Often better tolerated than chemotherapy, immunotherapy is increasingly used to fight cancers[1]. The main pitfall of this therapeutic strategy is that a significant proportion of patients do not respond. For example, in non-small cell lung cancer, only 10-20% of patients respond to anti-PD-1/anti-PD-L1 monoclonal antibody immunotherapy (see box). Although high PD-L1 expression is associated with a better therapeutic response, there is a lack of reliable markers to predict whether or not a patient will respond to an injection of anti-PD-1/anti-PD-L1 antibodies.
ImmunoPET imaging with radiolabeled ligands directed against PD-L1 is a technology that offers the possibility to visualize and quantify in real time and non-invasively the expression of PD-L1 in all tumor lesions, including those difficult to reach by biopsy. In addition, this allows for more accurate prediction of immunotherapy efficacy and longitudinal follow-up to tailor the therapeutic strategy to each patient.
Ideally, a good anti-PD-L1 radioligand should both penetrate and diffuse rapidly into the tumor tissue, while being rapidly cleared from the bloodstream, in order to obtain high contrast PET images with short post-injection times. The examination can then be performed only a few hours after administration of the anti-PD-L1 radioligand.
In addition to radiolabeled antibodies (89Zr-atezolizumab, 89Zr-avelumab or 89Zr-IgG C4), various formats of anti-PD-L1 radioligands with faster pharmacokinetics (PK) have been developed in order to optimize anti-PD-L1 immunoPET imaging, ranging from antibody fragments to small synthetic proteins. This is notably the case in a new study conducted by a team from BioMaps (SHFJ, for radiolabeling and in vivo PK study), in collaboration with the Laboratory of Cellular Immunogenicity and Biotechnologies (LICB, SIMoS/DMTS, for ligand production). To do so, the researchers first produced three radioligands - IgG C4; IgG C4 with a mutation on the Fc chain (H310A/H435Q) and Fab C4, all radiolabeled with 89Zr , and then compared their characteristics by PET/CT imaging in murine mice bearing a subcutaneous non-small cell lung cancer (NSCLC) xenograft. The conclusive results highlighted the potential of manufacturing smaller radioligands with shorter pharmacokinetics for PD-L1 immunoPET imaging in a preclinical model, encouraging further clinical application of such radioligands.
To evade the immune system, some tumor cells exploit the PD-1 co-inhibitory receptor mechanism of T cells by overexpressing the PD-L1 antigen on their surface. It should be noted that in healthy tissues, the expression of this antigen in the PD1/PD-L1 pathway normally prevents an excessive response from the immune system. Thus, thanks to this subterfuge, cancer cells are no longer detected by T cells and can proliferate more easily.
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[1]This strategy is not to attack the tumor cells themselves, but to make the immune system better able to recognize and destroy them.