Treatment of HIV and acute myeloid leukemia by allogeneic CCR5-d32 blood stem cell transplantation Elena Knops / Björn Jensen AREVIR, Cologne 2018
Chapter I .... .... one week before SCT AREVIR, Cologne 2018
Chapter II June 2013 total of 8 courses of 5-azacytidine + 4 donor lymphocyte infusions .... AREVIR, Cologne 2018
Chapter III + CMV, HHV8, HSV Tacrolimus + topical steroids .... - PBMCs - rectal + ileum - bone marrow - CSF AREVIR, Cologne 2018
Chapter IV Tacrolimus + topical steroids ABC/3TC/DTG <20 <20 505 318 .... 2016 2017 2018 <LOD <LOQ <LOQ <LOQ <LOQ <LOQ (884250) (10 Mio) (10 Mio) (3,8 Mio) (2,8 Mio) (15 Mio) in rectal and 1/20 repl 1/10 repl ileum biopsy lymph node qVOA biopsy (CD4 cell count) negative (23 Mio) 63 month after SCT qVOA in humanized mouse negative model (CD4 cell count) AREVIR, Cologne 2018
Chapter V C O - RECEPTOR TROPISM (sample before transplantation, PBMC) # sequencing genotypic prediction phenotypic analysis in Tcells FPR (%) Magi (R5/X4) MT2 (X4) Clone gp120-V3 amino acid sequence reads D1 CTRPNNNTREGIHIGPGRAFFTTGEIIGNIREASC 4 95,78 R5 R5 D2 CTRPNNNTRKSIHIGPGRAFFTTGEIIGNIKEAYC 2 95,64 R5 R5 D3 CTRPNNNTRKSIHIGPGRAFFTTGEIIGNIGEAYC 2 95,64 R5 R5 D4 CTRPNNNTRKGIHIGPGRAFFTTGEIIGNIREASC 2062 77,33 R5 R5 D5 CTRPNNNTRKGITIGPGRAFFTTGEIIGDIRQAHC 4886 30,67 R5 R5 D6 R5/X4 CTRPNNNTRKGIHIGSRKAFFTTGGIIGDIRQAYC 2 10,61 X4 D7 R5/X4 CTRPHTNTRKRIHIGPGRAFFTTGEIIGDIRQAYC 7 1,74 X4 D8 CTKPNNNTRKRIHIGPGRAFFTTGEIIGNIRQASC 2 1,74 R5 R5 D9 R5/X4 CTRPNNNIRKRIHIGPGRAFFTTGEIIGNIREAYC 3 1,16 X4 HxB2V3Bal control R5 51,8 R5 R5 HxB2 control X4 0 X4 X4 Monique Nijhuis, Utrecht, ICISTEM NGS: 0,14 % X4 before transplant AREVIR, Cologne 2018
WB and antibody titers p gp date 68 55 52 40 34 25 18 160 120 41 Architekt Liaison Ag Liaison Ab pos + + + + + + + + + + neg - - - - - - - - - - 02/2013 + + + + + + + + + + 619.53 NonReactive 56.4 06/2014 + - - - - "+/-" - + + + 200.52 NonReactive 60.5 02/2015 "+/-" - - - - "+/-" - + + + 154.32 NonReactive 66.4 07/2015 - - - - - "+/-" - + - - 167.61 NonReactive 50.0 12/2015 - - - - - - - + - - 97.65 NonReactive 53.9 01/2016 - - - - - - - + - - 69.91 NonReactive 43.3 04/2016 - - - - - + - + - - 77.83 NonReactive 53.6 06/2016 - - - - - - - + - - 85.07 NonReactive 52.7 08/2016 - - - - - - - + - - - 09/2016 - - - - - - - + - - - 05/2017 - - - - - - - + - - 79.55 01/2018 - - - - - - - "+/-" - - 57.15 NonReactive - 03/2018 - - - - - - - ((+)) - - 49.05 AREVIR, Cologne 2018
ATI ??? (Analytical treatment interruption) AREVIR, Cologne 2018
ATI • HIV plasma viral load – how often, how long? – depending on remaining size of viral reservoir – what is feasible for logistics? – what is reasonable for the patient? • other parameters (CD4, proviral load,…) • gut biopsies, lymph nodes? • risks of viral rebound: – acute retroviral syndrome – increased risk of HIV transmission (partner) – tropism switch – replenishment of viral reservoir AREVIR, Cologne 2018
