PII-055 - EVALUATION OF VARIOUS STRATEGIES TO UNLEASH DNAM1 SIGNALING AND BLOCK TIGIT/PVRIG AXIS.

O. Demin Jr¹, D. Shchelokov¹; ¹InSysBio CY.

Background: PVR (CD155) and CD112 are two ligands from Nectin/Nectin-like family which are frequently expressed on different types of tumor cells. PVR binds to inhibitory receptors TIGIT and CD96 triggering a direct inhibitory signal in T and NK-cells and binds to co-stimulatory receptor DNAM1 (CD226) causing its downregulation. CD112 binds to inhibitory receptor PVRIG expressed on T and NK-cells and to DNAM1 stimulating T and NK-cells. The aim of this work was to compare how inhibition of TIGIT, PVRIG, PVR, or their combinations affects engagement of TIGIT, CD96, PVRIG, and DNAM1.

Methods: We developed a mechanistic model describing surface PVR, CD112 on cancer cell and TIGIT, CD96, DNAM1, PVRIG on CD8 T-cell and interaction of these ligands and receptors in immunological synapse (IS) between CD8 T-cell and cancer cell in the tumor. In vitro data and data on expression of described ligands and receptors in blood and tumor were used to identify parameters. Validation of the model was done against data on downmodulation of DNAM1 and TIGIT on CD8 T-cells in the tumor in comparison to the blood. Total DNAM1 on the surface of CD8 T-cell in the tumor and engagement of TIGIT, CD96, PVRIG and DNAM1 in IS (i.e., numbers of PVR:TIGIT, PVR:CD96, CD112:PVRIG, PVR:DNAM1 and CD112:DNAM1 complexes) were simulated under 100% inhibition of TIGIT, PVR, PVRIG, TIGIT and PVRIG, or PVR and PVRIG.

Results: TIGIT blockade didn’t increase total DNAM1 and bound DNAM1 in IS. Inhibition of PVRIG resulted in an increase of bound DNAM1 (in ~1.3 times), but not total DNAM1. Combination of TIGIT and PVRIG blockade didn’t increase engaged DNAM1 above levels observed in anti-PVRIG monotherapy. Inhibition of PVR resulted in a strong increase of total DNAM1 and a moderate increase of bound DNAM1 (in ~1.3 times) in addition to disruption of TIGIT and CD96 engagements. Combination of PVR and PVRIG blockade resulted in the strongest increase of bound DNAM1 (in ~2 times) in addition to disruption of TIGIT, CD96 and PVRIG engagements.

Conclusion: The inability to increase DNAM1 engagement during TIGIT inhibition can be one of the reasons explaining lack of efficacy in the phase 3 trial of tiragolumab (anti-TIGIT mAb) used in combination with atezolizumab. Targeting PVR alone or in combination with PVRIG seems to be a better strategy than targeting TIGIT or TIGIT in combination with PVRIG.