Noxopharm has reported preclinical results showing that its technology can help the immune system recognise cellular RNA that would normally fail to trigger an anti-cancer response.
The Sydney-based clinical-stage biotechnology company said the findings provide proof of principle for its approach of using short synthetic RNA sequences called oligonucleotides to amplify the activity of Toll-like receptor 8, or TLR8. This receptor acts as an immune sensor that helps the body identify potential threats.
The immune system is already central to the fight against cancer, but some cancer cells can escape detection or become resistant to treatment. When cancer cells die, they leave behind debris containing RNA. In theory, that material could alert immune cells to cancer elsewhere in the body. However, cancer cells also contain large amounts of RNA that suppresses immune activation, making it difficult for immune cells to distinguish cancerous debris from material released by healthy cells.
Earlier research published by Noxopharm and its collaborators in Nature Immunology identified how this immune-suppressing RNA limits activation of the immune system. The researchers also found that increasing TLR8 activity could help overcome the effect.
In the latest study, the team tested cellular RNA in vitro with and without one of Noxopharm’s TLR8-amplifying oligonucleotides. The RNA alone produced no meaningful change in the TLR8-driven immune response. When combined with the oligonucleotide, however, the same RNA generated a strong response that reached 437 per cent of the level recorded in untreated cells.
The study used total RNA isolated from human HEK cells. The material included ribosomal RNA capable of producing fragments that inhibit TLR8. Human cells containing TLR8 were treated with five micrograms of the RNA, either alone or alongside five micromoles of a TLR8 potentiating oligonucleotide.
Noxopharm said the results demonstrate the potential of its Sofra technology to remove the blind spot affecting immune cells and enable them to respond to RNA released when cancer cells are destroyed. The approach could eventually support combination treatments involving existing therapies such as chemotherapy and radiotherapy.
The work was conducted with the Hudson Institute of Medical Research, which is collaborating with Noxopharm on the development of the Sofra technology platform.
Hudson Institute Professor Michael Gantier said, “This exciting finding is proof-of-principle that the anti-inflammatory nature of cellular RNA we recently discovered can be overcome by specific oligonucleotides. While follow-up work is underway to show how these potentiators could increase anti-tumoral responses, this finding establishes the validity of this concept.”
Noxopharm CEO Dr Olivier Laczka said, “We are very encouraged by the new findings as they significantly broaden the potential applications of our TLR8-potentiating technology. We have now shown that the technology enables TLR8 activation in response to the sensing of RNA, which has potentially significant benefits given that cancer patients around the world are already being treated with cancer cell-killing therapeutics.”
The company said the findings also highlight the broader potential of its platform, which is designed to regulate the same innate immune pathway in different directions depending on the disease being treated.
“There is an elegant scientific symmetry across our pipeline. In oncology, our TLR8-potentiating oligonucleotides seek to enhance immune recognition of RNA released following cancer cell death. In autoimmune disease, our inhibitory oligonucleotides are designed to suppress inappropriate immune activation driven by self-RNA. Together, these programs demonstrate our ability to modulate the same innate immune pathway in opposite directions to address very different diseases.”
Noxopharm is developing the Sofra platform for cancer, inflammatory and autoimmune diseases, mRNA drug enhancement and other RNA-based therapies. The company is also advancing its Chroma platform for oncology applications.
