PET Imaging of PD-L1 Occupancy for Preclinical Assessment of the Efficacy of Combined Anti–PD-L1 Immunotherapy and Targeted Therapy

The development of resistance significantly hampers the efficacy of immunotherapies in cancer treatment. The combination of JQ1, a BRD4 protein inhibitor, and anti-programmed death ligand 1 (PD-L1) immunotherapies has a synergic therapeutic potential to treat solid tumors. This study aimed to evaluate the potential of immuno-PET imaging for measuring pharmacodynamic biomarkers in response to this combination therapy targeting PD-L1. <b>Methods:</b> We synthesized different radioligands derived from the anti-PD-L1 C4 antibody and a minibody targeting murine CD8α for immuno-PET imaging. We conducted experiments on human non-small cell lung cancer and mouse colorectal carcinoma animal models to assess the efficacy of JQ1 and avelumab treatment on PD-L1 expression and immune cell infiltration by immuno-PET imaging. Taking advantage of the unique properties of the C4-derived minibody, we measured PD-L1 occupancy in tumors after treatment. <b>Results:</b> JQ1 efficiently reduced PD-L1 extracellular expression across all tested cell lines in vitro and in vivo. Avelumab and JQ1 treatments alone or in combination led to significant tumor growth reduction in the immunocompetent murine colorectal carcinoma model, reducing mean tumor growth from 725% in the control group to 125% in the combination group. Treatments also significantly increased the survival of mice by 4-12 d compared with the control group. Although imaging CD8-positive T-cell infiltration did not predict tumoral response, imaging the unoccupied fraction of PD-L1 after treatment was predictive of tumor growth reduction and survival. <b>Conclusion:</b> Immuno-PET imaging with noncompetitive radioligands throughout the treatment course could improve the efficiency and support rationalization of the dosing regimen of immunotherapies.