Recent Progress in Interferon Therapy for Myeloid Malignancies

Abstract

Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, caused by abnormalities in haematopoietic stem cells (HSCs) and myeloid progenitor cells that originate in the bone marrow niche. Each of these disorders are unique and present their own challenges with regards to treatment. Acute myeloid leukaemia (AML) is considered the most aggressive myeloid malignancy, only potentially curable with intensive cytotoxic chemotherapy with or without allogeneic haematopoietic stem cell transplantation. In comparison, patients diagnosed with chronic myeloid leukaemia (CML) and treated with tyrosine kinase inhibitors (TKIs) have a high rate of long-term survival. However, drug resistance and relapse are major issues in both these diseases. A growing body of evidence suggests that Interferons (IFNs) may be a useful therapy for myeloid malignancies, particularly in circumstances where patients are resistant to existing front-line therapies and have risk of relapse following haematopoietic stem cell transplant. IFNs are a major class of cytokines which are known to play an integral role in the non-specific immune response. IFN therapy has potential as a combination therapy in AML patients to reduce the impact of minimal residual disease on relapse. Alongside this, IFNs can potentially sensitize leukaemic cells to TKIs in resistant CML patients. There is evidence also that IFNs have a therapeutic role in myeloproliferative neoplasms (MPNs) such as polycythaemia vera (PV) and primary myelofibrosis (PMF), where they can restore polyclonality in patients. Novel formulations have improved the clinical effectiveness of IFNs. Low dose pegylated IFN formulations improve pharmacokinetics and improve patient tolerance to therapies, thereby minimizing the risk of haematological toxicities. Herein, we will discuss recent developments and the current understanding of the molecular and clinical implications of Type I IFNs for the treatment of myeloid malignancies.

Clearance of genome-damaged cells from the hematopoietic system via p53 without contribution by the cGAS/STING axis

“…Type I IFN exerts antiproliferative effects on numerous cell types (Bromberg, Horvath et al 1996, Sangfelt, Erickson et al 2000, McNab, Mayer-Barber et al 2015), sensitizes to programmed cell death and is used to treat leukemic disease (Healy, Dahal et al 2021). In addition to induction of type I IFN, STING activation was also shown to directly trigger cell death or senescence in a cell type and context-dependent manner (Gluck, Guey et al 2017, Gulen, Koch et al 2017, Li and Chen 2018, Paludan, Reinert et al 2019).…”

“…As expected, the enhanced expression of the type I IFN-induced surface protein Sca-1 in RH2 hKO control mice was abrogated by each of these additional knock outs (Figure 6A), demonstrating that the cGAS/STING axis translated the genome damage of RER-defective hematopoietic cells into activation of type I IFN signaling. Type I IFN exerts antiproliferative effects on numerous cell types (Bromberg, Horvath et al 1996, Sangfelt, Erickson et al 2000, McNab, Mayer-Barber et al 2015, sensitizes to programmed cell death and is used to treat leukemic disease (Healy, Dahal et al 2021). In addition to induction of type I IFN, STING activation was also shown to directly trigger cell death or senescence in a cell type and context-dependent manner (Gluck, Guey et al 2017, Gulen, Koch et al 2017, Li and Chen 2018, Paludan, Reinert et al 2019.…”

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

“…If patients survive prolonged neutropenia, they may achieve deep remission, longer remission duration, and a reduced frequency of relapse. Recombinant type I inflammatory cytokines ( 259 – 262 ), interferon inducers ( 263 – 265 ), and BCG inoculation ( 266 – 268 ) have been used to treat hematological and non-hematological neoplasms and have shown efficacy in the control of tumor growth or even the clearance of malignant clones. Other vaccine inoculations that can stimulate Th1 responses have also been shown to have antitumor effects ( 269 – 271 ).…”

Novel Pegylated Interferon for the Treatment of Chronic Viral Hepatitis

“…Furthermore, low-copy gene delivery of IFN beta by a lentivirus vector or the extrachromosomal gene expression by an adenoviral vector led to the significant inhibition of tumor formation [44,46]. Recombinant IFN alfa was approved for the treatment of hairy cell leukemia, malignant melanoma, AIDS-related Kaposi's sarcoma, and follicular non-Hodgkin's lymphoma, and its pegylated products with extended half-lives were under development for the treatment of more cancer types, e.g., acute myeloid leukemia [47][48][49][50][51][52][53]. IFN-alfa therapies were also noted to significantly reduce the risk of CHC-associated HCC occurrence [26,54,55].…”