Analysis of soluble high-affinity PD1 variants

Despite achieving significant clinical impact in several major cancer types such as melanoma or Hodgkin’s lymphoma, immunotherapies have not had much success in the treatment of pancreatic cancer. This cancer is characterised by a pro-inflammatory and immunosuppressive stroma which causes aggressive cancer growth and results in drug resistance. In this study we seek to overcome some of the challenges associated with drug delivery into the pancreatic cancer microenvironment and design a checkpoint inhibitor therapeutic to inhibit PD1/PD-L1 signalling. Mesenchymal stem cells (MSCs) offer an alternative drug delivery method for delivering this treatment to the pancreas due to their ability to infiltrate tumours and deliver a therapeutic pay load. In this study soluble PD1 (sPD1) variants were generated with increased binding properties to PD-L1. The sPD1 variants were analysed using solid-phase protein competition studies as well as live pancreatic cell assays to assess their immune checkpoint inhibitory functions. These studies revealed that one variant - expressed as an IgG fusion protein, that can completely outcompete wild-type PD1, even at very low concentrations. MSCs were then successfully engineered to produce and secrete this variant. These cells were termed MSC.sPD1. This way of delivering therapeutics into the tumour microenvironment holds great promise, however it should be noted that MSCs have been associated with several undesirable effects, and further research needs to be conducted on MSC.sPD1 to confirm their safety and efficacy.