Back to Search
Start Over
TLR3 agonism augments CD47 inhibition in acute myeloid leukemia.
- Source :
-
Haematologica [Haematologica] 2024 Jul 01; Vol. 109 (7), pp. 2111-2121. Date of Electronic Publication: 2024 Jul 01. - Publication Year :
- 2024
-
Abstract
- CD47-SIRPa is a myeloid check point pathway that promotes phagocytosis of cells lacking markers for self-recognition. Tumor cells can overexpress CD47 and bind to SIRPa on macrophages, preventing phagocytosis. CD47 expression is enhanced and correlated with a negative prognosis in acute myeloid leukemia (AML), with its blockade leading to cell clearance. ALX90 is an engineered fusion protein with high affinity for CD47. Composed of the N-terminal D1 domain of SIRPĪ± genetically linked to an inactive Fc domain from human immunoglobulin (Ig) G, ALX90 is designed to avoid potential toxicity of CD47-expressing red blood cells. Venetoclax (VEN) is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore apoptosis in malignant cells. In AML, VEN is combined with azanucleosides to induce superior remission rates, however treatment for refractory/relapse is an unmet need. We questioned whether the anti-tumor activity of a VENbased regimen can be augmented through CD47 inhibition (CD47i) in AML and how this triplet may be enhanced. Human AML cell lines were sensitive to ALX90 and its addition increased efficacy of a VEN plus azacitidin (VEN+AZA) regimen in vivo. However, CD47i failed to clear bone marrow tumor burden in PDX models. We hypothesized that the loss of resident macrophages in the bone marrow in AML reduced efficiency of CD47i. Therefore, we attempted to enhance this medullary macrophage population with agonism of TLR3 via polyinosinic:polycytidylic acid (poly(I:C)), which led to expansion and activation of medullary macrophages in in vivo AML PDX models and potentiated CD47i. In summary, the addition of poly(I:C) can enhance medullary macrophage populations to potentiate the phagocytosis merited by therapeutic inhibition of CD47.
- Subjects :
- Humans
Animals
Mice
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Bridged Bicyclo Compounds, Heterocyclic therapeutic use
Xenograft Model Antitumor Assays
Cell Line, Tumor
Macrophages metabolism
Macrophages drug effects
Sulfonamides pharmacology
Receptors, Immunologic metabolism
Receptors, Immunologic antagonists & inhibitors
Antigens, Differentiation metabolism
Phagocytosis drug effects
Poly I-C pharmacology
CD47 Antigen metabolism
CD47 Antigen antagonists & inhibitors
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 109
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 38152031
- Full Text :
- https://doi.org/10.3324/haematol.2023.283850