR #239 and Argos Therapeutics 22