Just about everyone has now heard of CAR-T therapies, and many already see CAR-modified natural killer cells as the next big thing. But a third lymphocyte type – the regulatory T cell, or Treg – has so far remained relatively obscure.
Not for long, if a small French company, TxCell, has a say about it. It went almost unnoticed when last November the group took up an option on a CAR-Treg patent from the Weizmann Institute’s Professor Zelig Eshhar, but its chief executive, Stéphane Boissel, doesn’t mince his words: “This could be the deal of my life,” he tells EP Vantage.
As evidence he points to other subtle moves into the Treg field by some of the biggest names in cell therapy. These include Juno’s work with the UCSF’s Professor Jeffrey Bluestone, and Professor Carl June’s University of Pennsylvania spin-out Tmunity; Penn is separately Novartis’s CAR-T partner.
Speaking to EP Vantage at this week’s Adopt Summit Professor Eshhar said he expected a sharp increase in interest in Tregs on the back of a significant body of existing academic work. He confirmed that he held the IP on Tregs genetically modified to express a CAR.
His CAR-T work is already the basis of Kite Pharma’s lead project, KTE-C19, and Mr Boissel calls Professors Eshhar and June respectively the academic and scientific fathers of CAR-T.
While CAR constructs are broadly similar, the big difference is the cell type in which they are engineered. Tregs are anti-inflammatory and damp down immune response, meaning that in contrast to CAR-Ts – used in cancer – CAR-Tregs could have potential in autoimmune disease.
TxCell has already worked on Tregs for over a decade – though in their unmodified form. Its lead project, Ova-Treg, is an autologous ex vivo procedure in phase II for Crohn’s disease, and involves exposing all the lymphocytes in a patient’s blood sample to ovalbumin, selecting only the Tregs, expanding them and reinfusing them into the patient.
Tregs naturally home to a site of inflammation, which in the case of Crohn’s is the gut, and when they encounter their antigen on antigen-presenting cells they become activated.
“Ovalbumin has nothing to do with the pathology of Crohn’s,” says Mr Boissel. “But it happens to be in the gut because it’s part of your diet.” So the logic is simply to use ovalbumin as an antigen to activate the Tregs.
And these Tregs have no memory, meaning that unlike with CAR-T “we are 100% sure there will be no long-term negative side effects”, says Mr Biossel. Ova-Treg has to be cryopreserved for each patient and reinjected every eight weeks.
The neat aspect is that while production of one batch is very expensive this can deliver several years’ treatment. “If you average it out over three to five years the costs are comparable with biologicals,” the chief exec reckons.
Lots of pain
That said, TxCell has had a rough time trying to get the production economics right, and when Mr Boissel took over last April it was mired in a disastrously unprofitable Ova-Treg deal with Ferring that involved it building its own manufacturing site. “We’ve been through a lot of pain,” he says.
His first moves were to close the facility, outsource manufacturing, cut jobs and unwind the Ferring deal, which he managed at the end of 2015. Now the focus is on restarting the phase II trial – this was suspended on the manufacturing switch – raising funds and partnering.
Unfortunately for Mr Boissel TxCell has very little cash and a market cap of only $90m – hardly a strong bargaining position. One plan is to generate much more animal data. “In this space today a compelling story based on preclinical in vivo data is good enough,” he states. “Look at Cellectis.”
Mr Boissel envisages either partnering individual assets or approaching companies with an established large disease presence and saying, “‘Let me be your cell therapy partner.’ I’m already discussing a few possible partnering deals; I know I’ll sign one without having clinical data.”
Still, while the CAR-Treg option with the Weizmann Institute could be TxCell’s secret weapon, all is not plain sailing here either; the patent is not granted, and in fact was nearly abandoned because of obviousness. But TxCell will rework the claims, and has until the mid-year to exercise the option.
After that, Mr Boissel reckons, a bigger deal could be on the cards: “The day [the patent] is granted in the US Kite or Juno will come after me.”
|CATS29||Double-blind, measures CDAI response vs placebo||NCT02327221|