ASH 2024 – Miltenyi throws its hat into the fast-Car ring

With Galapagos making an ASH splash with a seven-day Car-T vein-to-vein time and a decentralised manufacturing model, the private company Miltenyi Biotec got in on the act too. Like Galapagos's GLPG5101, Miltenyi's zamtocabtagene autoleucel uses fresh cells, with no freezing, and a fast vein-to-vein time that doesn't require patients to be bridged with chemo.

Studies of both projects featured at ASH on Saturday, and the last point appears as a shot across the bows to Novartis, which reported data from a trial of its fast-manufacturing contender rapcabtagene autoleucel in which 60% of the patients received bridging chemo. That said, Galapagos remains the only player so far to have made a push into decentralised Car-T manufacturing.

Miltenyi's zamto-cel, a dual anti-CD19/CD20 Car, uses what Medical College of Wisconsin's Dr Nirav Shah called a unique, "fresh-in-fresh-out" production system, with cells delivered unfrozen to a central facility, where they are manufactured in a closed, automated system before being delivered fresh to the treating site.

Patients start being lymphodepleted while manufacturing is still taking place, ensuring fast vein-to-vein time that in the study presented was said to amount to 14 days. It's not clear how the need to freeze is avoided, but presumably a clinical-trial setting makes this easier if participating hospitals are relatively close to the central manufacturing site. 

Galapagos has made much of its desire to decentralise manufacturing in favour of a network of blood centres. Miltenyi's goal is also to move towards this type of localised system, Shah revealed at ASH.

Pivotal phase 2

The ASH presentation concerned Daly II USA, a pivotal phase 2 study of zamto-cel in third-line aggressive lymphoma, where an interim analysis of 59 patients showed a 73% ORR, including a 51% complete response rate. The data concerned a rather old March 2024 cutoff, and the trial is set to continue enrolling patients up to a planned total of 110.

Shah said six patients got non-conforming product, and four had to have cells frozen and be bridged with chemo, but these were excluded from the analysis. 

This contrasted sharply with an ASH presentation on Novartis's rapca-cel, also in third-line DLBCL, where a 60-strong patient set yielded an 88% ORR and 65% complete response rate. However, 60% of the patients had bridging chemo, which in fact led to four of them being in complete remission before rapca-cel was even infused.

Rapca-cel uses Novartis's T-Charge system, which claims a two-day manufacturing time. However, it's notable for no longer being referred to as a fast-production process, and at ASH was called a "platform to preserve T-cell stemness". 

Asked why patients needed to be bridged when rapca-cel was manufactured within two days, the presenter, Dr Peter Riedell of University of Chicago, pointed to quality criteria that had to be met before cells were released. Thus, while cells were harvested within two days, "door-to-vein" time was around 13 days.

Fast-manufactured Car-T therapies in r/r DLBCL

Notes: *used in 4 patients, excluded from analysis set; ^includes 4 patients in CR before infusion; ^^safety data for ph1 only as no DLBCL pts included in ph2. Source: ASH.

It's still unclear how Novartis intends to proceed with rapca-cel in the real world, but notable that it has discontinued at least two other Cars that used T-Charge, including the BCMA-targeted PHE885.

While Miltenyi's zamto-cel is a dual construct, rapca-cel, like Galapagos's GLPG5101, targets just CD19. Zamto-cel was developed to reduce relapse by way of antigen loss, and Shah revealed that just four of 27 patients evaluable for antigen presence suffered loss of either CD19 or CD20, and only one experienced loss of both antigens.

Miltenyi is best known for selling the Clinimacs cell manufacturing instrument. The fact it also has an R&D pipeline of Car-T therapies is perhaps less well known.