Ash 2021 – the sun sets on Kymriah, but Novartis has a plan

Long-drawn-out manufacturing has been a running sore in the development of Kymriah, repeatedly hobbling the Novartis Car-T therapy’s efficacy and blunting its utility in rapidly progressing patients. But a new two-day manufacturing technology is ready for prime time, reckons the Swiss group, which used the Ash meeting to splash its clinical effectiveness.

The subjects of the so-called “T-Charge” technique are two second-generation Car-Ts, YTB323 and PHE885, and Ash today saw the first detailed clinical data for both. Stefan Hendriks, Novartis’s head of cell and gene, stresses that “we’re very confident in Kymriah”, but is also clear about the need to develop a “more potent and more durable” Car-T therapy.

For Novartis the need for something like this has been pressing. The Juliet study was notable for the fact that 40% of enrolled patients were never infused with Kymriah, most being lost to disease progression during the protracted manufacturing time; the failed Belinda trial, being presented at an Ash late-breaker tomorrow, is thought to have suffered similarly.

Bridging confusion

It has therefore been necessary to use bridging chemo to slow many patients’ disease while Kymriah is being manufactured. This in turn has made it difficult to interpret some data, as it can be unclear whether a responding patient is responding to Kymriah or to the bridging therapy.

It will be of interest to some that this problem persists in the phase 1 trial of YTB323, a next-gen CD19-directed Car based on T-Charge that Novartis has unveiled at Ash. Despite YTB323’s short manufacturing time many of the 19 lymphoma patients enrolled were bridged, and four (three post-bridging) were in complete remission before YTB323 was even infused.

Thus caution must be used in interpreting the cited three-month overall remission rate of 63%, which includes three of the four complete responders at baseline. However, a commercial product produced within two days would aim to do away with the need for bridging, Mr Hendriks tells Evaluate Vantage.

Meanwhile, the first clinical trial of PHE885, an anti-BCMA Car, has yielded 15 evaluable subjects, and all 11 treated at the highest two of three doses were in remission at one month. However, several relapses had occurred by 3.5 months’ median follow-up, Novartis said.

As for safety, there was one grade 4 cytokine release syndrome and two grade 3 neurotoxicities in the YTB323 study, and two PHE885 subjects experienced grade 3 cytokine release. Perhaps most importantly, both studies showed that T-Charge could work in practice.

What is it?

Still, Mr Hendriks is guarded about precisely what T-Charge involves, and how it makes manufacturing a Car-T product within two days possible. Vein-to-vein times for approved Car-Ts are two to six weeks, with real-world evidence suggesting that Kymriah’s is around 44 days, versus 28 days for Gilead’s Yescarta.

But the secret to T-Charge’s short manufacturing is that cell “expansion is happening in vivo, whereas in the first-generation platform it happens in vitro in the manufacturing setting. That’s the big difference,” he says.

The key to this lies in the generation of a product based on a different subset of T cells that are relatively young with a high degree of stemness – the quality of self-renewal and proliferation. Thanks to this there is no need for the ex vivo expansion step, and manufactured product can be reinfused quickly, with expansion taking place largely in the patient.

The idea of focusing on a specific T-cell subset is not new, of course: Bristol Myers Squibb’s Breyanzi employs an extra cell-sorting process to achieve a defined 50/50 CD4+/CD8+ T-cell ratio, while the Bluebird spin off 2seventy’s bb21217 adds a PI3k inhibitor during ex vivo culture to enrich for phenotypically young, memory-like T cells. But these are geared towards greater persistence rather than shorter manufacturing.

Until now the main proponent of quick Car-T production was Gracell, which claims 22 to 36-hour manufacturing with its FastCar process. This involves cell activation and transduction concurrently rather than in sequence, and a similar focus on T cells with memory and stemness and no ex vivo expansion, all in a closed, automated system, just like T-Charge.

Novartis today said T-Charge would serve as the foundation for various new Car-T therapies in its pipeline, and Mr Hendriks sees more projects, using more constructs, following in a “long-term game”.

It seems clear that, contrary to earlier rumours, Novartis is not scaling back on cell therapy. It is just that Kymriah might not be at the centre of its efforts for much longer.