T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumour immunity.


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Marta Canel1,David Taggart1,Norbert Kraut2,Irene C. Waizenegger2,Alan Serrels1
1University of Edinburgh,2boehringer-ingelheim

Abstract

Background

Focal Adhesion Kinase is emerging as a potentially important regulator of the immuno-suppressive tumour environment in multiple tumour types, and as a consequence FAK inhibitors are now undergoing clinical testing in combination with anti-PD1 immune checkpoint inhibitors. However, which patients are most likely to benefit from FAK inhibitor treatment, and what the optimal FAK / immunotherapy combinations are, is currently unknown.

Results

Using a panel of syngeneic transplantable murine cancer cell models we have identified that endogenous and exogenous expression of the immune costimulatory ligand CD80 on the surface of cancer cells correlates with response of tumours to the FAK kinase inhibitor BI853520. Thus, expression of CD80 by cancer cells may represent a novel biomarker for identification of patients more likely to respond to FAK kinase inhibitors.

CD80 is an immune costimulatory ligand that plays a role in T-cell activation through binding the T-cell co-receptor CD28. However, a previous clinical trial testing the safety of a CD28 superagonist reported severe life-threatening toxicity in all patients, suggesting that development of FAK inhibitor / CD28 agonist combinations would not be possible. We therefore set out to test the concept of T-cell costimulation in combination with BI853520 using agonistic antibodies targeting four T-cell costimulatory receptors for which agents are currently in clinical development, namely GITR, CD40, 41BB, and OX40. We observed a significant improvement in the anti-tumour activity of both 41BB and OX40 when used in combination with BI853520. Of particular note, the combination of OX40 + BI853520 resulted in complete regression of all SCC tumours and a significant growth delay of pancreatic tumours that was not observed with either therapy alone.

Conclusion

These studies support the continued development of FAK kinase inhibitors in combination with immunotherapies, and in particular identify FAK / OX40 as a promising candidate for further investigation.