PD-1 signaling and inhibition in AML and MDS

Abstract

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.

The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes

“…Also, MAPK and TLR inhibitors, which target overactive TLR pathways in MDS, are currently being evaluated in several clinical trials [ 8 , 37 , 38 ]. Checkpoint inhibitors are another family of drugs that have been approved for solid tumors and now being investigated in high risk MDS and other hematologic malignancies such as AML [ 1 ].…”

“…Adverse effects were noted in 10 of 28 patients with most common effects being fatigue and hypothyroidism. There was one case of grade 3 gastroenteritis and one case of grade 4 tumor lysis syndrome [ 1 ].…”

“…It is noteworthy that in cohort 1, patients received nivolumab alone after failing treatment with HMA and did not have any significant response, whereas the cohort receiving combination therapy with nivolumab and azacitidine had a good response rate, suggesting that both drugs are likely working synergistically. The higher response rate of azacitidine and nivolumab suggest that combination therapy is more effective than nivolumab monotherapy [ 1 ]. Data from cohort 6 is not yet available ( Table 2 ).…”

“…Myelodysplastic syndromes (MDS) are a complex set of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations, ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). Most patients are elderly with the vast majority diagnosed after the age of 60 years [ 1 ]. According to the World Health Organization (WHO) classification, diagnosis of MDS is still based mostly on histologic and cytologic examination of the bone marrow and peripheral blood.…”

Therapeutic vaccination with 4–1BB co-stimulation eradicates mouse acute myeloid leukemia

“…[29][30][31][32][33][34] There are currently phase 1 and 2 clinical trials for anti-PD-1 monotherapy, or combinations with chemotherapy or stem cell transplant against AML or Myelodysplastic Syndrome. 2,6,27,35,36 Given that tumors hijack host immune tolerance mechanisms to avoid detection, effective therapies must aim to enhance T cell immunity while relieving tumor-mediated immune inhibition 7,28 The co-stimulatory molecule 4-1BB (CD137) is widely expressed on hematopoietic cells and can contribute to proliferation, survival and enhanced activity of CD8 + T and NK cells. 13,[37][38][39] Addition of soluble 4-1BBL to cocultures of AML-derived DC and T cell, induces differentiation of T cells to effector and central memory CD8 + T cells.…”