Ash 2022 – fast production fails to cure Car-T's problem

One of the biggest problems cell therapies face in the west is lack of manufacturing capacity. Data presented at Ash by Novartis and Gracell suggested that manufacturing time can be cut drastically, from a few weeks to two days, but the elephant in the room remains: patients still have to wait weeks or months before they receive therapy.

This was made clear in trials of Novartis’s YTB323, an anti-CD19 construct, and of Gracell’s GC012F, a bispecific Car against BCMA and CD19. These are manufactured using a virtually identical process that employs concurrent activation and transduction, and in vivo cell expansion; Novartis and Gracell respectively call the technology T-Charge and Fastcar.

The selling point of what Novartis calls a pioneering technique providing reliable and rapid manufacturing is that cells can be ready within one or two days rather than the more common two or three weeks. However, it then takes a further period of time before the cells are purified, frozen and released for reinfusion.

How long?

This shortcoming was laid bare at Sunday's Ash session when the presenter, Dr Pere Barba of Vall d'Hebron University Hospital, repeatedly dodged questions about what the vein-to-vein time was in a phase 1 lymphoma study of the T-Charge-manufactured YTB323 (rapcabtagene autoleucel).

After insisting that a clinical trial setting was suboptimal to assess this, Dr Barba eventually admitted that vein-to-vein time – the time taken from apheresis to cell reinfusion – was “similar” to the industry norm for autologous Car-T therapies, implying two to six weeks.

This is only part of the problem. Current capacity constraints mean that, once a patient is deemed a candidate for Car-T therapy, it then takes weeks before a slot can be booked for their cells to be manufactured. Dr Barba said some patients were kept waiting for so long that they had to be bridged with chemo, and indeed some went into remission as a result; this had become evident at last year’s presentation.

Dr Barba presented a swimmers plot of responses that pointedly omitted patients’ time between enrolment and dosing. At Ash 2021 this was shown to be between two and three months, with one patient waiting as long as six months. Against this backdrop shaving a week or two off manufacturing time seems paltry.

“Temporary”

Speaking to Evaluate Vantage at Ash Gracell admitted that the cell therapy space had several problems to tackle, but insisted that the capacity shortage was “temporary. Once the industry catches up to patient demand then the key issue [will be] how do you get a therapy to patients faster?”

This is where shorter manufacturing comes in, and Gracell’s chief medical officer, Wendy Li, said the Chinese company had come out with Fastcar years before Novartis splashed T-Charge in 2021.

Ms Li cited an impressive vein-to-vein time of 12-15 days in the GC012F multiple myeloma study. However, as this was conducted in China it will have been subject to different capacity constrains versus those that have become common in the west.

Just like in the Novartis study patients were enrolled a long time before receiving treatment. Though the Gracell trial did not use bridging chemo, its confounding factor was that all patients got induction therapy of Revlimid/Velcade/dexamethasone over a couple of months.

This alone put most of them into remission by the time the GC012F cells were dosed, making it difficult to put the 100% ORR (and 88% complete response rate) claimed at Ash down to the Car-T cells. The trial was billed as a first-line study, but the use of induction means that it was done in something more akin to a first-line maintenance setting.

Ms Li explained the nuance, saying the typical treatment would have involved six cycles of induction, so what this trial was investigating was Car-T on top of a reduced induction regimen, and no stem cell transplant. Just two cycles alone would have yielded short-lived responses, she claimed, so what was important was that GC012F deepened remissions.

What vein-to-vein times Fastcar can achieve in the west might become apparent soon enough: Gracell aims to file a US IND shortly.