Two allogeneic cell therapy switches in a day

Adicet wasn’t the only allogeneic cell therapy player to pivot to a new strategy last Thursday. After markets closed it was joined by Allogene, which unveiled plans to phase out two key studies of its lead project, move away from late-line aggressive lymphoma and investigate Car-T therapy in autoimmune disease.

Though the details differ, in the broad sense Allogene’s new strategy strongly resembles that revealed by Adicet, an allogeneic player with a focus on gamma-delta T cells. “Now is the time to rethink development and trial design based on the unique attributes of allogeneic Car-Ts,” Allogene’s chief executive, David Chang, told an analyst call.

Betting the house

While Adicet has pivoted away from diffuse large B-cell lymphoma (DLBCL) entirely, in favour of the rarer mantle cell malignancy, Allogene is betting the house on DLBCL in a front-line consolidation study.

Such a trial, Alpha-3, will be enrol 230 DLBCL patients who are still in response to front-line R-Chop therapy but have minimum residual disease (MRD). Here Allogene’s lead anti-CD19 Car-T therapy, cemacabtagene ansegedleucel (previously coded ALLO-501A), will be compared against observation, with event-free survival as primary endpoint, Allogene said.

Meanwhile, cema-cel’s current DLBCL trials, Alpha-2 and Expand, in the third-line setting, are being closed. Chang said the decision to wind these down hadn’t been easy, and enrolment into Alpha-2 had ticked up since its expansion into Europe, but claimed that Alpha-3 could allow came-cel to “leapfrog all other Car-Ts” and yield subsequent autologous Car-T therapy “obsolete”.

That’s a bold claim, and despite the enthusiasm it’s hard not to see the pivot – Allogene’s and Adicet’s alike – as a response to recent changes in the DLBCL market.

In the third-line setting cell therapy is being challenged by CD20-targeting T-cell engagers, notably the recently approved Columvi (from Roche) and Epkinly (AbbVie/Genmab). Meanwhile, established autologous Car-Ts, Gilead and Bristol Myers Squibb’s Yescarta and Breyanzi respectively, are now available second line.

Notwithstanding Allogene’s earlier enthusiasm about Alpha-2 and Expand, these trials were effectively becoming untenable.

What chances?

Still, will Allogene fare any better in first-line consolidation? The community doctors who prescribe here might prove hard to convince, for instance. Already there are signs that Allogene is thinking ahead of the problems: one Alpha-3 cohort will do without co-administering ALLO-647, an anti-CD52 MAb that boosts expansion and persistence, but which brings its own risks.

The effort will also require accurate diagnosis of a patient’s MRD status, and for this reason Allogene yesterday tied up with Foresight Diagnostics on an “ultra-sensitive” liquid biopsy. 

DLBCL patients who respond to front-line R-Chop but remain MRD-positive represent a high-risk group that Allogene reckons have median PFS of six to 12 months, while some progress within one to two months. These numbers will set baseline expectations for cema-cel to beat in Alpha-3.

As part of yesterday’s pivot Allogene also moved to test cema-cel in chronic lymphoblastic leukaemia, where an allogeneic therapy is relevant because patients tend to have poor-quality T cells of their own. Here a CLL cohort of Alpha-2 will start in the first quarter, and yield data by the year end. And in autoimmune disease Allogene’s strategy differs from other Car-T players in its attempt to reduce or eliminate chemotherapy preconditioning. 

Any problems Allogene now faces won’t be unique to the company. Before Adicet’s pivot away from DLBCL another player, Precision BioSciences, sold its lead allogeneic Car-T therapy, azer-cel, to Imugene, and no longer talks about Car-T. News from Crispr Therapeutics and Caribou will be keenly awaited.

The key players in allogeneic Car-T therapy

Note: *gamma-delta Car-T therapy; all others use alpha-beta T cells. Source: company presentations.

After this story was published Caribou and Crispr Therapeutics issued strategy updates in preparation for the JP Morgan healthcare conference.