Interview – Maxcyte's chance to turn CAR-T manufacturing on its head
“Our business model fits here; it didn’t fit on Nasdaq.” Such is the blunt view of Maxcyte’s chief executive, Doug Doerfler, explaining his company’s recent London flotation – a counterintuitive move for a US biotech, given Nasdaq investors’ relative appetite for risk.
Still, US funds were probably on to something, wanting Maxcyte to focus purely on an electroporation technology dubbed Carma, and to ditch its fee-based business. If Carma works out it could revolutionise CAR-T economics, offering a one-day production process in place of one that currently takes up to two weeks.
The advantages could be huge, Mr Doerfler tells EP Vantage, slashing manufacturing and hospital costs, as well as allowing production of a relatively well-defined and reproducible CAR-T product.
Maxcyte must now deliver data; a Carma study with an electroporated, mesothelin-directed CAR-T project in collaboration with Johns Hopkins University will get under way early next year, and Maxcyte’s £10m ($15m) IPO on London’s Aim was what the chief exec calls a “bet on this clinical trial”.
In the meantime, the group is keeping the two other pillars of its business – selling electroporation technology to biopharma for drug development, and licensing it for clinical trials. Those two units count AstraZeneca, Roche, Crispr Therapeutics, Editas and Juno as customers, and operate at cashflow breakeven.
Investors, however, will keep an eye on a separate Maxcyte research alliance with the University of Pennsylvania’s Dr Carl June that uses an earlier generation of the mRNA electroporation procedure to develop CAR-T therapies. This should serve as an important blueprint for Carma.
Electroporation is a way of getting large molecules into a T cell by applying an electrical charge that temporarily makes the cell membrane permeable. In contrast, most current CAR-T approaches use a lentiviral or gamma-retroviral vector to get CAR-encoding genetic material into a cell’s nucleus.
Because there is no genetic integration an mRNA-electroporated CAR is transient – the cells typically wane within seven days. While for current indications long cell persistence is vital, “it’s not desirable if you’re concerned about on-target off-tumour toxicity”, says Mr Doerfler. “A highly potent mRNA CAR that only lasts for a short period of time could be beneficial for certain indications.”
Thus repeat dosing, possibly every other week for several months, is part of the equation: “Typically we’ll do a batch [of cells], and then aliquot and freeze them down. A single run on our instrument will give you 10 billion cells, which is about eight or nine doses.”
Precision and reproducibility
The second difference lies in manufacturing, which with CAR-T currently takes seven to 15 days, including viral transduction, cell expansion, cryopreservation and transport between the hospital and a dedicated facility.
With Maxcyte's pre-Carma electroporation method, thanks to transfection efficiency of around 90%, the cells can be expanded before transfection, resulting in a precise dose. In contrast, when cells are currently expanded after transduction their final composition is hard to define, and the resulting dose virtually impossible to predict.
“With a lentivector the initial dose is the smallest,” says Mr Doerfler. “With mRNA the highest dose is the initial dose.” Six CAR-T clinical trials of this system are ongoing at Penn under an alliance that dates back to 2008, before Penn’s groundbreaking deal with Novartis and at a time when Dr June was struggling to attract funding.
|Ongoing studies of CAR-T projects transfected using mRNA electroporation|
|Antigen||Academic centre||Indication(s)||Enrolment||Trial ID|
|CD123||University of Pennsylvania||AML||15||NCT02623582|
|CD19||University of Pennsylvania||Hodgkin's lymphoma||16||NCT02277522|
|CD19||University of Pennsylvania||Hodgkin's lymphoma||10||NCT02624258|
|c-Met||University of Pennsylvania||breast cancer||15||NCT01837602|
|mesothelin||University of Pennsylvania||pancreatic cancer||10||NCT01897415|
|mesothelin||University of Pennsylvania||mesothelioma||18||NCT01355965|
|Source: EP Vantage, Clinicaltrials.gov.|
Carma takes this a step further, eliminating even the preliminary expansion step, and simply using fresh cells from apheresis, the initial cell separation. Not only does this cut the process down to a day, “you can do it at the hospital, and not have to ship cells to a specialised facility”, says the chief exec.
Cutting up to 90% of the time, and presumably also the cost, of a CAR-T manufacturing run could revolutionise CAR-T economics. What Maxcyte needs to do is show that Carma can do this with high cell viability, and that it is as potent as mRNA in expanded cells; the Johns Hopkins clinical trial will be crucial.
And who owns Maxcyte's electroporated CAR-T projects? Not Novartis, it seems. “Our Penn relationship is only with Penn, and it’s a non-exclusive, non-commercial deal,” says Mr Doerfler. “No rights transfer to anyone on the work we’re doing with Carl June, because that predates ... the Novartis deal.”
He also notes that Dr June has “some other deals he’s working on”, such as his newly launched company Tmunity, though there is no indication yet whether this will include CAR-T therapies.
As for CAR-T assets using Carma, these remain the property of Maxcyte, which will own the US IND. Since Maxcyte has no intention of starting an R&D business the opportunities for business development could not be clearer.
The table in this story has been amended to correct an earlier error.