ArticleMolecular therapy : the journal of the American Society of Gene Therapy2020
DNA-Based Delivery of Checkpoint Inhibitors in Muscle and Tumor Enables Long-Term Responses with Distinct Exposure.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 18 citations in OpenAlex.
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- Expanding the Reach of Monoclonal Antibodies: A Review of Synthetic Nucleic Acid Delivery in Immunotherapy.Antibodies (Basel, Switzerland) · 2023Review
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- Exploring the Fate of Antibody-Encoding pDNA after Intramuscular Electroporation in Mice.Pharmaceutics · 2023Article
- Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors.International journal of molecular sciences · 2023Review
- Plasmid DNA for Therapeutic Applications in Cancer.Pharmaceutics · 2022Review
- Intratumoral DNA-based delivery of checkpoint-inhibiting antibodies and interleukin 12 triggers T cell infiltration and anti-tumor response.Cancer gene therapy · 2022Article
- Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model.Frontiers in oncology · 2022Article
- Nanomedicine for Immunotherapy Targeting Hematological Malignancies: Current Approaches and Perspective.Nanomaterials (Basel, Switzerland) · 2021Review
- DNA-based delivery of anti-DR5 Nanobodies improves exposure and anti-tumor efficacy over protein-based administration.Cancer gene therapy · 2021Article
- Nanomaterials for Protein Delivery in Anticancer Applications.Pharmaceutics · 2021Review
- Local Destruction of Tumors and Systemic Immune Effects.Frontiers in oncology · 2021Review
- Electroporation outperforms in vivo-jetPEI for intratumoral DNA-based reporter gene transfer.Scientific reports · 2020Article
- Electroporation as the Immunotherapy Strategy for Cancer in Veterinary Medicine: State of the Art in Latin America.Vaccines · 2020Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Checkpoint-inhibiting antibodies elicit impressive clinical responses, but still face several issues. The current study evaluated whether DNA-based delivery can broaden the application of checkpoint inhibitors, specifically by pursuing cost-efficient in vivo production, facilitating combination therapies, and exploring administration routes that lower immune-related toxicity risks. We therefore optimized plasmid-encoded anti-CTLA-4 and anti-PD-1 antibodies, and studied their pharmacokinetics and pharmacodynamics when delivered alone and in combination via intramuscular or intratumoral electroporation in mice. Intramuscular electrotransfer of these DNA-based antibodies induced complete regressions in a subcutaneous MC38 tumor model, with plasma concentrations up to 4 and 14 μg/mL for anti-CTLA-4 and anti-PD-1 antibodies, respectively, and antibody detection for at least 6 months. Intratumoral antibody gene electrotransfer gave similar anti-tumor responses as the intramuscular approach. Antibody plasma levels, however, were up to 70-fold lower and substantially more transient, potentially improving biosafety of the expressed checkpoint inhibitors. Intratumoral delivery also generated a systemic anti-tumor response, illustrated by moderate abscopal effects and prolonged protection of cured mice against a tumor rechallenge. In conclusion, intramuscular and intratumoral DNA-based delivery of checkpoint inhibitors both enabled long-term anti-tumor responses despite distinct systemic antibody exposure, highlighting the potential of the tumor as delivery site for DNA-based therapeutics.
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Registered trials
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