Asco 2022 – Adicet works hard to avoid the allo Car-T scenario

Adicet’s fate rests on showing that its off-the-shelf gamma-delta Car-T project ADI-001 is durable, and on avoiding the relapses that have paralysed allogeneic Car-T developers. So the fact that only one in five patients is still in remission at six months, revealed at Asco today, does not look good.

However, there is nuance to this update, which added a further two lymphoma subjects to those disclosed in an abstract that prompted Adicet to climb 10% last month. Investor focus will fall on two subjects no longer in remission – one because they died of Covid and the other with a skin relapse that Adicet insists cleared up with a minor intervention.

First the good news: ADI-001 continues to put lymphoma patients into remission. The Adicet study initially saw three of four lymphoma subjects develop complete responses, a rate that rose to four of six in the Asco abstract.

Today the ORR remained compelling, with six of eight subjects in complete remission. All patients had aggressive lymphomas – follicular lymphoma was not allowed at inclusion. Three had relapsed on autologous Car-T therapy, and all three went into remission after getting ADI-001 cells.

But there the story gets complicated. One of the patients in remission developed Covid before month three and died. Another remained in complete remission until month four, at which point they suffered a skin relapse, MD Anderson Cancer Center’s Dr Sattva Neelapu told Asco this morning.

Adicet worked hard to play this down, stating that the skin lesion resolved with local radiotherapy, and that “the patient continues to be cancer-free” at 7.5 months, as measured by PET/CT scan.

But its headline claim that two patients “remain cancer-free” after six months does not tell the whole story: the aforementioned patient did relapse, and counting the two initial non-responders only one of five patients evaluable at six months is in complete remission.

On the plus side safety seemed good, with no cytokine release or neurotoxicity at grade 3 or higher in any of the three ADI-001 doses used. Indeed, Dr Neelapu said dose escalation in this study was continuing, and that given the safety the protocol had been amended to add a higher fourth dose before recommending which should be used in phase 2.

CD20

ADI-001 hits CD20, and it is interesting that Adicet picked this as its first target; CD20 has been exploited by the likes of Rituxan and Gazyva, but as a Car-T target it has been beset with toxicity concerns, notwithstanding some impressive efficacy reports.

The key potential advantage of using a gamma-delta approach is that these cells do not cause a graft-versus-host response, and so can be given off the shelf.

Discussing the data, Fred Hutchinson Cancer Research Center’s Dr Brian Till said gamma-delta Car-Ts against CD19 would likely also be developed, but said more had to be learned about the susceptibility of these types of cells to exhaustion from chronic antigen exposure, and their dependence on the IL-2 cytokine.

However, he did not directly address the issue of relapse to which, mechanistically, gamma-delta T cells could be prone just as much as allogeneic Car-Ts; notably, relapses have derailed the allogeneic Car-T players Allogene, Precision and Crispr.

Perhaps the best Adicet can say coming out of Asco is that more time, and more treated patients, are needed to gauge whether there is a relapse problem or not. The debate over durability is not about to go away.