viral rebound? • immediate start of ART? • waiting for the immune response? • broadly neutralising Ab? AREVIR, Cologne 2018
Background - the Berlin patient – so far the only person presumed to be cured from HIV by hematopoietic stem cell transplantation (HSCT) from a homozygous CCR5-d32 donor AREVIR, Cologne 2018
Background - the Berlin patient – so far the only person presumed to be cured from HIV by hematopoietic stem cell transplantation (HSCT) from a homozygous CCR5-d32 donor - failed attempts to reproduce cure by HSCT - viral rebound or death due to underlying malignancy AREVIR, Cologne 2018
The whole story (drama in 5 acts) 48y old patient, alive, well and undetectable for HIV (RNA/DNA) over 4 years after allogeneic CCR5-d32 HSCT AREVIR, Cologne 2018
The beginning (prologue) induction consolidation AREVIR, Cologne 2018
The beginning (prologue) induction consolidation AML diagnosis in Jan 2011 AREVIR, Cologne 2018
The beginning (prologue) complete remission of AML induction consolidation AREVIR, Cologne 2018
The beginning (prologue) induction consolidation to avoid interactions with chemotherapy TDF/FTC/RAL AREVIR, Cologne 2018
Chapter I September 2012 female donor, 10 out of 10 HLA- 2 cycles high-dose cytarabine matched CCR5-d32 .... .... one week before SCT AREVIR, Cologne 2018
Chapter I stem cells from female, 10/10 HLA-matched CCR5-d32 donor .... .... one week before SCT AREVIR, Cologne 2018
Chapter I .... .... one week before SCT AREVIR, Cologne 2018
Chapter II during transplant and until today on ART .... AREVIR, Cologne 2018
Chapter III + CMV, HHV8, HSV 10 10 10 0 0 0 .... ................ ................ 2017 <LOD (884250) in rectal and ileum biopsy AREVIR, Cologne 2018
Chapter III + CMV, HHV8, HSV + increased liver values 10 10 10 0 0 0 .... ................ 2017 <LOD (884250) in rectal and ileum biopsy AREVIR, Cologne 2018
Chapter III + CMV, HHV8, HSV Tacrolimus + topical steroids 10 10 10 0 0 0 .... ................ 2017 <LOD (884250) in rectal and ileum biopsy AREVIR, Cologne 2018
Chapter III + CMV, HHV8, HSV Tacrolimus + topical steroids .... ................ 2017 <LOD (884250) in rectal and ileum biopsy AREVIR, Cologne 2018
Chapter III + CMV, HHV8, HSV Tacrolimus + topical steroids .... <LOD (884250) in rectal and ileum biopsy AREVIR, Cologne 2018
Chapter V month 39 40 41 42 after SCT 2016 Mar Apr May Jun ICISTEM (M. Nijhuis, Utrecht): HIV LTR-DNA not detected in >2 Mio PBMCs via ddPCR or qPCR, but positive signals in T-cell subsets: T CM : 0.2 Mio cells (ddPCR) – 6.7cop/10 6 cells T EM : 0.36 Mio cells (qPCR) – 5 cop/10 6 cells AREVIR, Cologne 2018
