Interview – UK cell therapy minnow squares up to Juno

The UK’s Catapult Therapy TCR might only have treated three patients so far but its study, which this week passed an interim phase I review, is only the second of an engineered T-cell receptor against the WT-1 antigen to yield preliminary data.

The other is from the Fred Hutchinson centre, and is now licensed to none other than Juno. “The key is having a T cell that recognises the target antigen with sufficient avidity that it responds, but isn’t of so high affinity that it binds to lower-level antigens on normal cells,” University College London’s Professor Emma Morris, the UK trial’s chief investigator, tells EP Vantage.

This is because, like all antigens currently targeted with CAR-T, WT-1 is tumour-associated rather than tumour-specific. And while Adaptimmune, for instance, touts its ability to develop high-affinity T-cell receptors (TCRs) Professor Morris says balance is critical: “If you enhance [a TCR] into the super-affinity range you increase the risk of cross-reactivity.”

No serious tox

Yesterday’s findings concerned the first three acute myeloid leukaemia patients given a low dose of the TCR-engineered cells, and the most important finding was the lack of serious toxicity.

Possible toxicities might, like with CAR-T, have included cytokine release syndrome and off-tumour effects. A higher dose will now be tested, and Professor Morris said the data also demonstrated reproducibility of manufacture and cell persistence, though “it’s too early to talk about efficacy.”

At the 2014 ASH meeting Juno reported that its WT-1 TCR project, now coded JTCR016, also showed good tolerability, with 12 of 15 patients having detectable WT-1-directed cells five to 368 days after their last infusion. However, there are differences between the two approaches.

Juno is specifically isolating cytotoxic (also known as CD8+) T cells, while Catapult Therapy TCR is reinfusing a mixture of helper (CD4+) and cytotoxic T cells. CD4+ T cells assist and enhance proliferation of CD8+ T cells by secreting cytokines, and Professor Morris believes that “if you use isolated CD8+ T-cell infusions on their own then their effects often are transient”.

As well as leukaemia, Juno is also targeting solid tumours, although this difference might simply be down to Professor Morris’s clinical background in haematological malignancies. “WT-1 is overexpressed in colon, breast and prostate cancers, mesothelioma, some lung cancers, and we’re beginning to explore its role in paediatric solid tumours,” she says.

Engineered TCR projects against the WT-1 antigen
Company Recruitment target Indications Trial ID Note
Juno Therapeutics 55 AML, MDS, CML NCT01640301 Uses virus-specific CD8+ T cells 
Juno Therapeutics 20 NSCLC, mesothelioma NCT02408016 Uses central memory to naive CD8+ T cells 
Catapult Therapy TCR 18 AML, CML NCT01621724 First patient dosed in Dec 2014
Catapult Therapy TCR 30 AML, MDS NCT02550535 Multicentre European study

In general the engineered TCR approach is related to CAR-T, though the latter transfects cells with a chimaeric receptor rather than a natural one (Big pharma picks Immunocore as a cell therapy player to watch, June 29, 2015).

Because CARs use an antibody motif they can only target cell surface proteins, while TCRs target intracellular antigens presented on a cell’s major histocompatibility complex (MHC).

This MHC restriction leads to a problem: in humans several different haplotypes of this complex exist, and the so-called HLA-A2 type, on which all TCR therapeutics have so far been studied, is present in only 40% of the Caucasian population.

A commercial therapy will likely have to include a panel of TCRs sufficient to cover about 90% of the existing haplotypes – with each effectively being a separate “product”. Commercialisation remains a big unknown for all adoptive cell therapies, and the complexity of TCRs makes cost at least as big a problem as for CARs.

Beyond academia

The WT-1 project, of which Professor Morris is co-inventor, might never have progressed beyond the academic setting were it not for Cell and Gene Therapy Catapult (CGTC).

CGTC, a UK body set up in 2012 to funnel £70m ($100m) of taxpayers’ money over five years specifically towards commercialising these types of novel treatments, financed the setting up of Catapult Therapy TCR as well as Chimeric Therapeutics, a company working on a CAR-T project against the Clec14a antigen at University of Birmingham.

However, not all members of the UK’s nascent adoptive cell therapy sector have chosen to have CGTC lead them by the hand. Adaptimmune completed a significant Nasdaq IPO, Leucid Bio is seeking financing elsewhere, and Autolus recently raised £40m from private investors including Woodford Investment Management and Perceptive Bioscience.

CGTC also conducts contract R&D and can provide manufacturing capacity at a new lab at Guy’s Hospital. It is constructing a major cell manufacturing centre to open in 2017 in Stevenage – strategically between three UK airports. This logistical approach mirrors the thinking behind Kite Pharma’s construction of a CAR-T facility near Los Angeles airport.

Speaking to EP Vantage in January, Keith Thompson, chief executive of CGTC, said companies could in future use their own staff at the specialised Stevenage centre for pivotal trials and initial market supply: “They can rent a suite for one to five years.”

Catapult Therapy TCR’s manufacturing was done at Great Ormond Street Hospital. While the group recently appointed a contract manufacturer, if things work out it will need far bigger capacity in future.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter

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