GSK deals cell therapy another setback

Having last year disappointed Immunocore, GSK has now dealt its sister company Adaptimmune a similar blow. Lete-cel, an engineered T-cell receptor project licensed from Adaptimmune, is dead in the water, along with the rest of GSK’s efforts against the NY-ESO-1 antigen.

Investors initially learnt of this in a circuitous fashion yesterday, by way of a low-key regulatory filing made by a third group, Lyell Immunotherapy. Lyell revealed that on October 24 GSK gave it notice to terminate an early-stage collaboration, saying GSK was “discontinuing its development of product candidates targeting NY-ESO-1”.

This morning Adaptimmune confirmed the worst: GSK is handing back rights to lete-cel, which is due to yield pivotal data next year, and a preclinical asset targeting Prame. Adaptimmune will continue to focus on in-house TCRs against Mage-A4 while determining the optimal development path for the projects on which GSK has pulled the plug.

Long-standing work

GSK had been working on NY-ESO-1 for some time, at one point holding rights to lete-cel as well as to Immunocore’s soluble TCR project GSK3537142. Last year GSK discontinued work on the latter, in what looked like a vote of confidence in lete-cel.

Under a separate deal with Lyell, the UK big pharma was investigating souped-up versions of lete-cel. This gave rise to LYL132, which used Lyell’s “reprogramming” technology to give the cells durable stemness, and LYL331, which modified them to overexpress the protein c-Jun and thus resist exhaustion.

LYL132 had entered human trials, and GSK was also clinically testing GSK3901961 and GSK3845097, which were NY-ESO-1 TCRs additionally co-expressing the CD8α chain and the dnTGF-βRII cell surface receptor respectively.

Now Lyell has revealed that all this work is apparently being scrapped. A US SEC filing from Lyell states that preliminary data from GSK’s lete-cel study in NSCLC did not yield the expected level of clinical activity, and this prompted the UK group to stop enrolment.

This morning’s statement from Adaptimmune attempted to sugarcoat the disappointment, claiming that GSK’s decision “was based on Adaptimmune's deep expertise in engineered T-cell therapies for solid tumour cancer indications”.

There has been no word yet from GSK, and lete-cel as well as the related NY-ESO-1 candidates still appear in its R&D pipeline. Both Ignyte-Eso, the pivotal phase 2 study of lete-cel, and a phase 1 trial of LYL132, GSK3901961 and GSK3845097 are listed as active and recruiting on clinicaltrials.gov. GSK has been contacted for comment. 

It can only be speculated whether GSK’s actions represent a setback for work against NY-ESO-1 in general or for Lyell’s Epi-R and Gen-R technologies in particular. When Vantage Analysis interviewed Lyell in February we speculated that the impending departure of Hal Barron as GSK’s head of R&D could threaten the tie-up, though Lyell rejected this.

Either way, targeting NY-ESO-1 has not gone smoothly, despite this antigen’s expression in numerous tumour types. In June Cytovant, an offshoot of Roivant Sciences, discontinued work on CVT-TCR-01, licensed from Medigene, and two months later Athenex terminated a phase 1 trial of TCRT-ESO-A2 citing poor recruitment.

Lyell opened down 13% today, and is now trading 65% under its June 2021 IPO price. Adaptimmune was off 12% but later recovered and was trading flat.

This article was updated to correct the pharmacology of GSK3901961.