Astra gives in vivo Car-T its biggest endorsement

AstraZeneca was late to the first wave of Car-T, but is making an early move into what could become the next big thing: in vivo Car-T. The UK group on Monday announced the acquisition of privately held EsoBiotec for $425m up front, on the back of very early clinical data.

Astra joins the likes of AbbVie, Novartis and Astellas, which have also struck in vivo Car-T deals, with the players Umoja, Vyriad and Kelonia respectively; however, these have generally been small research collaborations, and latest agreement is by far the largest.

Differentiated?

The in vivo approach involves generating Car-T cells within a patient's body, rather than through leukapheresis, ex vivo transfection and expansion, and reinfusion. This is typically achieved using mRNA delivered via a lentiviral vector, and it could overcome some problems of autologous Car-T, including long production times, the need for lymphodepletion, and cost.

On a media call to discuss the EsoBiotec purchase Astra’s head of oncology R&D, Susan Galbraith, said the company had been looking at the potential of in vivo Car-T “for a while”, but had previously come across “technical barriers”, including the fact that the viral vectors used were rapidly eliminated by patients’ immune systems.

The company believes that it has found the solution with EsoBiotec’s so-called EnaBL platform, which uses a viral vector said to be “immune shielded” via the removal of MHC1 protein and the overexpression of CD47, explained EsoBiotec’s chief executive officer, Jean-Pierre Latere.

He added that the company could also precisely target the cell of interest using a nanobody, but didn’t give any details about how such targeting was achieved.

These features, he said, allowed EsoBiotec’s projects to persist in a patient’s body, leading to more effective transduction of T cells. Indeed, Latere added that this had allowed the company to “reproduce exactly the behaviour of an ex vivo Car, but in vivo”.

Still, evidence for this is very early. EsoBiotec’s lead project is the BCMA-targeting ESO-T01, based on an autologous, ex vivo construct originated by China’s Pregene Biopharma. The asset only went into the clinic late last year.

All EsoBiotec has disclosed is that, in the first patient treated in a Chinese phase 1 trial, pharmacokinetics were “comparable” to ex vivo Car-Ts, and that by day 28 minimal residual disease in the bone marrow was undetectable. When asked for more details, Astra told ApexOnco that data would be presented at an upcoming medical meeting.

Big gamble

Astra is therefore taking quite a gamble on EsoBiotec, ahead of extensive clinical data. However, Galbraith said the group’s technology could be “transformative”, adding that size of the deal reflected excitement around the entire platform, not just ESO-T01. 

She mentioned the technology's combinability with other Astra projects, and also its potential outside cancer, in autoimmune or rare diseases, for example.

Astra only made a big move into traditional Car-T relatively recently, buying Gracell in early 2024 for its fast-manufactured autologous Car-T, and making waves with a GPC3-targeted project being developed in tandem with AbelZeta.

Galbraith noted that work continued “at pace” on AZD0120, the CD19 x BCMA bispecific autologous Car-T gained via the Gracell acquisition. But she also hinted that Astra could look at similar targets with in vivo Car-T.

The group has a long way to go here, but the latest deal could show an increasing appetite for in vivo Car-T. Interius is now the most advanced unpartnered player, but others have dropped out of this field, most notably Sana, which shelved its in vivo work in 2023.

Selected companies working on in vivo generated Car-T for oncology

Note: *investigator-sponsored trial. Source: company filings & OncologyPipeline.