Engineered exosomes with KrasG12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates
摘要
Oncogenic KRAS is amongst the key genetic drivers for initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with KrasG12D specific siRNA (iExoKrasG12D) reveal a 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 non-randomized single-arm classical 3 + 3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) (NCT03608631). The primary outcomes included safety, tolerability and target engagement, and the secondary outcomes aimed to assess disease control. Patients with advanced metastatic disease were enrolled after failure of multiple lines of therapy. iExoKrasG12D therapy was well-tolerated: the primary outcomes were met with iExoKrasG12D showing no dose-limiting toxicity. The maximum tolerated dose was not reached even at the highest dose. In some cases, iExoKrasG12D therapy was associated with stable disease response (secondary outcome). Downregulation of KRASG12D DNA and suppression of phospho-Erk was documented together with an increase in intratumoral CD8+ T cells following 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 pre-clinical anti-tumor efficacy via FAS mediated CD8+ T cell anti-tumor activity. This first-in-human, precision medicine clinical trial and supporting preclinical functional studies offer new insights into priming of immunotherapy by oncogenic Kras inhibitor for future opportunistic combination therapy for PDAC patients.