KRASG12D-Specific Targeting with Engineered Exosomes Reprograms the Immune Microenvironment to Enable Efficacy of Immune Checkpoint Therapy in PDAC Patients

Oncogenic KRAS drives initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with KrasG12D specific siRNA (iExoKrasG12D) reveal impressive biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKrasG12D in the iEXPLORE (iExoKrasG12D 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. iExoKrasG12D 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 KRASG12DDNA 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 iExoKrasG12D informed on potential efficacy of immune checkpoint therapy and lead to validation testing in preclinical PDAC models. Combination therapy of iExoKrasG12D 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.