HPB Immunotherapy
Therapeutic application of TNF family ligands?
CD40-targeted therapy
CD40, a member of the tumour necrosis factor receptor (TNFR) superfamily, and its membrane-bound homotrimeric ligand (CD40L/CD154) play a central role in orchestrating immune responses. Ligation of CD40 on dendritic cells enhances antigen presentation. CD40 is also expressed by certain cancers and ligation of CD40 on carcinoma cells enhances antigen presentation and recognition by tumour-specific CTLs and can, in the right context, induce cancer cell apoptosis. The effects of CD40 ligation in an epithelial context are complex with the precise form of the CD40 stimulus affecting the cellular response, the most profound effects in carcinoma cells being induced by membrane-bound (mCD40L) rather than recombinant soluble CD40L (rsCD40L) or agonist monoclonal antibody (mAb). Ligands of the TNF family are naturally expressed as membrane-bound homotrimeric molecules that are cleaved into soluble forms by members of the ADAM metalloproteinase (MP) family. Palmer’s group identified and deleted the MP cleavage site of CD40L and generated a mutated CD40L that is resistant to metalloproteinase cleavage, which retains ligand at the cell membrane and results in significantly enhanced apoptosis and more robust up-regulation of antigen-presentation machinery in cancer cells and more robust DC activation compared to wild-type CD40L or agonist mAb, making this a strong candidate for cancer immunotherapy (Elmetwali, Young and Palmer. J Immunol, 2010).
Hepatocellular carcinoma (HCC) possesses characteristics that render it a good target for immunotherapy with active recruitment of lymphocytes suggesting a potential for cytotoxic effector cell activation. However, immunosuppressive mechanisms prevent their maturation in to useful anti-tumour effectors. Dendritic cells (DC) are also present in HCC. However, these fail to mature and their immature phenotype contributes to the defective effector T cell responses and promotes the generation of regulatory T cells and a tolerogenic tumour micro-environment. Whilst HCC has a lymphocytic infiltrate, there is an absence of CD4+ T-cells. This lack of T-cell help may contribute to the failure of adequate DC maturation through an absence of CD40L with resultant immunotolerance. HCC also commonly expresses CD40 and we have demonstrated its sensitivity to membrane-expressed CD40 ligand. Thus, HCC is a strong target for our CD40 ligand therapy. In collaboration with Memgen Inc (San Diego) we have validated Ad-ISF35, a replication deficient adenovirus expressing a novel recombinant human-murine chimeric CD40-binding protein that also lacks metalloproteinase cleavage sites and is therefore retained at the cell membrane and, in collaboration with Birmingham ECMC, we plan to undertake the first solid tumour phase I clinical trial of this agent in patients with advanced HCC.
Cellular therapies
Allogeneic antigen presenting cell vaccine
In collaboration with Cancer Vaccines, we are also investigating a novel GMP allogeneic antigen-presenting cell platform in pre-clinical studies in our laboratory, with a view to first-in-human phase I trials in 2014.
Assessment of safety of immunotherapies
In order to monitor the safety of these immunotherapies, a battery of biological assays to quantify the humeral and cellular response are already established in the Liverpool MRC Centre for Drug Safety Science for an integrated pharmaco-toxicological approach, based on collaborations between oncologists and pharmacologists.
Furthermore, cell-based therapy trials are a component of the recently successful CDSS bid for a regenerative medicine platform for stem cell safety science by providing a vehicle for the first-in-human assessment of novel supraparamagnetic iron oxide nanoparticle labels to determine the distribution and viability of cells in vivo.
