TY - JOUR
T1 - 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
AU - Tian, Lei
AU - Xu, Bo
AU - Teng, Kun Yu
AU - Song, Mihae
AU - Zhu, Zheng
AU - Chen, Yuqing
AU - Wang, Jing
AU - Zhang, Jianying
AU - Feng, Mingye
AU - Kaur, Balveen
AU - Rodriguez, Lorna
AU - Caligiuri, Michael A.
AU - Yu, Jianhua
N1 - Funding Information:
This work was supported by grants from the NIH (NS106170, AI129582, CA247550, CA163205, CA223400, CA265095, CA210087, CA20175, and CA255250), the Leukemia & Lymphoma Society (1364–19), California Institute for Regenerative Medicine (DISC2COVID19–11947), the Breast Cancer Alliance, Markel Friedman Accelerator Fund, and the V Foundation for Cancer Research V Scholar Award. The authors thank the NIH Tetramer Core Facility for providing the herpes simplex virus type 1 glycoprotein B tetramer.
Funding Information:
M. Feng reports a patent for stimulating TLR/BTK signaling to promote CRT in macrophages licensed to Forty Seven, Inc. B. Kaur reports grants from NIH during the conduct of the study; nonfinancial support from Mesoblast outside the submitted work. M.A. Caligiuri reports grants from NIH during the conduct of the study; other support from CytoImmune Therapeutics outside the submitted work; also has a patent for OV-anti-CD47 pending. J. Yu reports grants from NIH during the conduct of the study; other support from CytoImmune Therapeutics outside the submitted work; also has a patent for OV-CD47 pending. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-1248
DO - 10.1158/1078-0432.CCR-21-1248
M3 - Article
C2 - 34645647
AN - SCOPUS:85123076302
SN - 1078-0432
VL - 28
SP - 201
EP - 214
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -
