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Abstract
Background Antisense oligonucleotides function by targeting the messenger RNA coding for a target protein, rather than the protein itself. This laboratory previously introduced Respirable Antisense Oligonucleotides (RASONs) into human clinical trials for asthma.1–5 In that work we demonstrated that RASONs delivered by inhalation are absorbed into surfactant lining the surface of the lung; are distributed with high efficiency throughout the bronchial epithelium; and are taken up with therapeutic effect by both bronchial epithelial cells and immune effector cells resident throughout the bronchial epithelium, as well as in bronchial-associated lymphoid tissue (BALT). We have now re-engineered this technology to adapt it to the treatment of primary and metastatic lung tumors via immune checkpoint inhibition. While immune checkpoints expressed on lung tumors are not amenable to RASON inhibition, immune cells resident in the bronchial epithelium and BALT represent good targets for the RASON approach to checkpoint inhibition. E.g., SIRP-alpha is a receptor expressed by myeloid lineage cells such as dendritic cells (DCs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). When CD47, found on the surface of tumor cells, binds to SIRP-alpha on immune effector cells, the anti-tumor action of such immune effector cells becomes significantly diminished. We hypothesized that RASONs targeting mRNA of immune checkpoint proteins found on immune effector cells would eliminate checkpoint proteins from their surface, such that when they were signaled to home in on lung tumors, they would arrive in the tumor-associated microenvironment in a state impervious to checkpoint ligands expressed on the surface of tumor cells. To test this hypothesis, we applied a RASON protocol to dogs with spontaneous lung tumors presenting to their veterinarians.
Methods In this preliminary, proof-of-principal study, two dogs with histologically confirmed metastatic lung tumors were administered RASONs targeting PD1, CTLA-4 and SIRP-alpha, by inhalation, twice weekly for eight weeks.
Results X-ray analysis performed two weeks after the conclusion of RASON treatment showed dramatic results. One dog showed complete tumor dissolution (figure 1), and the second dog showed near total tumor dissolution, with faint shadows remaining (figure 2).
Canine 2 presented with a 3-cm spherical tumor (circled, left). After RASON treatment (right), tumor underwent complete regression
Canine 1 presented with one 9-cm tumor and four smaller tumors ranging from 1–2 cm (tumors are marked with dot at their center). Left, before RASON treatment). Right, after RASON treatment near complete tumor resolution
Conclusions While these are preliminary results, and need to be dramatically expanded, they provide an initial indication that the RASON approach might prove to be an effective addition to immune checkpoint inhibition. It possesses certain advantages over small molecule or antibody approaches to checkpoint inhibition. For example, rather than being delivered systemically, RASONs are delivered by inhalation directly to the target tissues-- the bronchial epithelium and BALT. Furthermore, it may be possible to reduce the toxicity of systemic treatments targeting checkpoint proteins on tumor cells, by reducing or eliminating their ligands on immune effector cells. In as much as the RASON approach to the treatment of human asthma failed in clinical trials as a result of its induction of an influx of macrophages into the lung, the ability to render TAMs impervious to the presence of tumor-associated immune checkpoints suggests that the RASON approach may hold considerable promise for the treatment of lung tumors.
Ethics Approval All research reported here involved informed consent by owners of dogs with spontaneous lung neoplasms, for which no satisfactory alternative treatment was available, and was performed in strict compliance with both the Basle Declaration, to which the laboratory is a signatory member, as well as guidelines published by the International Council for Laboratory Animal Science (ICLAS).
Consent N/A
References
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