Engineered T-cell receptors have spent years overshadowed by CAR-T therapy, but they are bidding to capture investors’ imaginations again. One of the newest entrants, Norway’s Zelluna, will test the market’s appetite when it goes out to raise cash next year before starting its first clinical trial.
The study will be a key test of Zelluna’s approach, based on exclusive rights to Oslo University Hospital’s biobank of cancer vaccine “super responders” for development as engineered T-cell receptor (TCR) therapeutics. A prototype is already in the clinic in the university’s own trial, and data generated could be used to gauge the chances of the company’s autologous therapy.
The university’s trial started this year, and is testing an engineered TCR against the TGFβRII antigen in colorectal cancer. The TCR in question was isolated from the biobank, and has the same target as the project that Zelluna will aim to put into the clinic in early 2020.
The private company’s chief executive, Miguel Forte, urges caution with readacross, telling Vantage that there are key differences between an academic study and one using an industrial manufacturing process, as Zelluna aims to do via a tie-up with Masthercell. But the university’s “clinical data will give valuable information”, he states.
The biobank, established 10-15 years ago, comprises clinical material from patients with advanced solid cancers who had been treated with vaccines against KRAS, hTert and TGFβRII.
Across the population no particular benefit was evident, but some of these patients – “super responders” – showed unexpectedly long survival. Mr Forte characterises them as having experienced a “very good, long-term sustained immune response with a memory component plus a corresponding long-term clinical benefit.
“Cells isolated form those patients were cloned and expanded. The TCR from the cells that recognised peptides used in the vaccines are now being used through gene modification via a lentiviral vector to provide an adoptive cell therapy.”
Zelluna is thus the latest of several groups to step up TCR activity. Last month Regeneron took a $100m equity stake in Bluebird Bio under a tie-up focusing on six undisclosed TCR targets, and Medigene, a more established player, signed up Structured Immunity to improve an in-house TCR’s specificity and recognition properties.
If this is a sign of renewed interest after the stunning successes of CAR-T therapy in haematology then investors must bear in mind the complexity. One problem is that, unlike CARs, TCRs only recognise antigens presented on a target cell’s major histocompatibility complex; in humans many different haplotypes of this complex exist, and so each product must be matched appropriately.
Another is finding TCRs with just the right level of target affinity. In contrast to Adaptimmune, which aims to enhance the affinity of its TCRs, Zelluna reckons some cell clones in the Oslo biobank are already evolved into memory cells with affinities in the desired range.
“We are in a serendipitous position,” says the chief exec. A further twist is that a large number of the TCRs in the biobank have turned out to be class II restricted, meaning that they can be engineered onto patients' CD4+ T cells.
Zelluna believes that this is vital to hit solid tumours because of the broad immune system stimulation elicited by CD4+ cells, sometimes called T helper cells.
Meanwhile, most engineered TCR work has focused on class I constructs and CD8+ (cytotoxic) T cells. At present the only clinical-stage engineered TCR asset focusing on CD4+ T cells seems to be the NCI’s TCR against Mage-A3.
|Selected engineered TCR projects|
|Adaptimmune||MAGE-A10 TCR||MAGE A10||Phase I||NCT02592577|
|MAGE-A4 TCR||MAGE A4||Phase I||NCT03132922|
|AFP TCR||Alpha-fetoprotein||Phase I||NCT03132792|
|Gilead||KITE-718||MAGE A3/A6||Phase I||NCT03139370|
|KITE-439||HPV-16 E7||Phase I||NCT02858310|
|KRAS TCR||G12V variant of mutated RAS||Phase I||NCT03190941|
|NCI (NIH)||HPV-16 E6 TCR||HPV-16 E6||Phase I||NCT03197025|
|MAGE A3 TCR||MAGE A3||Phase I||NCT02153905|
|Bellicum||BPX-701||PRAME (rimiducid-activated suicide switch)||Phase I||NCT02743611|
|Cell Medica||CMD-602||WT-1||Phase I||NCT02550535|
|Tmunity||NYCE T cells||NY-ESO-1 (Crispr-edited, TCR-deleted, PD-1-deleted)||Phase I||NCT03399448|
|Medigene/Bluebird||None||Six undisclosed targets||Preclinical||NA|
|Regeneron/Adicet Bio||None||Undisclosed targets for allogeneic use||Preclinical||NA|
|Regeneron/Bluebird||None||Six undisclosed targets||Preclinical||NA|
|Source: company filings & clinicaltrials.gov.|
If autologous TCR-based adoptive cell therapy were not enough Zelluna has two other tricks up its sleeve. “A platform around off-the-shelf products, using NK cells as a vehicle for our TCRs, is integral to our strategy,” says its chief scientific officer, Namir Hassan. “The third arm is a soluble TCR approach.”
Despite a surge in interest three years ago NK therapeutics have made barely any progress, however, as problems handling the cells in manufacturing became apparent. As Mr Hassan was until recently a vice-president of Immunocore, soluble TCRs might be expected to play a more prominent role at Zelluna, though he cautions that the initial focus is adoptive cell therapy.
Zelluna might also want to distance itself from the problems at Immunocore, which has seen five senior executives exit since February (Amid Immunocore’s C-suite bloodletting Glaxo provides solace, August 20, 2018). There is no suggestion that the technology is flawed, but sources close to Immunocore have told Vantage of ideological differences while the company burned through most of its record $320m raise in just three years.
For Zelluna, which so far has attracted just $8m of start-up funding, raising too much cash would be a nice problem to have.