The stunning success of immunotherapies is not realized in every patient, putatively because current methods of assessing target levels rely on immunohistochemical techniques that have lacked the accuracy to assess the potential for patient response. While the immune system has the capacity to inhibit tumor growth, tumor cells can evade death through the expression of proteins, such as PD-L1 (programmed death ligand-1, B7-H1), that exert an immunosuppressive effect. PD-L1, upregulated through a variety of mechanisms, binds its cognate ligand PD-1 on T-cells, thus inactivating the cytotoxic effect of the T-cells. Current immunotherapies overcome this type of inhibition by preventing the interaction of PD-L1 and PD-1. Therefore, PD-L1 could serve as a predictive biomarker for immunotherapy. Quantification of PD-L1 levels by PET could avoid tissue sampling artifacts and provide real-time information of target levels to direct the commencement of immunotherapies in patients as well as in pre-clinical models. Currently, pre-clinical research in imaging PD- L1 is based on a handful of intact monoclonal Abs which, due to the long serum half-life of intact Mabs, will ultimately limit their use in preclinical or clinical longitudinal investigations that could elucidate whether PD-L1 could serve as a selection marker and predict response with immunotherapeutic Mabs such as anti-PD-1 (or PD-L1). From our recently developed scFv library, we already have isolated high affinity scFvs for PD-L1, where we can, through recombinant techniques, optimize the structure for high signal to noise in preclinical animal models of human cancer.
Although the human immune system has the capacity to destroy a tumor, the power of the immune system is sometimes turned off by the cancer. There are new treatments that restart the immune system but it is difficult to know when they will be useful. We are designing non-invasive, diagnostic imaging agents to determine when and if to administer those treatments.
| Abadjian, Marie-Caline Z; Edwards, W Barry; Anderson, Carolyn J (2017) Imaging the Tumor Microenvironment. Adv Exp Med Biol 1036:229-257 |
