Years of dreams about CARs turn into reality for Atara

The company’s nascent CAR-T portfolio includes technology licensed from one of the field’s most prominent pioneers.

Atara’s emergence last year as a CAR-T contender might have taken some investors by surprise. In fact, though it was not widely known, back in 2015 the group was already mooting the possibility of licensing CAR-T assets from the Memorial Sloan Kettering Cancer Center (MSKCC) to supplement its existing cell therapy offering.

It took a few years but deals have now been done, bringing in technology developed by none other than MSKCC’s Dr Michel Sadelain, one of the biggest names in the field. And some might see the recently announced departure of Atara’s chief executive as clearing the way to bring in a CAR-T leader to take the helm.

This is a suggestion the company does not entirely accept, insisting that it also recognises the importance of tab-cel, its late-stage cell therapy, which uses unmodified T cells. “We’re looking at [our portfolio] as different pillars,” Dietmar Berger, head of R&D, tells Vantage, “where the underlying principle is ... allogeneic T-cells.”

Last month Atara unexpectedly revealed the departure of its founding chief executive, Isaac Ciechanover, and the search is on for a successor.

While the group styles itself as an allogeneic player, hoping to take on the likes of Allogene and Cellectis, its leading current CAR-T assets are in fact autologous. The plan, says Mr Berger, is to develop CAR-T cells “autologous first, as proof of concept, and then put them on the allogeneic platform”.

Whether this means that the autologous CARs will never see the light of day beyond clinical trials is not clear, as the company will not reveal its commercialisation strategy.

Odd timing?

Given the problems Novartis and Gilead have had in turning CAR-T into a profitable business it seems an odd time for Atara to be jumping into the technology. But the group insists that its work represents an advance on those initial therapies.

Its lead CAR-T assets came via four recent deals. Two separate tie-ups are in place with Dr Sadelain, in addition to a deal with Dr Marco Davila, Dr Sadelain’s former MSKCC colleague who now works at the Moffitt Cancer Center, and a patent licence with the NIH.

To investors Dr Sadelain is best known as one of the scientific founders of Juno. That business now having been sold to Celgene, Dr Sadelain appears to be free to work with other companies, including Atara and Fate Therapeutics, which is working with him on an allogeneic project using an induced pluripotent stem cell line.

Most importantly, Atara's MSKCC tie-up involves a mesothelin-targeting CAR that in the clinic yielded a 15% overall remission rate, comprising two responses; a third response emerged on retreatment with an anti-PD-1. Atara plans to take this forward as ATA2271, an asset that will use Dr Sadelain’s novel 1XX co-stimulatory domain and a PD-1 dominant negative receptor to eliminate T cells’ checkpoint signal.

Other mesothelin CARs have disappointed, but Atara reckons the MSKCC project is different thanks to a binding domain that preferentially hits high-density mesothelin-expressing cells and not normal tissue. This binder had been developed at the NIH, hence the need for Atara to sign a separate licence with that US organisation.

Meanwhile, the Moffitt has given the company two CAR-T projects: ATA2431, a triple construct activated if either CD19, CD20 or CD22 antigens are encountered, and ATA2321, a dual CAR for acute myelogenous leukaemia. Mr Berger says the primary targets for the latter have not yet been selected, but that to reduce toxicity it is “and-gated”, meaning that both antigens have to be engaged for activity to be seen.

Atara also has rights to Dr Davila’s next-generation co-stimulatory domains, which like MSKCC’s involve variations on CD28. Interestingly, Mr Berger says Atara has not licensed one of Dr Sadelain’s most revolutionary projects, an auto/trans co-stimulated “armoured CAR” that impressed with initial clinical data in December (The (unsung) best of Ash 2018, December 5, 2018).

Welcome

So far investors have welcomed Atara’s embrace of CAR-T: the stock has trodden water despite the choppy biotech market.

“At least one [CAR-T asset] will move to IND at the end of this year or beginning of next,” Mr Berger promises. In the meantime, investors’ focus will be on two phase III studies of tab-cel, in EBV-positive post-transplant lymphoproliferative disorder, due to read out by mid-year, followed by a US filing.

Tab-cel has been Atara’s lead for the past few years; it comprises banks of EBV-sensitised T cells that can be partially HLA-matched to patients using an algorithm. The cell lines are already recommended for use at MSKCC, but Atara wants to commercialise the concept using its own manufacturing.

This fits neatly with the CAR-T projects, which are to be produced at the same 90,000-square foot manufacturing plant that Atara opened at Thousand Oaks, California, last year. Not only that, but the existing EBV-positive T cell lines will form the basis of Atara’s allogeneic CAR-T work, says Mr Berger.

Given such synchrony it is clear why the company wants to keep both of these pillars in place.

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