Over the past 12 months there has been a quiet surge of interest in the nascent approach to treating cancer with gamma-delta T cells. Yesterday the field got its biggest boost so far: the private Dutch company Gadeta effectively agreed to a future buyout by none other than Gilead, the acquirer of Kite Pharma.
This would not be the first example of consolidation, as last month Gammadelta Therapeutics bought out its Portuguese rival, Lymphact. Takeda, Baxalta and Bluebird Bio have provided financing to some of these players, though there is currently evidence of only a handful of human subjects having received gamma-delta T cell therapeutics.
Clinical trial databases reveal only one active study, involving Gadeta’s TEG001 and enrolling 18 blood cancer subjects at the University Medical Center Utrecht. The US company Incysus has a phase I trial set to start recruiting 38 participants next month, and filed a second US IND in January.
What is special enough about this approach to have triggered interest at such an early stage?
Gamma-delta T cells, a relatively recently discovered subset of T lymphocytes, have T-cell receptors composed of gamma and delta, rather than the more common alpha and beta, subunits. This apparently allows them to recognise antigens not presented on a target cell’s major histocompatibility complex (MHC).
The requirement for MHC presentation is a key limitation of engineered T-cell receptor approaches being pursued by Adaptimmune and others, because in humans many different haplotypes of the MHC exist, and each cell product has to be matched appropriately.
Gadeta’s phase I asset, TEG001, is a traditional alpha-beta T-cell therapeutic that expresses on its surface engineered gamma-delta T-cell receptors. Thus the aim is to find a way of targeting new cancer antigens.
Yesterday’s deal with Gilead was a research alliance under which the senior partner made an undisclosed equity purchase, agreed to future milestone fees and was given an exclusive option to acquire Gadeta. In 2016 Gadeta raised €7m in a series A round backed by Baxalta, now owned by Shire.
|Known γδ T-cell players|
|Company||Based in||Genetic modification?||Notes||Lead asset|
|Gadeta||Netherlands||Yes: αβ T cells expressing engineered γδ T-cell receptor||€7m series A (Baxalta) in 2016; Gilead exclusive buyout option in 2018||TEG001 (phase I)|
|Incysus||US||No: expanded allogeneic γδ T cells||US IND approved for leukaemia study, IND for glioblastoma filed||Phase I starting Aug 2018|
|Gammadelta Therapeutics||UK||Not clear; possibly CAR-engineered γδ T cells||$100m financing (Abingworth, Takeda); bought Lymphact in 2018||DOT-Cells technology|
|TC Biopharm||UK||Yes: CAR-engineered γδ T cells||Deal with Bluebird, $16m up front||ImmuniCAR technology|
|Immatics||Germany||Yes: engineered T-cell receptor γδ T cells||$58m funding 2017, $54m Genmab deal covering bispecifics in 2018||ACTallo technology|
|Puretech Health||US||Not clear||Formed Nybo Therapeutics subsidiary in 2017||Unknown|
|Medinet||Japan||Not clear||Contract manufacturer carrying out γδ T-cell expansion, named in patents||Unknown|
|Source: company filings.|
The fact that gamma-delta T-cell ligands are not MHC restricted could give rise to a second, perhaps even more important characteristic: low propensity to cause graft-versus-host disease, given that alloreactivity is typically MHC mediated. This means that gamma-delta T cells might be used off the shelf – the approach Germany’s Immatics is pursuing with its early-stage ACTallo technology.
Gammadelta Therapeutics, meanwhile, last year closed a $100m private round backed by Takeda and Abingworth, and last month bought Lymphact for the latter’s DOT-Cells technology. Gammadelta has not revealed the focus of its work, but has admitted that gamma-delta CAR-T cell therapeutics are a “logical next step”.
CAR-engineered gamma-delta T therapy is precisely the focus of Gammadelta’s UK rival TC Biopharm, which last December scored a deal with Bluebird worth $16m up front.
With Gammadelta and TC still some way from the clinic attention will fall on Gadeta as well as Incysus, which boasts of having the first expanded and activated allogeneic gamma-delta T cell candidate that the FDA has approved for clinical trials. Its first study enrols leukaemia patients, while a second will target glioblastoma.
Intriguingly a trial at Rennes University Hospital with buy-in from Innate Pharma, targeting hepatocellular carcinoma with gamma-delta T cells, got under way 10 years ago, but was terminated with just two patients recruited. Meanwhile, clinical work on gamma-delta T-cell function has been carried out in China.
Nevertheless, it is still unclear how easy it is to sort, activate, transduce and expand these cells. Perhaps learning from the CAR-T experience, however, some in the industry have seen the wisdom of getting in early.