Abstract Diffuse midline gliomas (DMGs) are very aggressive brain tumors with dismal prognosis affecting mainly children and adolescents. Therefore, there is an urgent need to develop innovative treatments for these patients. Oncolytic adenoviruses have provided a radically different approach for these tumors and have proven to be safe in clinical trials. Additionally, these viruses can also act as delivery vectors to express immunostimulatory molecules, enhancing the antitumor immune response while minimizing the risk of systemic toxicities. The blockade of CD47-SIRPα axis has been reported as an effective strategy for DMG treatment, along other malignancies, by enhancing innate immune response. In this work, we have generated a new oncolytic adenovirus, Delta-24-mEATME, armed with a murine CD47 (mCD47) blocking single-domain antibody (sdAb). In vitro, Delta-24-mEATME was able to secrete mCD47 sdAb, which was functional and bound to CD47 on the surface of DMG cells in a dose dependent manner. We have demonstrated the ability of Delta-24-mEATME to enhance macrophage-mediated phagocytosis on DMG cultures compared to parental virus Delta-24-RGD. In DMG animal models, Delta-24-mEATME promoted antitumor responses and its potency surpassed that of Delta-24-RGD. We observed a significant survival increase following Delta-24-EATME of a DMG model compared to Delta-24-RGD (P = 0.0069, median OS Delta-24-RGD 58 days vs Delta-24-EATME 69 days) and vehicle (P = 0.0035, median OS vehicle 47 days vs Delta-24-EATME 69 days). Due to these promising results with the murine CD47 sdAb, we have developed an inhibitory sdAb for human CD47 (hCD47). Using bio-layer interferometry, we checked that this hCD47 sdAb effectively blocked the interaction of CD47 with SIRPα. Furthermore, it effectively increased macrophage-mediated cell phagocytosis on human DMG cultures. We are currently developing another oncolytic adenovirus armed with this hCD47 sdAb. In summary, we demonstrated that CD47-SIRPα blockade combination with oncolytic virotherapy is an encouraging strategy for DMG treatment.
Palacios-Alonso et al. (Fri,) studied this question.