Article Text
PDF
Abstract
Background Immune checkpoint inhibitors (ICI) are considered as a breakthrough in cancer therapy, however only a subset of patients actually responds to current treatments, indicating a strong remaining medical need. Locked nucleic acid (LNA) modified antisense oligonucleotides (ASOs) allow for a specific target knockdown after systemic injection without delivery agents. The membrane bound multi domain protein neuropilin-1 (NRP1) is a promising therapeutic target, since it has been implicated in various pro-tumorigenic processes, including stability of regulatory T-cells, exhaustion of CD8+ T-cells, macrophage migration and polarization, and neovascularization. Since these effects are mediated by different domains, blocking antibodies that only bind to a single domain might only have limited effects. Thus, the knockdown of the complete protein is conceptually advantageous.
Methods Using our in-house Oligofyer™ bioinformatics system, we designed LNA-modified NRP1 specific ASOs and were able to identify potent candidates in cellular screens. The most promising candidates were tested by intraperitoneal injection in two syngeneic tumor models, either as a monotherapy, or in combination with an anti-PD-L1 antibody.
Results In syngeneic mouse models, systemically administered NRP1-specific ASOs achieved a potent target knockdown in several relevant cell types within the tumor microenvironment and a strong reduction in plasma levels of soluble NRP1. Furthermore we observed strongly reduced tumor growth-rates in animals treated with NRP1 ASOs as monotherapy. In combination with PD-L1 antibody we achieved a potent on-top effect with lasting complete tumor eradication in many animals and prolonged survival (figure 1). Re-challenge experiments with mice that were tumor-free after the treatment indicated establishment of anti-tumor immunity in treated mice.
Conclusions NRP1 is a promising new target with multiple pro-tumorigenic roles mediated by different domains. Simultaneous inhibition of all of these functions via knockdown of its expression by ASOs appears to be a favorable treatment modality in this regard, which could overcome limitations faced by alternative approaches. Systemically administered LNA-modified ASOs targeting NRP1 have the potential to become a new treatment option - both as a monotherapy and in combination with other ICIs - in various cancer indications that do not respond to current treatments. Further mechanistic research will be instrumental to translate these findings to the clinics.
Effects on survival in orthotopic syngeneic EMT6 model
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.