# Enhancing anti-tumor immunity through co-blocking PD-L1 and TIGIT by facilitating tumor-directed responses and additional VEGF inhibition

## TL;DR

This study explores combining PD-L1 and TIGIT blockade with VEGF inhibition to improve cancer immunotherapy by enhancing T-cell responses and tumor control.

## Contribution

A bispecific antibody for PD-L1 and TIGIT co-blockade is shown to enhance T-cell responses and tumor control, with additional benefits from VEGF inhibition.

## Key findings

- HB0036, a bispecific antibody, induced stronger T-cell proliferation than combined parental antibodies.
- Co-blocking PD-L1, TIGIT, and VEGF improved tumor control in preclinical models.
- PD-L1 and CD155 expression patterns and spatial distribution were analyzed to assess co-blockade potential in diverse tumors.

## Abstract

Combination therapy targeting the PD-1/PD-L1 and TIGIT pathways has been explored to enhance the efficacy of current immunotherapies. In this study, we investigated strategies to further potentiate the co-blockade of PD-L1 and TIGIT for cancer immunotherapy. Firstly, we demonstrated that the bispecific antibody (HB0036) for PD-L1 and TIGIT co-blockade induced a greater T-cell proliferative response in vitro compared to the combined administration of the parental antibodies. This response was associated with CD226 upregulation and PD-1 downregulation. HB0036 significantly enriched the TIGIT antibody at PD-L1+ tumors and achieved improved tumor control with favorable immunological characteristics in both syngeneic and xenograft tumor models. Secondly, we showed that tumor control by co-targeting PD-L1 and TIGIT can be further enhanced by additionally blocking VEGF, a key player in tumorigenesis and tumor angiogenesis, in preclinical studies. Lastly, considering the heterogeneity of tumors, we analyzed how the expression patterns of PD-L1 and CD155 influence T cell responses. We also examined the spatial distribution of PD-L1 and CD155, along with related immunological parameters from patient samples, to assess the potential of PD-L1 and TIGIT co-blockade in diverse tumor contexts.