Chapter V month 39 40 41 42 after SCT 2016 Mar Apr May Jun ICISTEM (M. Nijhuis, Utrecht): HIV LTR-DNA not detected in >2 Mio PBMCs via ddPCR or qPCR, but positive signals in T-cell subsets: T CM : 0.2 Mio cells (ddPCR) – 6.7cop/10 6 cells T EM : 0.36 Mio cells (qPCR) – 5 cop/10 6 cells G. Dunay, Hamburg: Ileum biopsy: 0.1 Mio cells measured: 1/4 replicates positive with LTR-, but negative with gag primers AREVIR, Cologne 2018
Chapter V month 39 40 41 42 after SCT 2016 Mar Apr May Jun ICISTEM (M. Nijhuis, Utrecht): HIV LTR-DNA not detected in >2 Mio PBMCs via ddPCR or qPCR, but positive signals in T-cell subsets: T CM : 0.2 Mio cells (ddPCR) – 6.7cop/10 6 cells T EM : 0.36 Mio cells (qPCR) – 5 cop/10 6 cells G. Dunay, Hamburg: Ileum biopsy: 0.1 Mio cells measured: 1/4 replicates positive with LTR-, but negative with gag primers ICISTEM (J. Martinez-Picado & M. Salgado, Barcelona): qVOA: 23 Mio CD4 + T cells negative (IUPM < 0.031/10 6 CD4 T cells) 0.007 Mio CD45+ cells negative (<143/10 6 CD45+ cells) Ileum biopsy: 0.0297 Mio CD45+ cells negative (<34/10 6 CD45+ cells) Rectum biopsy: AREVIR, Cologne 2018
Chapter V month 39 40 41 42 after SCT 2016 Mar Apr May Jun ICISTEM (M. Nijhuis, Utrecht): HIV LTR-DNA not detected in >2 Mio PBMCs via ddPCR or qPCR, but positive signals in T-cell subsets: T CM : 0.2 Mio cells (ddPCR) – 6.7cop/10 6 cells T EM : 0.36 Mio cells (qPCR) – 5 cop/10 6 cells G. Dunay, Hamburg: Ileum biopsy: 0.1 Mio cells measured: 1/4 replicates positive with LTR-, but negative with gag primers ICISTEM (J. Martinez-Picado & M. Salgado, Barcelona): qVOA: 23 Mio CD4 + T cells negative (IUPM < 0.031/10 6 CD4 T cells) 0.007 Mio CD45+ cells negative (<143/10 6 CD45+ cells) Ileum biopsy: 0.0297 Mio CD45+ cells negative (<34/10 6 CD45+ cells) Rectum biopsy: I. Hauber, Hamburg: mVOA: negative in plasma, negative in histology AREVIR, Cologne 2018
Chapter V Rag#1DD hu-CD3 HIVp24Ag Spleen Liver LN I. Hauber, Hamburg: mVOA: negative in plasma, negative in histology AREVIR, Cologne 2018
Chapter V P HENOTYPIC C O - RECEPTOR T ROPISM A NALYSIS (sample before transplantation, PBMC) # sequencing genotypic prediction phenotypic analysis in Tcells FPR (%) Magi (R5/X4) MT2 (X4) Clone gp120-V3 amino acid sequence reads D1 CTRPNNNTREGIHIGPGRAFFTTGEIIGNIREASC 4 95,78 R5 R5 D2 CTRPNNNTRKSIHIGPGRAFFTTGEIIGNIKEAYC 2 95,64 R5 R5 D3 CTRPNNNTRKSIHIGPGRAFFTTGEIIGNIGEAYC 2 95,64 R5 R5 D4 CTRPNNNTRKGIHIGPGRAFFTTGEIIGNIREASC 2062 77,33 R5 R5 D5 CTRPNNNTRKGITIGPGRAFFTTGEIIGDIRQAHC 4886 30,67 R5 R5 D6 R5/X4 CTRPNNNTRKGIHIGSRKAFFTTGGIIGDIRQAYC 2 10,61 X4 D7 R5/X4 CTRPHTNTRKRIHIGPGRAFFTTGEIIGDIRQAYC 7 1,74 X4 D8 CTKPNNNTRKRIHIGPGRAFFTTGEIIGNIRQASC 2 1,74 R5 R5 D9 R5/X4 CTRPNNNIRKRIHIGPGRAFFTTGEIIGNIREAYC 3 1,16 X4 HxB2V3Bal control R5 51,8 R5 R5 HxB2 control X4 0 X4 X4 Monique Nijhuis, Utrecht, ICISTEM AREVIR, Cologne 2018
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