Ritchie, A. J. | bioRxiv Science

bioRxiv2020

Activating Immune Recognition in Pancreatic Ductal Adenocarcinoma Using Autophagy Inhibition, MEK blockade and CD40 Agonism

Pancreatic ductal adenocarcinoma (PDA) patients have not yet benefitted from the revolution in cancer immunotherapy due in large part to the dominantly immunosuppressive tumor microenvironment (TME). MEK inhibition combined with autophagy inhibition leads to transient tumor responses in some PDA patients. We find that co-inhibition of MEK (using cobimetinib, COBI) and autophagy (using mefloquine, MFQ), but not either treatment alone, activates the Type I Interferon/STING pathway in tumor cells which in turn reprogram tumor associated macrophages (TAMs) in paracrine to foster an immunogenic switch. This effect is augmented by a CD40 agonist (aCD40). Triple therapy (COBI+MFQ+aCD40) achieved cytotoxic T cell activation in an immunologically "cold" mouse PDA model, leading to enhanced anti-tumor immunity. Collectively, MEK and autophagy co-inhibition coupled with CD40 agonism invokes immuno-reprograming and is an attractive therapeutic approach for PDA immunotherapy development.

cancer biology↗

bioRxiv2020

Characterisation of factors contributing to the performance of nonwoven fibrous matrices as substrates for adenovirus vectored vaccine stabilisation

The global network of fridges and freezers known as the "cold chain" can account for a significant proportion of the total cost of vaccination and is susceptible to failure. Cost-efficient techniques to enhance stability of vaccines could prevent such losses and improve vaccination coverage, particularly in low income countries. We have previously reported a novel, potentially less expensive thermostabilisation approach using a combination of simple sugars and glass micro-fibrous matrix, achieving an excellent recovery of vaccines after storage at supraphysiological temperatures. This matrix is, however, prone to fragmentation and currently not suitable for clinical translation. Here, we report an investigation of alternative, potentially GMP compatible, fibrous matrices. A number of commercially-available matrices permitted good protein recovery, quality of sugar glass and moisture content of the dried product but did not achieve the thermostabilisation performance of the original glass fibre matrix. We therefore further investigated physical and chemical characteristics of the glass fibre matrix and its components. Our investigation shows that the polyvinyl alcohol present in the glass fibre matrix assists vaccine stability. This finding enabled us to develop a custom-produced matrix with encouraging performance, as an initial step towards a biocompatible matrix for clinical translation. We discuss the path to transfer of the technology into clinical use, including potential obstacles.

pharmacology and toxicology↗