Adicet scores the first hit for gamma-delta

Three of four lymphoma patients given ADI-001 go into remission, and Adicet soars 30%.

It has been a long time coming, but some three years after claims about the potential of gamma-delta T cells caused a ripple of enthusiasm the first Car-T therapy based on this cell type has shown clinical efficacy.

The success has come from Adicet, a group that back then was in stealth mode, but which last year gained a US listing by reversing into Restorbio. The data with Adicet’s lead asset, allogeneic ADI-001 cells, concern just four lymphoma subjects, but with three of these going into remission they were enough to send the group’s stock up 30% at today’s open.

True, these are initial responses, and nothing is yet known about how durable they might prove to be. Adicet claims that improved persistence versus current Car-T therapies is a key advantage of gamma-delta cells, but clearly it is too early to tell whether such claims have a basis in clinical fact.

However, all three responders had been heavily pretreated, having failed four or five prior therapies, including in one case Bristol Myers Squibb’s Car-T therapy Breyanzi. Two remissions were complete, and the third was partial but termed “near complete”. Two were reported in patients at the lowest ADI-001 dose, 30 million cells.

Off the shelf

Excitement about gamma-delta T cells is due not only to claims about their persistence, but also because by their nature they are well suited for allogeneic use.

Gamma-delta T cells feature T-cell receptors comprising gamma and delta, rather than the more common alpha and beta, subunits. Since alpha-beta T-cell receptors are the ones responsible for autoimmunity, gamma-delta T cells have low propensity to cause graft-versus-host disease, and might therefore be used off the shelf.

Standard Car-T therapies being developed for allogeneic use have to include additional gene editing to remove their propensity for autoimmune reactions, something not needed for gamma-delta therapies. In any case, the efficacy of allogeneic Car-T projects, notably from Allogene and Crispr, has underwhelmed clinically, and the former is on clinical hold over the risk of genetic abnormalities.

As for targeting, ADI-001 employs a Car construct directed against the CD20 antigen, and Adicet has positioned it as its first gamma-delta Car-T asset, with ADI-002, a solid tumour project targeting GPC3, still in preclinical development. These both arise from a collaboration with Regeneron, which retains rights to opt in to ADI-002 at IND filing.

Business development

Competition in this field has remained fairly steady since a 2018 deal and fund-raising flurry, though in October Takeda bought out the UK’s Gammadelta Therapeutics for an undisclosed amount, shortly after In8bio completed a disappointing IPO at the second time of asking.

Moreover, most companies seem to be working initially on unmodified gamma-delta T cells. Gadeta is in the clinic with a Car construct, but strictly speaking this does not involve gamma-delta cells, merely a gamma-delta receptor, and in any case this has still not yielded clinical data.

True Car-engineered gamma-delta T cell projects, from In8bio, TC Biopharm and possibly others, remain at the preclinical stage. For now Adicet seems to have stolen the march on them all.

Selected γδ T-cell players
Company Based in Genetic modification? Notes Lead γδ-based asset
Adicet US Allogeneic Car-engineered γδ T cells (includes preclinical ADI-002) Deal with Regeneron; reversed into Restorbio in Apr 2020 ADI-001 (75% ORR in 4 lymphoma pts in ph1)
In8bio (formerly Incysus) US INB-300 is Car-modified, targeting cholotoxin (preclinical); also non-Car modified and unmodified γδ T-cell therapeutics Failed to float in Nov 2020; raised $40m (aim was $69m) in Aug 2021 IPO INB-200 (modified for resistance to chemo, ph1)
Gadeta Netherlands αβ T cells expressing engineered γδ T-cell receptor €7m series A (Baxalta) in 2016; Gilead exclusive buyout option in 2018 TEG001 (ph1)
TC Biopharm UK Yes, but Car-engineered γδ T cells work still preclinical Deal with Bluebird, $16m up front OmnImmune (unmodified cells, ph1)
Gammadelta (Takeda) UK subsidiary Yes, but unclear whether Car-engineered; DGX014, GDX023 & GDX015 are all preclinical Gammadelta bought Lymphact in 2018, then was acquired by Takeda in Oct 2021 GDX012 (unmodified cells; preclinical)
Immatics Germany Allogeneic engineered T-cell receptor γδ T cells $54m Genmab deal covering bispecifics in 2018; listed via Spac, but has more advanced eTCR therapeutics ACTallo IMA30x (preclinical)
Acepodia US No, antibody conjugation is used for targeting vs CD20, PD-L1 or other antigens $109m series C in Dec 2021 ACE1831 (preclinical)
Source: company filings.

This story has been amended to mention Acepodia.

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