Who will capitalise on CAR-T at last? Not big pharma, says Tmunity

While praising Novartis for kickstarting the CAR-T revolution, the chief exec of Tmunity has no doubt where cell therapy’s development engine really lies.

Novartis sent shockwaves through biopharma when in 2016 it unwound its cell therapy division, losing the head of this business, Oz Azam, in the process. Mr Azam’s resurfacing as chief executive of Tmunity made it clear to everyone that the pupil was preparing to do battle with the master.

Now the chief is set to take Tmunity to the next level. In an interview with Vantage he takes a subtle swipe at his former employer, which in cell therapy has shown little desire to progress beyond two CAR-T projects, and lays out a battle plan that, he says, will make Tmunity “the Genentech of the cell and gene industry”.

He is quick to give praise where it is due, however, and accepts that Novartis has to be given “huge kudos ... for making the initial investment without which none of this would have happened”. This is a reference to the Swiss group’s backing of the Penn team that until then had struggled to raise any cash at all, and whose work led to the development of Kymriah, the first commercial CAR-T therapy.

But Mr Azam sees in Tmunity a chance to build on this work “in a different and more agile way”. He states bluntly: “Honestly, it’s going to be companies like Tmunity that do this. Big pharmas can be great partners, but the innovation is really going to come from companies like ourselves.”

Falling out

It is precisely Dr Carl June’s team at Penn, which discovered Kymriah, that now stands behind Tmunity. If, as industry rumours suggest, there had been a falling out between Penn and Novartis then it was triggered by the Swiss firm’s decision not to look beyond CD19 and BCMA as investable cell therapy targets.

Tmunity’s stance is diametrically opposed. Mr Azam says he has no interest in developing yet another therapy targeting CD19 or BCMA, stating pointedly: “There’s no need.” What he does want is for Tmunity to achieve a decent valuation, perhaps with the help of external partnerships.

The first sign of the group looking beyond Penn occurred this month in a deal for an engineered T-cell receptor (TCR) against the H3.3K27M neoantigen discovered at University of California at San Francisco by Dr Hideho Okada. The drivers for this were Mr Azam’s personal focus on childhood cancers – the mutation is found in 70% of paediatric pontine gliomas – and an acceptance that, in TCRs at least, Tmunity was never going to be a discoverer.

The introduction to Dr Okada came through the Parker Institute, Tmunity’s series A investor, which Mr Azam reveals gives the company “access to the world’s ‘who’s who’ in cancer biology and translational medicine”.

Still, it will be at least 2021 before this TCR is in the clinic, and Tmunity’s plan is to enhance its binding affinity with a view to improving efficacy. 

The TCR is restricted to the HLA 0201 haplotype, meaning that it could be applicable to 30-40% of children with diffuse intrinsic pontine glioma.

As well as TCRs Tmunity's pipeline contains CAR-T projects – a somewhat unusual stance; academics tend to fall into one of the two camps, and never the twain shall meet. “We are agnostic,” says Mr Azam. “It’s a case of what you scientifically have commitment to... and good companies will not box themselves in.”

As such, the group’s pipeline lead is an anti-PSMA CAR that also encodes a decoy receptor that blocks TGF-β signalling. TGF-β is increasingly being recognised as a potent exhauster of T cells in the microenvironment, but the trick is to block it specifically in T cells rather than peripherally.

It is this kind of approach that Mr Azam sees as key for CAR-T to have any chance at hitting solid tumours; first clinical data, in prostate cancer, are expected late this year. That puts the PSMA CAR ahead of what had at one point been Tmunity’s lead, a Crispr-edited TCR against NY-ESO-1.

That asset had been subjected to a US FDA review so protracted that the “IND felt like a BLA”, Mr Azam jokes, though he stresses that the result made Tmunity the first company to dose US patients with a Crispr-based product. Clinical data, perhaps in a multiple myeloma cohort, could come at Ash in December.

Disclosed Tmunity R&D pipeline
Target Project type Indication Data?
PSMA CAR-T with dominant-negative TGF-β receptor Prostate cancer Phase I readout late 2019
NY-ESO-1 TCR-deleted, PD-1-deleted, HLA-A 0201 restricted TCR Various Phase I multiple myeloma data possible at Ash 2019
Tn-Muc-1 CAR-T Various IND planned H1 2019
GFRα4 CAR-T Medullary thyroid cancer IND planned H2 2019
CD33 CD33-knockout CAR-T AML IND 2020-21
FRα CAR-T Ovarian cancer IND 2020-21
FRβ CAR-T AML & others IND 2020-21
IL13Rα2 CAR-T Glioblastoma IND 2020-21
H3.3K27M HLA-A 0201 restricted TCR Diffuse intrinsic pontine glioma Phase I trial possible in 2021

Another key aspect of becoming a commercial cell therapy player is manufacturing. Tmunity has leased its own plant, and intends to have multicentre trial capacity in place next year. A separate plan could see the company make its own lentivirus vectors at research scale, before seeking a partner for commercial supply.

And beyond? “Five years from now I think we will [be] a company that has branched beyond the US, maybe into China, probably into Europe,” says Mr Azam. “Maybe one day we’ll have branched out beyond T cells.”

However praiseworthy the goal to become a commercial entity might be, he says it might be difficult for Tmunity to stand alone: “We know, if you are successful, the spectre of M&A creeps up on you.”

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