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Updated: Dec 19, 2025
Immunostimulatory Agent Evaluation: Lymphoid Tissue Extraction and Injection Route-Dependent Dendritic Cell Activation
Published on: September 16, 2018
Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics
Colin G Buss1,2, Sangeeta N Bhatia3,2,4,5,6,7,8
1Harvard-MIT Health Sciences and Technology Program, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
Abstract:
The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.
Insights
Novel nanoparticles delivering immunostimulatory CpG DNA activate anti-tumor immunity. This approach enhances responses to checkpoint inhibitors, offering a promising strategy for cancer therapy.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Immune checkpoint inhibitors (CPI) have transformed cancer therapy but have limited efficacy due to immunosuppressive tumor microenvironments.
- Delivering immunostimulatory molecules into tumors is a potential strategy to enhance anti-tumor immunity.
- Nanoparticle formulations can improve the delivery and efficacy of these immunostimulatory agents.
Purpose of the Study:
- To develop and evaluate a modular nanoparticle system for delivering immunostimulatory oligonucleotides to enhance anti-tumor responses.
- To investigate the therapeutic potential of these nanoparticles in combination with CPI therapy.
- To assess the efficacy of systemically administered nanoparticles with tumor-homing peptides.
Main Methods:
- Development of modular nanoparticles encapsulating immunostimulatory oligonucleotides (CpG DNA ligand for TLR9).
- In vitro assessment of immune cell activation.
- In vivo evaluation of nanoparticle efficacy in suppressing tumor growth in various cancer models.
- Assessment of abscopal effects and combination therapy with anti-CTLA4 antibodies.
- Incorporation of tumor-homing peptides for systemic delivery and evaluation of intravenous administration.
Main Results:
- Engineered nanoparticles carrying CpG DNA demonstrated in vitro potent activation of inflammatory signaling.
- Intratumoral administration of these nanoparticles suppressed tumor growth in multiple cancer models.
- A significant abscopal effect was observed on distant tumors.
- Combination therapy with anti-CTLA4 antibodies showed enhanced anti-tumor efficacy.
- Systemic intravenous administration of nanoparticles with tumor-homing peptides also facilitated anti-tumor efficacy.
Conclusions:
- Immunostimulatory nanoparticles are effective in suppressing tumor growth and enhancing anti-tumor immunity.
- These nanoparticles can improve the efficacy of immune checkpoint inhibitor therapies, particularly when administered intratumorally.
- Systemic delivery of engineered nanoparticles with tumor-homing peptides offers a promising strategy for broader therapeutic application in cancer treatment.
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