Engineered exosomes with KrasG12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates

Valerie S. Kalluri (), Brandon G. Smaglo, Krishnan K. Mahadevan, Michelle L. Kirtley, Kathleen M. McAndrews, Mayela Mendt, Sujuan Yang, Ana S. Maldonado, Hikaru Sugimoto, Maria E. Salvatierra, Luisa M. Solis Soto, Cara Haymaker, Rick Finch, Mihai Gagea, Adam C. Fluty, Steven J. Ludtke, J. Jack Lee, Abhinav K. Jain, Gauri Varadhachary, Rachna T. Shroff, Anirban Maitra, Elizabeth Shpall, Shubham Pant and Raghu Kalluri
Additional contact information
Valerie S. Kalluri: The University of Texas MD Anderson Cancer Center
Brandon G. Smaglo: The University of Texas MD Anderson Cancer Center
Krishnan K. Mahadevan: The University of Texas MD Anderson Cancer Center
Michelle L. Kirtley: The University of Texas MD Anderson Cancer Center
Kathleen M. McAndrews: The University of Texas MD Anderson Cancer Center
Mayela Mendt: The University of Texas MD Anderson Cancer Center
Sujuan Yang: The University of Texas MD Anderson Cancer Center
Ana S. Maldonado: The University of Texas MD Anderson Cancer Center
Hikaru Sugimoto: The University of Texas MD Anderson Cancer Center
Maria E. Salvatierra: The University of Texas MD Anderson Cancer Center
Luisa M. Solis Soto: The University of Texas MD Anderson Cancer Center
Cara Haymaker: The University of Texas MD Anderson Cancer Center
Rick Finch: The University of Texas MD Anderson Cancer Center
Mihai Gagea: The University of Texas MD Anderson Cancer Center
Adam C. Fluty: Baylor College of Medicine
Steven J. Ludtke: Baylor College of Medicine
J. Jack Lee: The University of Texas MD Anderson Cancer Center
Abhinav K. Jain: The University of Texas MD Anderson Cancer Center
Gauri Varadhachary: The University of Texas MD Anderson Cancer Center
Rachna T. Shroff: University of Arizona Cancer Center
Anirban Maitra: The University of Texas MD Anderson Cancer Center
Elizabeth Shpall: The University of Texas MD Anderson Cancer Center
Shubham Pant: The University of Texas MD Anderson Cancer Center
Raghu Kalluri: The University of Texas MD Anderson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63718-2

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