Nature Communications | Engineered exosomes with KRASG12D-targeting siRNA in pancreatic cancer: a Phase I clinical study

This study is the first to evaluate the safety and targeting efficacy of engineered exosomes carrying KRASG12D-targeting siRNA in humans with pancreatic cancer and reveals their synergistic potential with immune checkpoint therapy. It provides a novel combination strategy for pancreatic cancer treatment.

 

Literature Overview
This article, titled "Engineered exosomes with KrasG12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates" published in Nature Communications, reviews preclinical and Phase I clinical studies of KRASG12D-targeted siRNA-modified exosomes in pancreatic ductal adenocarcinoma (PDAC). The article highlights that KRAS mutations drive PDAC pathogenesis, while engineered exosomes (iExoKrasG12D) demonstrate favorable biodistribution and tolerability in murine and rhesus monkey models. Clinical Phase I trials further validate their safety and targeting capabilities.

Background Knowledge
Oncogenic KRAS serves as a critical genetic driver for PDAC initiation and progression, with KRASG12D mutations occurring in approximately 50% of KRAS-mutant PDAC cases. Although direct KRAS-targeting small molecule inhibitors (e.g., MRTX1133) have entered clinical trials, drug resistance and off-target effects remain significant challenges. Exosomes, as naturally occurring lipid bilayer nanoparticles with low immunogenicity, excellent biocompatibility, and targetable properties, represent ideal RNA delivery vehicles. iExoKrasG12D employs electroporation to load KRASG12D-specific siRNA, aiming to induce immunogenic cell death in PDAC cells and enhance CD8+ T cell-mediated antitumor responses. This study integrates preclinical models with Phase I clinical trials to explore the therapeutic potential of exosome-delivered siRNA in PDAC, particularly its combination with immune checkpoint inhibition therapies.

 

 

Research Methods and Experiments
1. Preclinical studies: Biodistribution and toxicity of iExoKrasG12D were evaluated using murine and rhesus monkey models. iExoKrasG12D was characterized via NanoSightTM, flow cytometry, and cryo-electron microscopy.
2. Clinical trial design: A non-randomized, single-arm, 3+3 dose-escalation protocol (Phase Ia) followed by accelerated titration design (Phase Ib) was implemented to assess safety and targeting capabilities of iExoKrasG12D in patients with advanced KRASG12D-mutant PDAC.
3. Post-clinical analysis: KRASG12D expression dynamics and immune microenvironment remodeling—including CD8+ T cell recruitment and activation of FAS/FASL pathways—were evaluated through circulating free DNA (cfDNA) and tissue biopsies.
4. Combination therapy validation: Antitumor efficacy of iExoKrasG12D combined with anti-CTLA-4 or anti-PD-1 antibodies was tested in mouse models.

Key Conclusions and Perspectives

• iExoKrasG12D demonstrated favorable biodistribution and tolerability in preclinical models, primarily accumulating in pancreas and liver.
• In Phase Ia/b trials, iExoKrasG12D treatment was well-tolerated with no dose-limiting toxicities, inducing disease stabilization in some patients.
• KRASG12D DNA levels decreased post-treatment, p-ERK signaling was suppressed, and CD8+ T cell recruitment enhanced, indicating immune activation.
• iExoKrasG12D enhances FAS upregulation and CD8+ T cell recruitment, providing mechanistic rationale for subsequent immune checkpoint therapies.
• In murine models, iExoKrasG12D combined with anti-CTLA-4 showed significant antitumor synergy, while no synergistic effect was observed with anti-PD-1 combination.

Research Significance and Prospects
This study represents the first human validation of KRASG12D-specific siRNA engineered exosomes' safety and targeting capabilities, complemented by preclinical evidence of immunomodulatory potential. Results support iExoKrasG12D application in PDAC, particularly its synergy with immunotherapy. Future research should optimize iExoKrasG12D delivery systems, validate efficacy in larger clinical trials, and explore combination strategies with diverse immune checkpoint inhibitors. Additionally, the molecular mechanisms underlying KRAS-targeted therapy and immune microenvironment remodeling require deeper investigation to advance personalized PDAC treatments.

 

 

Conclusion
This study represents the first human evaluation of KRASG12D-specific siRNA-engineered exosomes (iExoKrasG12D) in advanced pancreatic ductal adenocarcinoma, demonstrating safety and target engagement. Preclinical and clinical Phase I data showed no significant toxicity, with effective KRASG12D silencing, signaling pathway suppression, and enhanced CD8+ T cell recruitment. Notably, murine models revealed significant antitumor synergy between iExoKrasG12D and anti-CTLA-4 antibodies, but not with anti-PD-1. These findings establish a foundation for combination therapies in KRAS-driven PDAC and provide critical insights for developing exosome-based RNAi platforms in tumor immunotherapy. With advancing exosome engineering technologies, their applications in precision medicine and personalized oncology hold great promise.

 

Valerie S Kalluri, Brandon G Smaglo, Krishnan K Mahadevan, Shubham Pant, and Raghu Kalluri. Engineered exosomes with KrasG12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates. Nature Communications.