Juan Pablo Marquez Manriquez
Sonora Cancer Research Center (CICS), USA
Title: Targeting pancreatic ductal adenocarcinoma with multi-peptide immunotherapy and repurposing drugs
Biography
Biography: Juan Pablo Marquez Manriquez
Abstract
The immunology context, tumor stroma, active-antigen specific multi peptide immunotherapy and the use of repurposing drugs in pancreatic ductal adenocarcinoma (PDAC) clinically speaking are mainly unexplored. We first analyze retrospectively N=37 samples, median age= 47 yrs old from PDAC to study the adaptive and innate immune infiltration of CD8, Th1, Th2 and Tregs cells in tumor tissue and tumor stroma. We also evaluated by siRNA and systematic review 24 potential clinically relevant targets from biologically and clinically relevant proteins. Then we did in vitro using human PBMC’s and tumor cells lines according to systematic reviews of 20 cancer repurposing drugs to determine, if they were able to either improve granzyme B production and/or immunogenic cell death in order to validate what we found in the systematic reviews, Finally we predict from selected proteins 20 peptides in total as they were immunogenic by granzyme B ELISPOT and IgA + IgG + IgM antigen-specific ELISA. With this proof of principle, the local ethics committee approved the enrollment of eleven PDAC patients refractory but with a Karnofsky > 80% to be treated with this treatment approach. We found that peptides VCP 7 (P=0.001), fascin 8 (p=0.0001), FAP 2 (p=0.005), ALDH1 –B (p=0.002), Beclin-1 -E (P=0.01), IL-6R 4 (p=0.0001), NF-kB 5 (p=0.001), Muc-1 (0.001) and Alpha methylacyl-CoA racemase n (p.01) were the immunogenic according with prism and STAT3 analysis. Paladin and Galectin-3 were N.S. In these pilot trial eight peptides showed immunological correlation with a PFS (median=26 months). In terms of the drugs meloxicam (p=0001), enoxaparin (p=0001), clopidogrel (p=005), bortezomib (o.0001), naproxen (o.003), ursodeoxycholic acid (p=0.001 and thalidomide (p=0001) showed clinical activity in the combo therapy without significant adverse effects not even autoimmunity. As preliminary conclusion, the future in clinical oncology is rationally combine different therapies especially for challenge tumors such as PDAC and many others. Combining immuno treatment with validated repurposing drugs is a promising and safe approach. The next step is to publish this preliminary data and then a phase I clinical trial