# Dual Bcl-2/Bcl-xl inhibition via AZD0466 combines with immune checkpoint blockade to enhance anti-tumour activity

## TL;DR

This study shows that combining AZD0466 with immunotherapy improves tumor response by killing cancer cells without harming immune cells.

## Contribution

The novel finding is that AZD0466, a Bcl-2/Bcl-xl inhibitor, synergizes with anti-PD-L1 to enhance anti-tumor immunity.

## Key findings

- AZD0466 induces tumor cell death without impairing CD8+ T cell function.
- Combining AZD0466 with anti-PD-L1 improves anti-tumor effects and survival in mice.
- Bcl-2/Bcl-xl inhibition supports immune checkpoint blockade in tumor treatment.

## Abstract

Small molecule inhibitors designed to specifically target oncogenic proteins have demonstrated potent anti-tumour activities due to direct effects on tumour cells survival and/or proliferation. However, the effects of these compounds on normal cells, specifically immune cells and their potential to impede or enhance anti-cancer immunotherapies has yet to be fully explored. Using an in vitro co-culture system to assess CD8+ T cell killing of tumour cells, we identified compounds that inhibit Bcl-2 and Bcl-xl as agents that can induce tumour cell death without impacting the differentiation or function of anti-tumour T cells. Accordingly, in vivo treatment of mice bearing solid tumours with a combination of the Bcl-2/Bcl-xl inhibitor AZD0466 and anti-PD-L1 immunotherapy resulted in enhanced anti-tumour effects and improved survival compared to equivalent monotherapies.