Translation to the clinic of EVT801: A novel immune-oncology agent for addressing innate-driven immunosuppression into the tumor microenvironment and expanding patient population responding to immune checkpoint therapies

Amongst resistance mechanisms of immune checkpoint therapies (ICTs), expansion and recruitment of immunosuppressive innate cells and in particular Myeloid Derived Suppressor Cells (MDSCs) can be a major cause of resistance to ICTs. Here we describe joint efforts of clinicians and researchers to translate the promising EVT801 action on MDSCs into the clinic. We have identified a highly selective drug candidate targeting VEGFR3, EVT801, showing intermediate in vivo activity on tumours, accompanied by a decrease of MDSCs, when VEGFR3 is expressed in the tumour microenvironment. To evaluate the potential to combine with ICTs, the 4T1 orthotopic mammary carcinoma mouse model, was used. We have demonstrated that EVT801 increases the therapeutic activity of an anti-PD-1 antibody (Ab) on primary tumours as compared to single agent treatment but also results in a decrease of lung metastasis. Furthermore, the decrease of MDSCs in the blood in response to EVT801 is correlated with tumor shrinkage and therapeutic efficacy. In parallel, Immuno Histo Chemistry analyses have shown that treatment with EVT801 increases CD8 + T-cells infiltration inside the tumor. Taken together, these results indicate that EVT801 represents an innovative drug for cancer immunotherapy that improves the frequency of response to ICT by controlling MDSCs immunosuppressive activity and in turn by unleashing tumor-specific T-lymphocytes. To translate these promising results into the clinic, we have evaluated different biomarkers to properly select patients and monitor efficacy of EVT801: (1) We refined an antiPD1 Ab resistance gene signature and correlated it with VEGFR3 pathway gene overexpression. (2) We investigated VEGFR3 expression in the tumor microenvironment (TME) for different cancer indications. Taken together, these results will facilitate patient stratification as based on the PD1 resistance gene signature associated with VEGFR3 expression in the TME. (3) In non-small cell lung cancer patients, we validated that a high-level baseline of circulating M-MDSCs is associated with poor survival. In correlation with EVT801 activity on circulating MDSC as deciphered on preclinical mouse models, we propose that circulating MDSC levels could be a biomarker of activity for EVT801 in non-responder patients to ICTs. EVT801 represents a novel agent for cancer immunotherapy for non-responder patients to ICT. Patient stratification strategy, target engagement biomarker and biomarkers of activity have been identified and will enable the initiation of a planned Phase I clinical trial with EVT801. Citation Format: Pierre Fons, Michael Esquerre, Julien Mazieres, Philippe Rochaix, Anne Gomez-Brouchet, Antoine Alam, Florie Bertrand, Celine Poussereau-Pomie, Jerome Meneyrol, Anne Pradines, janick selves, Isabelle Rouquette, Isabelle Blanc, Francoise Bono, Donogh P. O9Brien, Michael Paillasse, Joanna Lisztwan, Mark Whittaker. Translation to the clinic of EVT801: A novel immune-oncology agent for addressing innate-driven immunosuppression into the tumor microenvironment and expanding patient population responding to immune checkpoint therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2753.