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Programmed death-1 checkpoint blockade in acute myeloid leukemia.

ABSTRACT: Immune checkpoints are regulatory pathways induced in activated T lymphocytes that regulate antigen responsiveness. These immune checkpoints are hijacked by tumors to promote dysfunction of anti-tumor effector cells and consequently of tumor escape from the host immune system.Programmed death-1/programmed death ligand (PD-1/PDL-1), a checkpoint pathway, has been extensively investigated in leukemia mouse models. Expression of PD-1 on the surface of activated immune cells and of its ligands, PD-L1 and PD-L2, on leukemic blasts has been documented. Clinical trials with PD-1 inhibitors in patients with hematological malignancies are ongoing with promising clinical responses.Therapy of hematological cancers with antibodies blocking inhibitory receptors is expected to be highly clinically effective. Checkpoint inhibitory receptors and their ligands are co-expressed on hematopoietic cells found in the leukemic milieu. Several distinct immunological mechanisms are likely to be engaged by antibody-based checkpoint blockade. Co-expression of multiple inhibitory receptors on hematopoietic cells offers an opportunity for combining blocking antibodies to achieve more effective therapy. Up-regulation of receptor/ligand expression in the leukemic milieu may provide a blood marker predictive of response. Finally, chemotherapy-induced up-regulation of PD-1 on T cells after conventional leukemia therapy creates a solid rationale for application of checkpoint blockade as a follow-up therapy.

SUBMITTER: Sehgal A

PROVIDER: S-EPMC4778424 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Programmed death-1 checkpoint blockade in acute myeloid leukemia.

Sehgal Alison A Whiteside Theresa L TL Boyiadzis Michael M

Expert opinion on biological therapy 20150603 8

<h4>Introduction</h4>Immune checkpoints are regulatory pathways induced in activated T lymphocytes that regulate antigen responsiveness. These immune checkpoints are hijacked by tumors to promote dysfunction of anti-tumor effector cells and consequently of tumor escape from the host immune system.<h4>Areas covered</h4>Programmed death-1/programmed death ligand (PD-1/PDL-1), a checkpoint pathway, has been extensively investigated in leukemia mouse models. Expression of PD-1 on the surface of acti ...[more]

PMID: 26036819

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Project description:BackgroundExperience with immune checkpoint inhibitors (ICIs) in the treatment of acute myeloid leukemia (AML) is still limited and based on early clinical trials, with no reported randomized clinical data. In this study, we reviewed the available evidence on the use of ICIs, either in monotherapy or in combination with other treatments, in different AML settings, including newly diagnosed AML, relapsed or refractory (R/R) AML and maintenance treatment after allogeneic-HSCT (allo-HSCT).Materials and methodsA systematic literature review was conducted using PubMed electronic database as primary source to identify the studies involving immune checkpoint inhibitors in first-line and R/R AML. We recorded Overall Response (ORR), Complete Response (CR) and Complete Response with incomplete count recovery (CRi) rates, overall survival (OS) and immune-related adverse events ≥ grade 3 (irAEs). Hereafter, we analyzed the overall profile of these ICIs by performing a meta-analysis of the reported outcomes.ResultsA total of 13 studies were identified where ICI was used in patients with AML. ORR across these studies was 42% (IC95%, 31% - 54%) and CR/CRi was 33% (IC95%, 22%-45%). Efficacy was also assessed considering the AML setting (first-line vs. relapsed/refractory) and results pointed to higher response rates in first-line, compared to R/R. Mean overall survival was 8.9 months [median 8 months, (IC95%, 3.9 - 15.5)]. Differences between first line and R/R settings were observed, since average overall survival in first line was 12.0 months, duplicating the OS in R/R which was 7.3 months. Additionally, the most specific adverse events (AEs) of these therapies are immune-related adverse events (irAEs), derived from their inflammatory effects. Grade ≥3 irAEs rate was low and similar among studies [12% (95%CI 8% - 16%)].ConclusionICIs in combination with intensive chemotherapy, hypomethylating agents or other targeted therapies are gaining interest in the management of hematological malignancies such as AML. However, results obtained from clinical trials are modest and limited by both, the type of design and the clinical trial phase. Hopefully, the prospective study of these therapies in late-stage development could help to identify patients who may benefit from ICI therapy.

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Programmed death-1 checkpoint blockade in acute myeloid leukemia.

Publications

Programmed death-1 checkpoint blockade in acute myeloid leukemia.

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