aGvHD

Investigating the feasibility of induced pluripotent stem cell (iPSC) banking and transplantation in allogeneic settings

Graft-versus-host disease (GvHD) can result from human leukocyte antigen (HLA) allele mismatch after allogeneic hematopoietic stem cell transplantation (allo-HSCT) where donor T cells recognize mismatched host tissue and induce a severe inflammatory reaction. Novel transplant strategies aim to reduce the consequences of HLA allele mismatch. Induced pluripotent stem cells (iPSCs) are pluripotent stem cells that are made from reprogramming adult cells. As iPSCs have the same properties as embryonic stem cells, they can self-renew and differentiate into all cell types, therefore, collecting homozygous iPSCs could allow for the readily available transplantation of cells from one source into multiple patients, with higher engraftment rates and reduced immunological events. An iPSC banking system that collects HLA-typed cells from cord blood banks, marrow donor registries, and HLA-matched platelet donor registries to be readily available for iPSC transplantation in the allogeneic setting has recently begun.1

Yasuo Morishima and colleagues, Aichi Cancer Center Research Institute, Nagoya, JP, analyzed 5,017 single cord blood transplantation (CBT) pairs to evaluate transplants which paired donor HLA types with respective recipient HLA types. They were specifically interested in the outcome of 39 pairs using HLA homozygous (homo) donor cells in HLA heterozygous (hetero) recipients as preliminary analysis by Yasuo Morishima et al., indicated that iPSC transplantation from HLA homo donors resulted in favorable engraftment. Other pairs were homo-to-homo and hetero-to-hetero (Table 1). These pairs were investigated for engraftment, mortality, and GvHD.

Study design1

  • 5,017 CBT pairs from the Japanese Data Center for Hematopoietic Cell Transplantation were analyzed

  • The inclusion criteria were: 1) transplantation pairs typed for HLA-A, -B, -C and -DRB1 alleles at the field 1 and 2 levels; 2) first transplantation from single-unit cord blood; 3) patients that survived > seven days after transplantation (Table 1)

  • All 39 pairs of HLA-homo cord blood and HLA-hetero patients were KIR2DL and KIR3DL1 ligand-matched and resulted in reduced engraftment failure

Table 1. Patient characteristics
HLA homo/heterogeneity hetero from donor to patient (HLA allele * MM ⁎⁎ number) Total   Homo to hetero Hetero to homo Homo to homo Hetero to hetero (0 MM) Hetero to hetero (1 MM) Hetero to hetero (≧2MM)
     N= 5,017 n= 39 n= 40 n= 21 n= 236 n= 569 n= 4,112
Age              
0–15 787 6 3 0 97 203 478
16–39 1,011 7 6 3 23 81 891
40+ 3,219 26 31 18 116 285 2,743
Diseases              
AML 2,238 16 23 8 87 220 1,884
ALL 884 9 4 4 53 118 696
MDS 514 2 5 4 18 58 427
Other hematological malignancies 1,007 10 8 3 40 90 856
Non-hematological malignancies 374 2 0 2 38 83 249
GvHD prophylaxis              
Cyclosporine based 1,325 12 12 5 58 155 1,083
Tacrolimus based            3,630 25 28 15 173 406 2,983
Others or missing 62 2 0 1 5 8 46
ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; GvHD, graft-versus-host disease; hetero, heterogeneity; HLA, human leukocyte antigen; homo, homogeneity; MM, mismatch; MDS, myelo-dysplastic syndrome
*HLA-A B C DRB1 allele; ** HVG direction.
HLA zygosity definitions. HLA homozygosity of HLA-A, -B, -C, -DRB1 alleles were defined when only one allele was present in each HLA loci; HLA heterozygosity was defined when two alleles were present in any of the four loci. The combination of donor HLA homozygote (homo) and patient HLA heterozygote (hetero) was simplified as homo-hetero, donor hetero and patient homo as hetero-homo, donor homo and patient homo as homo-homo, and donor hetero and patient hetero as hetero-hetero. Hetero-hetero combination was again subdivided into three categories by the number of HLA-A, -B, -C and -DRB1 mismatched loci in host-versus-graft (HVG) indication (at allele level): hetero-hetero (0 MM), hetero-hetero (1 MM) and hetero-hetero (≥2 MM)

