Programmed death-1 checkpoint blockade in acute myeloid leukemia

Abstract

Introduction 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. Areas covered PD1/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. Expert Opinion 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.

Biochemical mechanisms implemented by human acute myeloid leukemia cells to suppress host immune surveillance

“…4 However, the interaction of PD-Ls with PD-1 on the surfaces of NK cells and CTCs leads to their rapid inactivation, and, as a result, they lose capacity to kill AML cells. 1 In addition, AML cells are often capable of expressing the CTLA4 ligand CD86. The interaction of CD86 and CTLA4 rapidly leads to the inactivation of effector T cells.…”

“…AML cells are capable of escaping immune attack, even though they are permanently exposed to host immune cells, including cytotoxic T cells (CTCs) and natural killer (NK) cells. 1 AML cells successfully implement biochemical mechanisms that allow them to inactivate cytotoxic lymphoid cells (NK cells and CTCs) both upon direct contact and at a distance. 2 In this case, they not only "fight back" against immune cells but also effectively prevent the actual process of cytotoxic immune attack.…”

“…2 It has become evident that AML cells are capable of expressing surface proteins such as programmed death-1 (PD-1) receptor ligands (PD-Ls) 1 and 2 and CD86, the ligand of cytotoxic T-cell antigen 4 (CTLA4). 1…”

Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies

“…Finally, a third option would be the administration of PD-1 blockers after the cytotoxic treatment, boosting the antitumor response during a period of immune reconstitution subsequent to chemotherapy-induced myelosuppression 57. Also, chemotherapy induces PD-1 expression on immune cells, favoring the immune checkpoint blockade being administered postcytotoxic treatment 21,70,71. Based on this reasoning, anti-PD-1 therapy could be applied either before autologous/allogeneic stem cells transplantation (ASCT), or to target residual disease after transplantation, when PD-1 pathways may serve as a tumor survival mechanism 52,72,73…”

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia

“…PD-1 blockade can restore anti-leukemia T cell functions and thus may offer therapeutic advantages in acute leukemia. Given the acceptable tolerability, pre-clinical rationale, and immunological activity of PD-1/PD-L1 blockade, clinical trials of anti-PD-1 mAbs are underway in acute leukemia patients [191]. Several other checkpoint molecules are known [192, 193] and are under investigation in acute leukemia, including CTLA-4, TIM-3, lymphocyte activation gene-3 (LAG-3), and B and T cell lymphocyte attenuator (BTLA).…”