Immune Escape after Hematopoietic Stem Cell Transplantation (HSCT): From Mechanisms to Novel Therapies

Abstract

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Recent advances in understanding its molecular basis have opened the way to new therapeutic strategies, including targeted therapies. However, despite an improvement in prognosis it has been documented in recent years (especially in younger patients) that allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment in AML and the first therapeutic option for high-risk patients. After allo-HSCT, relapse is still a major complication, and is observed in about 50% of patients. Current evidence suggests that relapse is not due to clonal evolution, but instead to the ability of the AML cell population to escape immune control by a variety of mechanisms including the altered expression of HLA-molecules, production of anti-inflammatory cytokines, relevant metabolic changes and expression of immune checkpoint (ICP) inhibitors capable of “switching-off” the immune response against leukemic cells. Here, we review the main mechanisms of immune escape and identify potential strategies to overcome these mechanisms.

A 5’UTR polymorphism in NT5E gene but not fludarabine systemic exposure influences HCT outcome in patients with high-risk β-thalassemia major

“…Low NT5E activity has been reported to be associated with a good prognosis in many malignancies 46,51,52 probably due to the production of less adenosine that suppresses antitumor immunity and by not contributing to metastasis. The role of NT5E activity in HCT setting has not been explored except for few mice model studies, where it was suggested that low NT5E activity could lead to GvL/GvT (Graft Versus Leukemia/Tumor) phenomenon favoring HCT outcome, again reinstating the probable role of Adenosine 5'-triphosphate (ATP)-Adenosine axis in transplant immunology [53][54][55][56] . We could thus hypothesize that due to the reduced NT5E activity in patients carrying the variant genotype for this polymorphism, there is a lower production of adenosine and higher extracellular ATP activity, which in turn could prevent graft rejection and help in immunosuppression, eventually favoring better HCT outcome.…”

Extra-medullary recurrence of myeloid leukemia as myeloid sarcoma after allogeneic stem cell transplantation: impact of conditioning intensity

“…As a less effective GvL-effect is considered to be causative for the formation of MS, donor lymphocyte infusion and tapering of immunosuppression are recommended [6][7][8]10]. Hypomethylating agents might enhance GvL by increasing HLA and tumor-associated antigen expression [13,35,47]. Another therapeutic option is the application of gemtuzumab ozogamizin [13,35].…”

“…Whenever suitable, use of targeted therapies, i.e. tyrosine kinase inhibitors for FLT3-ITD, is recommended [11,47]. In addition, inhibition of CTL-4 may prevent immune escape and can result in complete response of MS [48].…”

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients

“…Unlike these observations, in the present study, the donor HO-1 A/A or A/T genotype (plausibly associated with the higher inducibility of HO-1) was associated with better survival outcomes without increasing the risk of disease relapse after allo-HSCT in patients with high-risk patients. However, allo-HSCT can exert a robust graft-versus-leukemia (GVL) effect [38], which may eliminate the adverse effect associated with the higher HO-1 inducibility to potentially to promote progression and relapse. This hypothesis may be supported by the current findings that post-transplant progression and relapse rates in patients with CML were comparable between the donor HO-1 A/A or A/T genotype vs. the donor HO-1 T/T genotype, with 33% vs. 33% (p = 0.82) in the high-risk group, and 21% vs. 42% (p = 0.14) in the standard-risk group.…”