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Abstract 4149: Knock-down of Neuropilin-1 by locked nucleic acid antisense oligonucleotides facilitates cancer immune control


 Immune checkpoint inhibitors have become an important tool for the treatment of cancer. However, the majority of patients does not respond to the currently employed antibody-based treatments, indicating a need for additional targets and new treatment modalities. The invention of 3rd generation chemistries like locked nucleic acids (LNAs) has allowed the development of highly specific and efficacious antisense oligonucleotides (ASOs) that allow target knockdown in vivo without the need for complex delivery formulations.
 The membrane-bound protein neuropilin-1 (NRP1) was initially identified as a factor involved in cell migration, -survival, and neoangiogenesis making it an attractive target for cancer therapy. It was subsequently shown that it has additional immune-mediated pro-tumorigenic roles. It can suppress anti-tumor immune activity via regulation of trafficking of tumor-associated macrophages, phenotypic stability of Tregs, and exhaustion of effector T cells. Considering that these effects are mediated by multiple domains of NRP1, there is a conceptual advantage to down-regulate the expression of the whole protein over the functional or steric blockade of individual domains.
 We used our in-house Oligofyer™ bioinformatics system to design both human NRP1 specific LNAplus™ ASOs, as well as murine surrogates, which both achieved target knock-down of more than 85% in vitro. Furthermore, the murine surrogate down regulated NRP1 in tumor mouse models. Systemic application of mouse-specific ASOs without additional carriers or adjuvants has led to a strong delay of tumor growth or complete eradication in syngeneic mouse models. This effect was almost completely abrogated in immune-compromised NSG mice. Furthermore, re-challenge of immune-competent mice after tumor eradication did not result in new tumor growth, suggesting induction of a long-lasting immunity by LNAplus™ ASO-mediated knockdown of NRP1. Taken together, these encouraging results indicate that the ASO-mediated down-regulation of NRP1 has the potential to become a promising treatment option for patients in need. We are currently performing further experiments to fully elucidate the mechanisms that underlie the observed anti-tumor efficacy.
 Citation Format: Andre Maaske, Nicole Kirchhammer, Julia Festag, Laura Fernandez Rodriguez, Mélanie Buchi, Monika Schell, Stefanie Raith, Sven Michel, Richard Klar, Alfred Zippelius, Frank Jaschinski. Knock-down of Neuropilin-1 by locked nucleic acid antisense oligonucleotides facilitates cancer immune control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4149.