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KRAS G12D -Specific Targeting with Engineered Exosomes Reprograms the Immune Microenvironment to Enable Efficacy of
Abstract:
Oncogenic KRAS drives initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with Kras G12D specific siRNA (iExoKras G12D ) reveal impressive biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKras G12D in the iEXPLORE (iExoKras G12D 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. iExoKras G12D 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 KRAS G12D DNA 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 iExoKras G12D informed on potential efficacy of immune checkpoint therapy and lead to validation testing in preclinical PDAC models. Combination therapy of iExoKras G12D 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.
Insights
Engineered exosomes targeting KRAS G12D (iExoKras G12D) showed safety and pancreatic biodistribution in early trials. This pancreatic cancer therapy enhanced anti-tumor immune responses, suggesting combination potential with immunotherapy.
Area of Science:
- Oncology
- Nanomedicine
- Immunotherapy
Background:
- Oncogenic KRAS is a key driver in pancreatic ductal adenocarcinoma (PDAC) initiation and progression.
- Targeting KRAS offers a potential therapeutic strategy for PDAC, a disease with limited treatment options.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary efficacy of engineered exosomes delivering Kras G12D specific siRNA (iExoKras G12D) in patients with advanced PDAC.
- To investigate the molecular and immunological effects of iExoKras G12D therapy in PDAC patients.
- To explore the potential of iExoKras G12D in combination with immune checkpoint inhibitors.
Main Methods:
- Phase I clinical trial (iEXPLORE study) using a 3+3 dose escalation design followed by accelerated titration.
- Administration of engineered exosomes (iExoKras G12D) to patients with advanced metastatic PDAC.
- Assessment of safety, pharmacodynamics (KRAS DNA, phospho-Erk), and immune cell infiltration (CD8+ T cells).
- Preclinical validation of combination therapy with iExoKras G12D and immune checkpoint antibodies (anti-CTLA-4, anti-PD1).
Main Results:
- iExoKras G12D therapy was well-tolerated with no dose-limiting toxicity observed, and the maximum tolerated dose was not reached.
- Treatment led to KRAS DNA downregulation, suppressed phospho-Erk signaling, and increased intratumoral CD8+ T cell infiltration.
- Combination therapy with iExoKras G12D and anti-CTLA-4 antibodies demonstrated robust anti-tumor efficacy in preclinical models, mediated by CD8+ T cells.
Conclusions:
- Engineered exosomes (iExoKras G12D) represent a safe and well-tolerated therapeutic approach for advanced PDAC.
- iExoKras G12D treatment can prime the tumor microenvironment for immunotherapy by enhancing CD8+ T cell activity.
- Combination therapy with iExoKras G12D and anti-CTLA-4 antibodies shows promise for treating PDAC.
