Definition of HLA-DP permissiveness in HSCT: from amino acid polymorphism to Functional Distance among HLA-DPB1 alleles

Transcription

1 Definition of HLA-DP permissiveness in HSCT: from amino acid polymorphism to Functional Distance among HLA-DPB1 alleles Pietro Crivello Institute for Experimental Cellular Therapy University Hospital Essen Rio de Janeiro

2 HLA mismatches in Stem Cell Transplantation Graft versus Host Disease (GvHD) Graft versus Leukemia (GvL) Leukemia GvL Patient HLA mismatches Donor Alloreactive T cells Healthy tissues GvHD Rejection Major targets of alloreactivity post-transplantation

3 Permissive mismatches: limited alloreactivity Permissive Mismatches HLA matched HSCT Relapse Disease Control Acceptable Toxicity GvHD HLA mismatched HSCT Strength of the alloreactive T cell response

4 HLA-DPB1 as window of opportunity to permissive mismatches in SCT HLA-DPB1 mismatches High GvHD Low Relapse No effect on Overall Survival Shaw et al Blood 2007

5 HLA-DPB1 matching in allogeneic stem cell transplantation DP DQ DRB3/4/5 DRB1 B C A 8/8 high expression loci Recombination hot spot Low expression loci (LEL) Weak linage disequilibrium between HLA-DPB1 and the other loci due to an hot-spot of recombination between HLA-DP and HLA-DQ loci. (Cullen et al Am J Hum Genet 1995) More than 80% of unrelated donor SCTs are performed across HLA-DPB1 mismatches. (Petersdorf et al Blood 1001; Fleischhauer et al Lancet 2012) HLA-DP alloantigens are target of GvL or GvHD mediated by alloreactive T cells. (Rutten et al Leukemia 2008, BBMT 2013; Gaschet et al J Clin Invest 1996, BMT 1998)

6 The HLA-DP alloantigens HLA-DP HLA class II DPA1 Polymorphism 67 alleles encoding for 29 proteins α-chain DPA1 β-chain DPB1 DPB1 Polymorphism 1014 alleles encoding for 692 proteins IMGT-HLA Databank release

7 T cell epitope (TCE) groups and TCE matching TCE groups defined by T cell crossreactivity Permissive (66%) inside the same TCE group HLA-DPB1* T Cell Epitope (TCE) groups T cells 10:01 17:01 others TCE1 recognized by ALL Alloreactive to HLA-DPB1*09:01 (DP9) 03:01 14:01 others 02:01 04:01 04:02 others TCE2 recognized by SOME TCE3 recognized by NONE Non Permissive (33%) across different TCE groups 72/692 encoded HLA-DPB1 proteins Zino et al Blood 2004

8 High T cell alloreactivity in-vitro against non-permissive TCE mismatches Standard mixed lymphocyte reactions Response to single HLA-DP antigen in HeLa Sizzano et al Blood 2010, Meurer et al Front Immunol under second review

9 Clinical impact of TCE matching Non permissive mismatches confer higher risk of mortality after HSCT P=0.10 Relapse incidence: Similar protection for both permissive and non-permissive P=0.002 P< Non-relapse mortality: Higher risk for non-permissive N= 5428 UD-HSCT (10/10) Years after Transplantation Years after Transplantation Fleischhauer et al Lancet Oncol 2012

10 HLA-DPB1 permissive mismatches as the best option HLA-DPB1 matched Relapse HLA-DPB1 Permissive Mismatches Disease Control Acceptable Toxicity GvHD Non-permissive HLA-DPB1 mismatch Strength of the alloreactive T cell response

11 Further reports on the effect of TCE matching in SCT Similar predictive value of TCE mismatches was observed in other different single and multicenter studies (Pidala et al Blood 2014, Moyer et Human Immunol 2017, Martin et al Blood 2017, Morishima et al Blood 2018) Value of TCE mismatches was also shown in the presence of in vivo T cell depletion (Oran et al Blood 2018) Identification of permissive TCE mismatches in donor search in 59-70% of the cases (Tram et al BBMT 2015)

12 TCE matching available online and on registry platforms Implemented by donor registry

13 Molecular insights into HLA-DPB1 T cell alloreactivity 12 point mutants at 10 polymorphic amino acid positions Wild-type HLA-DP9 Pocket 4 Pocket 9 Response of 17 T cell effectors Val 8 Pocket 1 Crivello et al BBMT 2015

14 Insights into HLA-DP alloreactivity Peptide contacts Impact on T cell Alloreactivity Non conservative residues Crivello et al Blood 2016

15 From FD scores of the amino acids to scores of the entire allele FD aa FD allele = Sum of each FD aa Crivello et al BBMT 2015

