ABSTRACT
Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.
ABSTRACT
Biomethane, as a replacement for natural gas, reduces the use of fossil-based sources and supports the intended change from fossil to bio-based industry. The study assessed different biomethane utilization routes for production of methanol, dimethyl ether (DME), and ammonia, as fuel or platform chemicals and combined heat and power (CHP). Energy efficiency and environmental impacts of the different pathways was studied in a life cycle perspective covering the technical system from biomass production to the end product. Among the routes studied, CHP had the highest energy balance and least environmental impact. DME and methanol performed competently in energy balance and environmental impacts in comparison with the ammonia route. DME had the highest total energy output, as fuel, heat, and steam, among the different routes studied. Substituting the bio-based routes for fossil-based alternatives would give a considerable reduction in environmental impacts such as global warming potential and acidification potential for all routes studied, especially CHP, DME, and methanol. Eutrophication potential was mainly a result of biomass and biomethane production, with marginal differences between the different routes.
