Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

Abstract

Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the "graft-vs.-leukemia" effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.

Clinical Utility of the Detection of the Loss of the Mismatched HLA in Relapsed Hematological Patients After Haploidentical Stem Cell Transplantation With High-Dose Cyclophosphamide

“…Rescue treatment options after relapse post-Haplo-HSCT with PTCy aimed at improving the GVL effect (such as DLIs and immunosuppression withdrawal) could be a good option when patients present a lower disease burden ( 12 , 13 , 31 , 32 ). However, such treatments would be ineffective in cases of HLA-loss relapses ( 33 ).…”

“…One of the results of the best-characterized tumor-intrinsic mechanisms of immune evasion and relapse is the “striking out” of interactions between T-cells and the tumor. This can occur when blast cells become “invisible” to T-cells, for instance due to alterations in the antigen processing and presenting machinery or because their interaction is inefficient, such as when inhibitory immune checkpoints are imposed ( 13 ). The genomic loss of HLA (copy neutral loss of heterozygosity), the epigenetic downregulation of class II HLA and the epigenetic upregulation of inhibitory molecules ( PDL1, B7H3, PVR or PVRL2 ) are the three known tumor-intrinsic mechanisms ( 14 ).…”

“…In other words, LOH might not be due to a loss of chromosomal material. aUPD consists of the loss of a region of the chromosome and the replacement by the exact copy of the homologous chromosome (either paternal or maternal), resulting in acquired homozygosity of that region without the loss of genomic material ( 13 ).…”

“…At the time of relapse, various rescue treatments can be employed, such as withdrawing immunosuppressive drugs and infusing donor lymphocytes (DLIs) (to improve the GVL effect) ( 12 , 17 ) and chemotherapy (to achieve complete remission as a “bridge” prior to a second transplantation) ( 12 , 18 ). Nevertheless, in HLA-loss relapses, attempting to improve GVL through DLIs would not be an optimal strategy, given that leukemic cells become invisible to donor T cells ( 13 ). Furthermore, such approaches can cause severe complications such as GVHD ( 19 ).…”

HLA-haplotype loss after TCRαβ/CD19-depleted haploidentical HSCT

“…Other smaller case reports in adults affected by lymphoid malignancies receiving mismatched HSCT showed a similar incidence of HLA. Notably, HLA loss relapses have been recently reported to occur with similar frequency also after haplo-HSCT employing posttransplant cyclophosphamide (PT-Cy) [3], further demonstrating that HLA loss is an intrinsic relapse mechanism after HSCT [4] and especially when using mismatched donors [5,6]. This finding also suggests that even though PT-Cy can dramatically decrease the risk of severe GvHD after haplo-HSCT, it does not eliminate T-cell alloreactivity against the partially HLA-mismatched leukemia.…”