Results1

The clinical outcome of patients with HLA-homo CBT

Engraftment

  • Engraftment analysis showed that HLA homo-hetero pairs (n= 39) had a reasonable neutrophil engraftment risk (hazard ratio [HR]= 1.18; p= 0.285) and engraftment was not statistically different in homo-homo pairs (n= 21) (HR= 0.92; p= 0.627) when compared with HLA allele-matched hetero-hetero pairs (n= 236) (Table 2)

  • Engraftment occurred in all assemble pairs but there was evidence of favorable engraftment of HLA homo-to-hetero pairs in platelet engraftment. Thirty HLA homo-to-hetero pairs had engrafted platelets (20,000/μl count in peripheral blood) at a median of 46 days vs 12 HLA homo-to-homo pairs (20,000/μl) at a median of 48 days

  • Thus, the authors suggested the collection of HLA homo donors to produce iPSC panels in iPSC banking is appropriate as it results in favorable iPSC engraftment

Table 2. Risk of HLA homozygosity on neutrophil engraftment, aGvHD, and mortality
Homo/hetero-zygosity of HLA haplotype*(no. of HLA allele MM**) n Neutrophil engraftment aGvHD (II–IV) aGvHD (III–IV) Mortality
    HR *** 95% CI p HR *** 95% CI p HR *** 95% CI p HR *** 95% CI p
Hetero to hetero (0 MM) 236 1     1     1     1    
Homo to hetero 39 1.13 0.85–1.51 0.4 1.58 0.94–2.67 0.09 2 0.55–7.6 0.29 0.96 0.58–1.59 0.88
Hetero to homo 40 0.74 0.52–1.06 0.1 1.08 0.6–1.94 0.81 1.3 0.26–5.9 0.78 1.23 0.79–1.9 0.37
Homo to homo 21 0.92 0.64–1.32 0.64 0.8 0.33–1.97 0.64 1.3 0.17–10.4 0.79 1.16 0.63–2.1 0.63
Hetero to hetero (1 MM) 569 0.87 0.75–1.01 0.07 1.21 0.91–1.61 0.18 2.5 1.3–5.2 0.01 0.91 0.72–1.15 0.43
Hetero to hetero (≥ 2 MM) 4,112 0.74 0.64–0.85 < 0.001 1.38 1.07–1.77 0.01 3.3 1.7–6.5 < 0.001 1.1 0.9–1.35 0.36
aGvHD, acute graft-versus-host disease; hetero, heterozygosity; HLA, human leukocyte antigen; homo, homozygosity; MM, mismatch
*HLA-A B C DRB1 allele. ** HVG direction. ***Hazard ratio. Other variables for adjustment: patient age, sex matching, diseases, leukemia risk, transplanted CD34+ cell number/body weight, conditioning, GvHD prophylaxis, transplanted year 
Acute GvHD (aGvHD)
  • HLA homo-to-hetero pairs had a higher risk of aGvHD grade II–IV (HR= 1.58) and aGvHD grade III–IV (HR= 2.04) when compared with HLA allele-matched hetero-hetero (0 MM) pairs (n= 236), although this was not statistically significant (p= 0.087 and p= 0.285, respectively)

Mortality
  • There was a comparable mortality risk (HR= 0.96; p= 0.883) in the homo-hetero pairs with HLA allele-matched hetero-hetero pairs. Death as a result of aGvHD was observed in 17% (3 of 18) of patients transplanted with homo-hetero pairs, whereas 2% (2 of 100) of patients died of HLA allele-matched hetero-hetero pairs (p= 0.025)

Conclusion

In conclusion, homozygous CBTs, consisting of major conserved extended HLA haplotypes which were transplanted into heterozygous recipients, showed a comparable neutrophil engraftment rate and mortality rate. Rates of aGvHD were numerically higher in homo-to-hetero pairs, although this was not statistically significant and well-managed by GvHD prophylaxis. The authors explained that these results have important clinical implications as they confirm the feasibility of using HLA-homo iPSC for transplantation, and it was recommended to further pursue the banking of iPSC with major conserved extended HLA haplotypes.

References
  1. Morishima Y. et al., Impact of homozygous conserved extended HLA haplotype on single cord blood transplantation: Lessons for induced pluripotent stem cell banking and transplantation in allogeneic settings. 2019. Biology of Blood and Marrow Transplantation. DOI: 10.1016/j.bbmt.2019.09.009 [Epub ahead of print]
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