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Systemic nano-delivery of low-dose STING agonist targeted to CD103+ dendritic cells for cancer immunotherapy
Aatman S Doshi1, Susan Cantin2, Laura B Prickett2
1Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Waltham, MA 02451, United States of America; Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 360 Huntington Ave, Boston, MA 02115, United States of America.
Abstract:
Current methods of STING activation based on intra-tumoral injections of cyclic dinucleotides (CDNs) are not suitable for addressing tumor heterogeneity or for inaccessible, metastatic and abscopal tumors. In this study, we developed systemically administered CD103+ dendritic cell (DCs) targeted liposomal formulations and evaluated the anti-tumor efficacy with low dose. Liposomal CDN formulations were prepared using Clec9a targeting peptide and evaluated therapeutic efficacy in vitro and in vivo in subcutaneous MC38 and B16F10 tumor models. Targeted delivery of CDNs is expected to enhance anti-tumor immune response as well as reduce off-target toxicities. With intravenous 0.1 mg/kg systemic CDN dose of the targeted liposomal formulation, our results showed robust immune response with significant antitumor efficacy both as a monotherapy and in combination with anti-PD-L1 antibody. These results show that a CD103+ DC targeted CDN formulation can lead to potent immune stimulation upon systemic administration even in relatively "cold" tumors such as B16F10.
Insights
Systemic delivery of targeted liposomal cyclic dinucleotides (CDNs) activates immune responses and combats tumors, even "cold" ones. This novel approach offers a low-dose, effective cancer immunotherapy strategy.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Intra-tumoral cyclic dinucleotide (CDN) injections face limitations in treating diverse and inaccessible tumors.
- Systemic delivery methods are needed for broader anti-tumor immune response.
Purpose of the Study:
- To develop systemically administered, CD103+ dendritic cell (DC)-targeted liposomal CDN formulations.
- To evaluate the anti-tumor efficacy of these targeted formulations at low doses.
Main Methods:
- Liposomal CDN formulations were created using Clec9a targeting peptide.
- Therapeutic efficacy was assessed in vitro and in vivo using MC38 and B16F10 subcutaneous tumor models.
- Targeted delivery aimed to enhance anti-tumor immunity and reduce off-target toxicity.
Main Results:
- A low intravenous dose (0.1 mg/kg) of the targeted liposomal CDN formulation induced a robust immune response.
- Significant anti-tumor efficacy was observed as monotherapy and in combination with anti-PD-L1 antibody.
- Potent immune stimulation was achieved even in "cold" B16F10 tumors.
Conclusions:
- CD103+ DC-targeted CDN formulations enable potent immune stimulation via systemic administration.
- This approach overcomes limitations of current intra-tumoral injection methods.
- Targeted liposomal CDNs represent a promising low-dose cancer immunotherapy strategy.
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