Engineered exosomes with Kras^G12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates

Valerie S Kalluri ^1,2, Brandon G Smaglo ³, Krishnan K Mahadevan ⁴

¹Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. vlebleu@mdanderson.org.
²Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA. vlebleu@mdanderson.org.
³Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, USA.
⁸Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹Verna Marrs and McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
¹⁰Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹²Division of Hematology/Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
¹³Department of Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵Department of Bioengineering, Rice University, Houston, TX, USA.
¹⁶Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
¹⁷Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.

⁰Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. vlebleu@mdanderson.org.

Nature Communications +

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September 30, 2025

View abstract on PubMed

Summary

Engineered exosomes targeting KRAS G12D (iExoKrasG12D) showed safety and potential for pancreatic cancer treatment. This therapy may prime the immune system for combination immunotherapy, offering new hope for pancreatic ductal adenocarcinoma (PDAC) patients.

Area Of Science

Oncology
Nanomedicine
Immunotherapy

Background

Oncogenic KRAS mutations are key drivers of pancreatic ductal adenocarcinoma (PDAC).
Targeting KRAS mutations is crucial for effective PDAC treatment.
Novel drug delivery systems are needed to target KRAS in PDAC.

Purpose Of The Study

To evaluate the safety, tolerability, and target engagement of engineered exosomes with KrasG12D specific siRNA (iExoKrasG12D) in a Phase I clinical trial for advanced PDAC.
To assess the preliminary efficacy and immunomodulatory effects of iExoKrasG12D therapy.
To explore the preclinical efficacy of iExoKrasG12D in combination with immunotherapy.

Main Methods

A Phase I clinical trial (iEXPLORE study) using a 3+3 dose escalation design (Phase Ia) and accelerated titration design (Phase Ib) was conducted.
Patients with advanced metastatic PDAC received iExoKrasG12D therapy after failure of multiple lines of treatment.
Preclinical studies validated target engagement, immunomodulatory effects, and combination therapy potential.

Main Results

iExoKrasG12D therapy was well-tolerated with no dose-limiting toxicity observed.
Stable disease response was noted in some patients, indicating potential anti-tumor activity.
Treatment led to KRASG12D DNA downregulation, suppressed phospho-Erk, and increased intratumoral CD8+ T cells.
Preclinical studies showed combination therapy with anti-CTLA-4 antibodies enhanced anti-tumor efficacy via CD8+ T cell activity.

Conclusions

Engineered exosomes (iExoKrasG12D) represent a safe and tolerable therapeutic approach for PDAC.
iExoKrasG12D demonstrates target engagement and immunomodulatory effects, including CD8+ T cell recruitment.
This therapy shows promise for priming the tumor microenvironment for immunotherapy, suggesting potential for combination strategies in PDAC treatment.