Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI

Abstract

Donor lymphocyte infusion (DLI) is a standard of care for relapse of AML after allogeneic hematopoietic stem cell transplantation (aHSCT). Currently it is poorly understood how and when CD8+ αβ T cells exert graft-versus-leukemia (GvL) activity after DLI. Also, there is no reliable biomarker to monitor GvL activity of the infused CD8+ T cells. Therefore, we analyzed the dynamics of CD8+ αβ T cell clones in DLI-patients. In this prospective clinical study of 29 patients, we performed deep T cell receptor β (TRB) sequencing of sorted CD8+ αβ T cells to track patients' repertoire changes in response to DLI. Upon first occurrence of GvL, longitudinal analyses revealed a preferential expansion of distinct CD8+ TRB clones (n=14). This did not occur in samples of patients without signs of GvL (n=11). Importantly, early repertoire changes 15 days after DLI predicted durable remission for the 36 months study follow-up. Furthermore, absence of clonal outgrowth of the CD8+ TRB repertoire after DLI was an early biomarker that predicted relapse at a median time of 11.2 months ahead of actual diagnosis. Additionally, unbiased sample analysis regardless of the clinical outcome revealed that patients with decreasing CD8+ TRB diversity at day 15 after DLI (n=13) had a lower relapse incidence (P=0.0040) compared to patients without clonal expansion (n=6). In conclusion, CD8+ TRB analysis may provide a reliable tool for predicting the efficacy of DLI and holds the potential to identify patients at risk for progression and relapse after DLI.

Spectral flow cytometry cluster analysis of therapeutic donor lymphocyte infusions identifies T cell subsets associated with outcome in patients with AML relapse

“…Dose-escalated (0.5-1 log increase of CD3 + cells/kg BW) subsequent DLI were applied if no complete remission was achieved after 4-6 weeks post DLI and no clinical signs of GVHD were detected. All patient samples post DLI were rated for presence of GVL via minimal residual disease chimerism analysis and as defined elsewhere ( 14 ) at the time point of sampling. In short, GVL was noted either when relative decrease by ≥50% or absolute decrease by ≥1.00% of host chimerism compared to the previous time point, conversion of MRD from positive to negative or decrease of MRD level by ≥10-fold occurred.…”

“…Many leukocyte subsets have been shown to contribute to GVL, however the main effect seems to be driven by CD8 + T cells (5,(12)(13)(14). Besides the numbers of CD3 + , and in some centers CD4 + and CD8 + T cells, no further details on the composition of donor lymphocyte cell product are assessed in clinical practice.…”

Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives

“…Absence of such expansion in patients not achieving a GVL effect after DLIs was predictive of relapse in a median of 11 months before diagnosis. The clonal expansion correlated to the GVL effect involved clones both pre-existing to DLI and newly introduced with the DLI [ 58 ].…”

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

“…The analysis of CD8+ T-cells TCR repertoire of DLI recipients is characterized by a lower diversity, suggesting, in the context of effective GvL with low or absent graft-versus-host disease (GvHD), a lower reactivity towards minor histocompatibility antigens (34). Patients receiving DLI for relapse of the hematological disease after HCT, the expansion of CD8+ clones after the infusion is a viable tool able to predict durable remission (35). DLI are conventionally infused in two different scenarios: in patients deemed to be at higher risk of disease relapse after HCT, such as those with unfavorable cytogenetics and/or molecular profile, active disease at the time of transplant, or those receiving T-cell depleted grafts, DLI is given for prophylaxis of relapse.…”

“…The analysis of CD8+ T-cells TCR repertoire of DLI recipients is characterized by a lower diversity, suggesting, in the context of effective GvL with low or absent graft-versus-host disease (GvHD), a lower reactivity towards minor histocompatibility antigens ( 34 ). Patients receiving DLI for relapse of the hematological disease after HCT, the expansion of CD8+ clones after the infusion is a viable tool able to predict durable remission ( 35 ).…”