Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation

Abstract

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade (ICB) in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GvL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the ETCTN 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T cell populations and increased expression of markers of T cell activation and co-stimulation such as PD-1, HLA-DR and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GvL outcomes.

Checkpoint-blocked T cells checkmate AML

“…They report a high incidence of TET2 mutations, including the detection of these as a postulated precursor cell lesion in the myeloid compartment. 1 As a novel biologic and diagnostic hallmark of CLPD-NK, this finding provides a clinically useful marker for distinguishing CLPD-NK from reactive NK-cell expansions as well as for the discrimination of defined CLPD-NK subsets. The bilinear presence of TET2 variants substantiates existing epidemiological links between CLPD-NK and myeloid disorders.…”

“…They show distinct cytokine and cellular changes in responders and add to our understanding of graft-versus-leukemia (GVL) effects. 1…”

Natural Barcodes for Longitudinal Single Cell Tracking of Leukemic and Immune Cell Dynamics

“…HSCT is arguably the longest standing and the most successful immunotherapy with the graft-versus-leukemia/lymphoma (GvL) effect at its core (116). Research into target antigens of GvL and processes such as donor reconstitution or immunomodulation post-HSCT have advanced our understanding of fundamental immune processes (117)(118)(119). Despite these insights, many questions remain unanswered such as the exact mechanisms of response to immune modulation post-HSCT like donor-lymphocyte infusion (DLI) or interactions between donor and host under conditions of mixed chimerism.…”

Insights into Modern Therapeutic Approaches in Pediatric Acute Leukemias

“…Furthermore, Penter et al proved that ipilimumab can enhance the graft-versus-leukemia (GVL) effect and reinvigorate T-cells. Three of 44 patients reached CR, and three reached transient response statuses [ 223 ]. Treatment of relapsed AML with ipilimumab and decitabine is now in clinical trials (NCT02890329), but results have not been published yet [ 224 ].…”