Adenovirus-based oncolytic products for fighting cancer are the next step beyond COVID-19 vaccines. However, there are critical biomanufacturing challenges to be overcome. During a GEN interview, that was a key point expressed by Manel Cascalló, PhD, general director of VCN Biosciences SL, a Synthetic Biologic’s European subsidiary. whose colleague, Ernest Milian, PhD, manager, chemistry manufacturing & controls, gave a talk at Bioprocessing Summit Europe last week.
What are the key manufacturing challenges for oncolytic viruses?
Cascalló: Oncolytic viruses are a growing field of interest, but there are some limitations. One of these is the need for intratumoral administration because cancer is a systemic, sometimes metastatic, disease. Although the systemic dose and the design of the virus seems, on first sight, to be a scientific question, it’s not that straightforward. There are overlapping manufacturing needs.
What are these overlapping manufacturing and scientific issues?
Cascalló: When you design a virus for selective replication, you introduce genetic modifications, and some of these can have impacts on the viral fitness and its ability to reproduce in the cell line. If there’s a certain attenuation, which happens with a significant number of oncolytic viruses now, the productivity decreases.
What are the implications of that?
Cascalló: You can’t dose at the high levels you need for systemic dosing. When you dose for intratumoral administration, you might need 1 x 107-10 viral particles, but you need 1 x 1011-13 viral particles per dose for intravenous.
How can you increase productivity?
Cascalló: You need to select the right candidate. Obviously, your characterization and manufacturing process needs to be scalable up to bigger batches than intratumoral administration. Also, the regulatory environment is different for intratumoral and intravenous administration, as different amounts of impurities are accepted, so you need to eliminate these.
What are you doing as a company?
Cascalló: We’re taking a lot of care about the size of the virus and have several candidates. The platform selection is critical because it defines whether you can have systemic delivery or not. Adenovirus is a well-suited platform for systemic delivery. It’s well characterized and has a master gene for controlling expression of the remaining genes.
We do extensive work to define the optimal position of each gene mutation, which is a process that requires a deep knowledge of the genome of the product. Also, from a manufacturing point of view, you must define the best producer cell line, media, time of harvest, and infection. All these manufacturing parameters must be defined for best efficiency.
All this implies that you have extensive knowledge about your product during development and, although the current trend is to outsource your product to CMOs, you can lose this knowledge during manufacturing.
