Construction and characterization of OV-Q1, OV-CD47-G1, and OV-CD47-G4. cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex computer virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma. Subject terms:Malignancy microenvironment, Immunotherapy, CNS cancer, Malignancy immunotherapy Oncolytic herpes simplex computer virus-1 TAS 103 2HCl lyses cancer cells while increases their immunogenicity. Blocking the CD47 dont eat me signal on cancer cells promotes their phagocytosis by macrophages. Authors here show that oncolytic viruses expressing anti-CD47 antibodies improve glioblastoma survival in mouse models. == Introduction == Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. GBM patients who undergo the standard of care, including surgical resection, chemotherapy, and radiotherapy, have a median survival of approximately 15 months1. Due to the early infiltrative nature of the disease, a complete surgical resection of GBM is largely unachievable. The intrinsic resistance of GBM to chemotherapy and radiotherapy also contributes to poor clinical outcomes. Given these attributes, new therapeutic brokers are urgently needed for improving the outcome of GBM patients. Oncolytic TAS 103 2HCl computer virus CD274 (OV) provides a potentially unique therapeutic approach for GBM as its mechanism of action is completely different from the standard approaches for the treatment of GBM. Oncolytic herpes simplex computer virus-1 (oHSV), one of the most widely investigated oncolytic viruses, is usually genetically designed so that TAS 103 2HCl it can selectively lyse cancer cells while leaving normal cells largely intact. Like many other OVs, oHSV can also alert the patients immune system to attack tumor cells. Talimogene laherparepvec (Imlygic), the first FDA-approved oncolytic viral therapy, is based on the oHSV vector2. oHSV has proven to be relatively safe and has shown some activity in treating GBM3. In our previous studies, we found that oHSV treatment dramatically increased the intratumoral infiltration of immune cells49. However, tumor cells have evolved to engage the immune checkpoints, e.g., CD47 and PD-L1, and down-modulate the immune cells, thereby evading the antitumor immune response10,11. Thus, engineering oHSV to express a transgene(s) that could enhance immune responses and/or block engagement of immune checkpoints could be an effective approach to improve the overall efficacy of oHSV against GBM. Tumor-associated macrophages (TAMs) are the major tumor-promoting immune cells in the GBM microenvironment12,13. Hence, re-education of TAMs in GBM may provide a promising antitumor strategy14,15. The CD47-signal regulatory protein alpha (SIRP) pathway is one of the most studied phagocytosis checkpoints in macrophages16. CD47-SIRP myeloid checkpoint blockade has been shown to effectively enhance tumor phagocytosis and reduce tumor burden1720. A humanized anti-CD47 monoclonal antibody (mAb), which directly inhibits the CD47SIRP conversation, is currently in clinical trials21and shows a strong activity against GBM in multiple murine models18. For safety concerns, this antibody was usually engineered on a human IgG4 scaffold to minimize Fc-dependent effector functions of innate immunity such as natural killer (NK) cell antibody-dependent cellular cytotoxicity (ADCC) and macrophage antibody-dependent cellular phagocytosis (ADCP)22. An IgG1 form of anti-CD47 antibody should possess ADCP and ADCC anti-GBM activity; however, infusion toxicities and difficulty in penetration through the bloodbrain barrier (BBB) are current challenges that limit the systemic treatment of GBM with an IgG1 form of anti-CD47 antibody. In this work, we generate an oHSV carrying a transgene encoding a full-length anti-CD47 antibody on a human IgG1 scaffold (termed OV-CD47-G1) and the other as control carrying a transgene encoding a full-length anti-CD47 antibody on a human IgG4 scaffold (OV-CD47-G4). Antibodies secreted by GBM cells infected with OV-CD47-G1 or OV-CD47-G4 enhance tumor phagocytosis by blocking the CD47SIRP axis, while the secreted CD47-G1 instead of CD47-G4 also induces Fc receptor-mediated tumor phagocytosis by macrophages and tumor cytotoxicity by NK cells. In vivo, intracranial (i.c.) administrations of OV-CD47-G1 and OV-CD47-G4 result in the continuous release of both antibodies specifically into the GBM tumor microenvironment, while OV-CD47-G1 shows a superior effect and significantly prolongs survival of GBM-bearing TAS 103 2HCl mice when compared to OV-CD47-G4 or their parental OV-Q1. Our findings indicate that engineering oHSV to express a full-length anti-CD47 antibody, especially the IgG1 version, with locoregional delivery is usually a promising and non-toxic approach to enhance oncolytic virotherapy of GBM. == Results == == OV-CD47-G1-.
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