Abstract

The rapid advance of cancer immunotherapy is changing fundamentally the way we think about cancer care and cancer biology. To a significant degree, recent progress in the clinic was made possible by the understanding that the immunosuppressive mechanisms deployed by tumors to subvert T cell attack represented a key rate-limiting step in many patients. Interestingly, these mechanisms are not tumor-specific specializations but rather manifestations of the normal regulatory mechanisms used by all cells and tissues to maintain immune homeostasis. The best validated of these is the interaction between the negative regulator of T cells PD-1 with its ligand PD-L1 expressed by tumor cells or tumor infiltrating immune cells in response to IFNγ release. Antibodies that block this interaction, and the interaction of PD-L1 with a second T cell negative regulator CD80, have proved to be highly effective in the clinic over a wide array of solid and hematologic tumor indications. Yet, in important tumor types such as non-small cell lung cancer, only a fraction of patients respond clinically: ~20% overall, with responses enriched 2-3 fold in patients whose tumors express PD-L1 at baseline. To improve and extend the benefit of this therapy, it has now become critical to understand the use of biomarkers to aid patient selection and also to devise combinations of anti-PDL1/PD-1 with other immunological, oncogene-targeted, or standard of care chemotherapies. Progress in the clinic has been so rapid, however, that our understanding of how the PD-L1/ PD-1 axis works at the mechanistic level has lagged considerably. Mechanistic understanding is not only a scientifically compelling problem but also will be invaluable to therapeutic efforts. We have, therefore, engaged a series of investigations guided by results of our clinical studies, particularly by the detailed biomarker analysis to discover the immune correlates of “response” and “lack of response” in large patient cohorts. Our analysis to date has revealed a number of fundamental insights into the mechanism of action of PD-1, which in turn has informed strategies for undertaking combination therapies in the clinic.