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Poster Display session

128P - Non-coding DNA lipid nanoparticles elicit antitumor immune responses and synergize with anti-PDL1 antibodies in mouse models of hepatocellular carcinoma

Date

12 Dec 2024

Session

Poster Display session

Presenters

Alba Rodriguez Garcia

Citation

Annals of Oncology (2024) 24 (suppl_1): 1-26. 10.1016/iotech/iotech100745

Authors

A. Rodriguez Garcia1, S. Yum2, J. Castellsagué3, M. Giménez-Alejandre3, G. Colell3, S. Colell3, R. Zhang2, X.M. Anguela2, A. Nahvi2, M. Walsh2, P. Cejas2, S. Armour2, S. Guedan3

Author affiliations

  • 1 IDIBAPS - Fundació de Recerca Clinic Barcelona, Barcelona/ES
  • 2 Spark Therapeutics, Philadelphia/US
  • 3 IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona/ES

Resources

This content is available to ESMO members and event participants.

Abstract 128P

Background

Immune checkpoint inhibitors (ICI) have opened a new era in the clinical management of hepatocellular carcinoma (HCC). Unfortunately, not all patients benefit from this treatment. Nucleic acid-based therapies, particularly those utilizing lipid nanoparticles (LNPs) as delivery vehicles, offer promising avenues for cancer treatment. In this study, we hypothesized that intracellular delivery of non-coding double-stranded DNA (dsDNA) by LNPs can activate the innate system to induce antitumor immune responses and potentiate ICI.

Methods

Non-coding DNA-LNPs were formulated by mixing promoterless plasmid and lipid components using a microfluidic device. Their antitumor efficacy, alone or in combination with anti-PD-L1 antibodies, was interrogated in genetically and chemically induced mouse models of HCC. Cytokine levels in serum were measured 4 hours post-treatment. At the study endpoint, livers were harvested for macroscopic evaluation, immunohistochemistry staining, and gene expression analysis. Survival was also analyzed.

Results

Administration of non-coding DNA-LNPs in mice induced a rapid and dose-dependent elevation in serum cytokines including IFN-γ, TNF-α, IL-6 or IFN-β. This immune activation led to the recruitment of endogenous CD8+ T cells, which mediated a significant antitumor effect as indicated by increased overall survival and reduced liver/body weight ratio and tumor nodule count. Depletion of CD8+ T cells abrogated therapeutic efficacy. Neither cytokine elevation nor antitumor effects were observed after treatment with empty LNPs, suggesting that these responses were triggered by the activation of cytosolic DNA-sensing pathways. Combining DNA-LNPs with anti-PD-L1 antibodies showed a synergistic effect, with 90% of mice remaining disease-free at the endpoint as compared to 20% and 50%, respectively, with either treatment alone.

Conclusions

Non-coding DNA-LNPs represent a promising therapeutic strategy for HCC, capable of eliciting potent antitumor immune responses. Their efficacy, particularly in combination with ICI, highlights their potential for clinical application in treating HCC.

Legal entity responsible for the study

Spark Therapeutic Inc.

Funding

Spark Therapeutics.

Disclosure

S. Yum, M. Walsh, P. Cejas, S. Armour: Financial Interests, Personal, Full or part-time Employment: Spark Therapeutics Inc.; Financial Interests, Personal, Licencing Fees or royalty for IP: Spark Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Spark Therapeutics Inc. R. Zhang: Financial Interests, Personal, Licencing Fees or royalty for IP: Spark Therapeutics Inc. X.M. Anguela: Financial Interests, Personal, Licencing Fees or royalty for IP: Spark Therapeutics Inc. A. Nahvi: Financial Interests, Personal, Licencing Fees or royalty for IP: Spark Therapeutics Inc. S. Guedan: Financial Interests, Personal, Licencing Fees or royalty for IP: IDIBAPS. All other authors have declared no conflicts of interest.

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