Abstract
Oncogenic KRAS drives initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with Kras (G12D) specific siRNA (iExoKras (G12D) ) reveal impressive biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKras (G12D) in the iEXPLORE (iExoKras (G12D) in Pancreatic Cancer) Phase I study employed a classical 3+3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) ( NCT03608631 ). Patients with advanced metastatic disease were enrolled after failure of multiple lines of therapy. iExoKras (G12D) therapy was well-tolerated with no reported dose-limiting toxicity with some cases of stable disease response, and maximum tolerated infusion was not reached even at the highest dose. Downregulation of KRAS (G12D) DNA and suppression of phopho-Erk was documented with increased intratumoral in CD8 (+) T cell infiltration in patient samples upon treatment. The CD8 (+) T cell recruitment priming by iExoKras (G12D) informed on potential efficacy of immune checkpoint therapy and lead to validation testing in preclinical PDAC models. Combination therapy of iExoKras (G12D) and anti-CTLA-4 antibodies, but not anti-PD1, revealed robust anti-tumor efficacy via FAS mediated CD8 (+) T cell anti-tumor activity. This first-in-human, precision medicine clinical trial offers new insights into priming of immunotherapy by oncogenic Kras inhibitor and an opportunistic combination therapy for PDAC patients.