Immunologi mm. Per Ljungman

Interactions of the immune system of donor and host

HLA genes on chromosome 6 HLA klass I HLA klass II

HLA-typing (tissue typing) There are two basic techniques for HLA-typing: Serological HLA-typing (antibody-based typing). Old school! Genomic HLA-typing (PCR-based). PCR-SSP, PCR-SSO, SBT, NGS.

Definition of a ”HLA match” Potential allele match Allele mismatch A*2301 Patient Definition of a ”HLA match” A2 Serological mismatch A9 Serological ”broad antigen” A23 (9) Serological split antigen A*23 Low resolution (DNA) A*2301 High resolution (DNA) level Match

Allele Frequency Data U.S. populations 98%

Skillnader mellan HLA-alleler

Do we have a donor? The best is a matched family donor Only in 25 – 30% of patients

Family investigations Possibilities: 25 % of all patients which are tissue typed have one HLA matched sibling Ca 5 % av of all patients which are tissue typed have one phenotypic HLA matched parent.

Do we have a donor? The best is a matched family donor Only in 25 – 30% of patients Unrelated donors (27 million in registries) Difficult in some populations

Where are the registries for URD?

The HLA lottery 150 billion combinations The distribution of HLA types vary between regions

HLA antigens och alleles (2009 & 2014). (2009) Alleles (2014) A 28 853 2579 B ≈60 1249 3285 C 10 463 2133 DR 24 659 1512 DQA ND 34 51 DQB 9 99 509 DPA 27 37 DPB 6 135 248

Acceptable matches

Probability of finding a matched donor for the next patient depending on the size of the German registry.

Probability of finding a matched donor for the next patient in the american registry depending of ethnic group (NMDP).

Match N= 8-9/12 11 10/12 71 11/12 223 12/12 199 11/12 (n=223): C-MM 70 DPa-MM 123 DQb-MM 30 10/12 (n=71): C+C 7 C+DPa 37 C+DQb 12 DPa+DQb 2DPa 4

Maligna 5y OS 11/12 n=223, 58% 12/12 n=199, 57% 10/12 n=71, 52%

Maligna 5y RFS 11/12 n=223, 55% 10/12 n=71, 50% 12/12 n=199, 49%

Maligna 11/12 5y OS C MM n=70, 62% DPa MM n=123, 57% DQb MM n=30, 54%

Maligna 11/12 5y RFS C MM n=70, 62% DPa MM n=123, 57% DQb MM n=30, 54%

Maligna 10/12 5y OS *

Maligna 10/12 5y RFS *

Patient in need of allogeneic HSCT HLA typing of patient and core family Patient in need of allogeneic HSCT HLA matched relative No HLA matched relative Search for URD HLA matched donor found:Transplantation No HLA matched donor found: haploidentical HSCT, CBU Extended family typing

Do we have a donor? The best is a matched family donor Only in 25 – 30% of patients Unrelated donors (27 million in registries) Difficult in some populations Other family member (haploidentical) Parent, child, sibling Almost everybody has a donor

Survival of CMV seronegative patients; influence of donor serostatus HLA id siblings Unrelated donors CMV pos donor CMV neg donor Ljungman et al Clin Infect Dis 2014

Survival of CMV seropositive patients; influence of donor serostatus Myeloablative conditioning Reduced intensity conditioning CMV pos donor CMV neg donor Ljungman et al Clin Infect Dis 2014

Leukemia therapy 1012 Relapse 109 106 Remission 103 Minimal residual Relapse Remission Minimal residual disease Course 1 Course 2 Course 3 Course 4

What to do? Use the T-cells!

Graft-versus-leukemia (GVL) effekt IBMTR, Horowitz et al-90

Första publikationen om DLI

Tidiga data Lymfocyter gavs i ”bulk” Behandling vid hematologisk relaps Risk för svår GVH Risk för märgaplasi ffa vid KML Utveckling av ”eskalerande DLI” Lägre risk för GVH och märgaplasi

DLI vid maligniteter Hematologiskt recidiv Cytogenetiskt recidiv Kvarvarande MRD mätt med FACS Kvarvarande MRD mätt med molekylära metoder DLI pga kvarvarande recipientceller mätta med chimerismteknik

Olika sjukdomar har olika känslighet för DLI. KML > KLL/Foll NHL > AML/MDS > ALL/DLBCL > Hodgkin/myelom Kombinationer av annan terapi och DLI

Influence of initial cell dose on OS Probability of survival after DLI.Check marks indicate censored patients. (A) In all patients (n = 344); (B) in groups of initial cell dose: group A, less than or equal to 0.2 × 108 MNC/kg (n = 98, dotted line); group B, 0.21 to 2.0 × 108 MNC/kg (n = 107, thin line); group C, more than 2 × 108 MNC/kg (n = 93, thick line). Cesare Guglielmi et al. Blood 2002;100:397-405 ©2002 by American Society of Hematology

Varifrån kan man ta produkten? Från PBSC skörden Från lymfaferes Spelar det någon roll?

Effekt av DLI inducerad GVH på OS

Andra indikationer Vända hotande rejektion Behandla svåra virusinfektioner

Effect of CTL Uhlin et al CID 2012

Multi-specificity T-cells Leen AM. Blood 2013

Multi-specificity T-cells Leen AM. Blood 2013