Cellectis has taken to heart recent criticism over how slowly its allogeneic CAR-T projects have been advancing. “Of course we’re not fast enough, but the fact is that we have to respect the speed of the dose escalation,” André Choulika, its chief executive, told EP Vantage at the JP Morgan conference yesterday.
A particularly prominent critic has been Dr Stephan Grupp, who on a CAR-T investor call hosted by Slingshot Insights and Loncar Funds last month blasted Cellectis’s lack of progress. With the French company’s stock climbing 27% in the run-up to JP Morgan, investors clearly hope for an acceleration.
Of course, Cellectis bulls will note Dr Grupp's conflicts of interest. As a pioneering CAR-T doctor at the Children’s Hospital of Pennsylvania he was closely involved in developing Novartis’s Kymriah, leading several studies, including the pivotal Eliana trial in paediatric ALL.
Conflicted or not, it was unusual to hear a doctor speaking in such scathing terms. “It is astonishing to me how [Cellectis] have done nothing to leverage their leadership” in allogeneic CAR-T therapy, Dr Grupp told the investor call, which took place on December 21.
The first patient case report with Cellectis’s UCART19 was over two years ago, but formal trials began in 2017, and so far just 12 subjects have been dosed; at the Ash meeting Cellectis’s partners Servier and Pfizer presented data showing impressive initial remissions, but also near-term relapses and hints of toxicity.
“I’m going to say a bad word and I apologise, but it does express my point of view: where the fuck are their clinical trials?” asked Dr Grupp. “They had a two-year lead and they’ve blown it. Are they bad at execution or is there a reason why they haven’t been able to move faster?”
Yesterday, Mr Choulika pointed to more mundane reasons, stating: “In any oncology trials it’s always a bit tedious at the start. When we know the right dose we can immediately move to multicentre trials and enrol 150 patients in three months. I would like to put the pedal on the metal today ... but we have to give time.”
Meanwhile, Dr Grupp had told the investor call: “That is a late 2015/early 2016 question – what's the dose we should be giving. They should have knocked this one out fast.”
Still, Mr Choulika is used to criticism, and at Ash told EP Vantage about the attacks he has faced: “People are shooting at us really hard; we’re taking hits every day, people saying [our technology] is bad, there are side effects” (Cellectis interview – if at first you don't succeed..., December 20, 2017).
But toxicity is a live issue, and some have hinted that this is one reason why UCART19 has not been dosed higher. Dr Grupp put the blame squarely on Cellectis’s Talen gene-editing technology, which causes “substantial chromosomal abnormalities” that are not harmful only because “the T cells don’t persist”.
Overall, the biggest fear with an allogeneic product is graft-versus-host disease, and so far Cellectis has seen hints of this in mild skin rashes. “One of my big concerns is that their product has too high a percentage of T‑cell receptor-positive cells, which are the cells that can cause graft-versus-host disease,” said Dr Grupp.
Deleting endogenous T-cell receptors, Dr Grupp said, “should be a complete triviality; [Cellectis] should be so far beyond this now.”
Cellectis has recently played up the possibility of redosing patients – something that could minimise the risk of infusing large amounts of allogeneic CAR-T cells, and get around lack of persistence – and this was a focus of its JP Morgan presentation.
And, though the Ash data showed only one redosed subject, Dr Grupp agreed that this could be a game-changer: “If ... reinfusion works my excitement about the allo platform goes way up because then all of a sudden this could actually be a substitute [for autologous CAR-T].”
Among other themes at JP Morgan was multiple myeloma, with Mr Choulika saying he thought CS1 was a better antigen than BCMA – the hot myeloma target being pursued by Bluebird and others. Cellectis hopes to file an IND for UCARTCS1 early next year, and is prioritising this over UCART38, saying CD38 is not a clean target.
It is not abandoning BCMA: the UCARTBCMA asset is part of its collaboration with Pfizer. Looking into the future Mr Choulika told JP Morgan that Cellectis would file an IND for “something outside CAR-T and oncology, eventually”.
And, however much ire Dr Grupp has directed at Cellectis, there seems to be no rancour from Mr Choulika. “I fully buy into what Dr Grupp has said,” the chief exec told EP Vantage. “I think he’s an awesome doctor and I’d love to work with him. If he could speed up the process with us that would be fantastic.”
See our full coverage from the JP Morgan conference here.