Data from Targeting Fc Receptor-Mediated Effects and the “Don't Eat Me” Signal with an Oncolytic Virus Expressing an Anti-CD47 Antibody to Treat Metastatic Ovarian Cancer
Year: 2023
Type: other
Abstract: Purpose: mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the “don't eat me” pathway. However, this strategy is associated with severe toxicity. Experimental Design: To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G4). Results: Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47–SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. In vivo, these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection. Conclusions: Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Awards: Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin, G2244471940, Elucidate and Modulate Cell Signaling in NK Cells for Glioma Treatment, scFvPD1-FLT3 CAR T Cells for the Treatment of Relapsed Acute Myeloid Leukemia, Persistent Off-the-Shelf meACE2-CAR-IL-15 NK Cells Derived from CD34(+) Cord Blood Stem Cells to Prevent and Treat COVID-19, Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells, G9000226092, Human natural killer cells: Advancing biology and clinical applications, Targeting FLT3 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia, Identifying and engaging a universal adjuvant for breaking macrophage immune tolerance in cancer
OpenAlex ID: W4361956705