16 In silico prediction of any known and new allele TCE v1.0 TCE v2.0 FD-based classification of all HLA-DPB1 alleles TCE based on crossreactivity 72/675 (10.6%) TCE classified TCE1 FD < 0.6 TCE2 0.6 < FD > 2.00 TCE3 FD > /675 (100%) TCE classified In-silico prediction of TCE groups Crivello et al BBMT 2015

17 TCE v1.0 and v2.0 in comparison Cross-tabulation TCE-X (v1.0) TCE-FD (v2.0) Non-permissive Permissive Total Non-permissive Permissive Total Cohort (N=2730) AML, ALL, MDS and CML 8/8 HLA matched Discordancies due to re-assignment of HLA-DPB1*06:01 and *19:01 TCE v1.0: group 3 TCE v2.0: group 2 Arrieta-Bolaños and Crivello et al Blood Adv 2018

18 Similar risk prediction in SCT for TCE v1.0 and v2.0 TCE v1.0 TCE v2.0 TRM Non-permissive mismatches vs permissive mismatches multivariate analysis v1.0 v2.0 HR (95% CI) p-value HR (95% CI) p-value OS 1.15 ( ) ( ).028 TRM 1.31 ( ) < ( ) <.001 Relapse 0.93 ( ) ( ).194 cgvhd 1.20 ( ) ( ) <.001 agvhd II-IV 1.16 ( ) ( ) <.001 agvhd III-IV 1.08 ( ) ( ).759 Arrieta-Bolaños and Crivello et al Blood Advl 2018

19 TCE v1.0 and v2.0 online v1.0 72/675 proteins classified (Zino et al Blood 2004) v2.0 all alleles classified (Crivello et al BBMT 2015)

20 Other models to HLA-DP permissiveness Differential expression of HLA-DPB1 due to SNP in the 3 UTR associated with the risk of GvHD (Petersdorf et al NEJM 2015) Clustering of HLA-DPB1 alleles in 2 evolutionary defined groups (DP2 and DP5) associated with outcome of SCT (Morishima et al Blood 2017)

21 Differential expression of mismatched HLA-DPB1 in SCT rs a rs g Low expression High expression Prediction of agvhd G A Petersdorf et al NEJM 2015

22 DP2/DP5 groups and TCE in SCT Two evolutionary defined groups Association of single DP5 mismatches to a GvHD DP2 Linkage to expression polymorphism DP5 DP2 rs a Low expression DP5 rs g High expression Morishima et al Blood 2016

23 TCE groups and HLA-DP expression levels TCE 1 TCE 2 TCE 3 Matching algorithms Fleischhauer et al NEJM 2015 TCE Structural model Expression model (Petersdorf/Morishima) Permissive Non-permissive Patient TCE typing 1/1 1/2 1/3 2/2 2/3 3/3 Donor TCE typing 1/1 1/2 1/3 2/2 2/3 3/3 Low Risk High Risk Not Applicable Patient rs A/A A/G G/A G/G Donor rs A/A A/G G/A G/G

24 TCE and expression models in the clinic Applicability Cohort: 379 SCT for AML, ALL and MDS in Essen Concordance: 36.7% Discordance: 73.3% Meurer et al Front Immunol under second review

25 Conclusions Permissive/non premissive HLA-DPB1 TCE mismatches in SCT are based on evidence on the the role of amino acid polymorphism on T cell alloreactivity. Different studies confirmed the value of the TCE approach at the clinical level for prediction of outcome after transplantation, in particular OS. Prediction can be easily performed on any patient/donor pair by using available online tool as well registry search softwares. Other models based on differential expression or evolutionary defined allele groups can be used to predict GvHD after transplantation. The different models might be partial surrogates of each other and risk association of discrodant pairs need to be investigated.

26 Thank you for the attention Institute for Experimental Cellular Therapy University Hospital Essen Katharina Fleischhauer Esteban Arrieta-Bolaños Meurer Thuja Müberra Ahci Fabienne Maaβen Heba Islam Maryam Mohamaddokht Karin Stempelmann Kopmann Susanne Department of Bone Marrow Transplantation Dietrich Beelen Institute of Transfusion Medicine Peter A. Horn Monika Lindemann Andreas Heinold Falko Heinemann Departement of Hematology, Leiden University Medical Center J.H. Frederik Falkenburg Kees Van Bergen Peter van Balen Michel Kester Stephen R. Spellman Stephanie J. Lee Bronwen E. Shaw Kwang Woo Ahn Hai-Lin Wang

27 Delta FD between patients and donors of SCT Lower ΔFD scores correlate with better survival after HSCT Crivello et al Blood 2016