The data, presented at the virtual 47th European Society for Blood and Marrow Transplantation (EBMT) meeting in March 2021, provides the first real-world insights into axicabtagene ciloleucel (Axi-cel) manufacturing for European, Swiss, and Israeli adult patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) and primary mediastinal large B cell lymphoma (PMBCL), said the biopharma company.
The analysis also highlights the potential benefits of CAR T cell therapies, and Kite’s continued commitment to reach those patients who have limited treatment options, it said.
“We saw a high manufacturing success rate,” Didier Hallard, Director Qualified Person (QP) at Kite, told us. In the study, 96% of Axi-cel lots met marketing authorization (MA) specifications, he said.
Also of note, he remarked, was the reliable turnaround time from apheresis to QP release seen – a median of 25 days. “This treatment is often the last hope for these patients so timing is very important,” said Hallard.
The results align with Kite’s pivotal ZUMA-1 clinical trial on Axi-cel in the US and Europe in terms of complete response. However, that Phase 2 study was limited in comparison as it was only done on a cohort of 101 patients, he explained.
The current dataset covers a large patient population analysis, with over 1,000 patients scheduled for treatment with Axi-cel. “Kite is a real pioneer in this respect, one of the only CAR T therapy providers with now such extensive data on the treatment,” Hallard commented.
Yescarta was approved for use in the EU in August 2018 as a treatment for adult patients with aggressive lymphoma, after two or more lines of systemic therapy. “We have a study underway currently exploring the use of the treatment at an earlier stage but for now it is given after two lines of systemic therapy.”
Considering the COVID-19 related travel and logistics complications in place since March 2020, the company said by working with suppliers and stakeholders to continue manufacture and delivery of Axi-cel between the European and US-based Kite manufacturing facilities, it was also able to ensure limited disruption to the supply chain.
European manufacturing brings advantages
Kite is aiming to rapidly reduce treatment turnaround time now through several initiatives, by having European manufacturing, by shortening its quality control time, and also by automating some of its activities, said Hallard. “We are aiming to go to 21 days or less in terms of apheresis to QP release.”
Indeed, a percentage of the patients whose treatment was documented in the retrospective analysis were able to benefit from accelerated cell delivery via Kite’s newly established end-to-end manufacturing facility site near Amsterdam in the Netherlands, which went online in June 2020.
Before the facility’s approval from the European Medicines Agency (EMA) last year, cells, following isolation from patients in Europe, were cryopreserved at either the manufacturing site near Amsterdam or at a CMO facility near Maastricht, shipped to Los Angeles, US, for manufacturing, and then transported back to those patients in Europe.
The new site, which is close to Schiphol airport, can reduce delivery time to European, Swiss, and Israeli treatment centers by three to four days. It is anticipated that the facility could facilitate treatment for up to 4,000 patients per year.
Along with the time gained given that there is no longer the requirement to fly cryopreserved leukapheresis cells to the US, the new facility gives the company greater control over the process. “We are still using the CMO site near Maastricht but not for much longer. In the near future, the facility near Schiphol will take over the whole of commercial manufacturing for EU patients.”
Continuous process improvement
Process innovation is also key. In terms of next steps, the further scaling up of Axi-cel, the company is also looking to shift from manual processing to a semi-automatic, if not a fully automatic platform. The anticipated timeline on that switch is, hopefully, within five years, said Hallard.
"Speed is essential in terms of turnaround time for us and the patient. We have tried to reduce our testing time without comprising any aspects of the process. One way to do that was to reduce sterility testing to seven instead of the normal 14 days, without any loss in relation to quality. We achieved this through the use of digital continuous monitoring for color change indicating microorganism presence," said Hallard.
Cryopreserved leukapheresis cells were selected as the preferred starting material over fresh material in Kite’s initial application to the EU regulator for Axi-cel approval to meet the demands of its manufacturing model, given the delays that arose from the previous need to ship cells to the US.
But, again in the interest of a speedier process, and now that it has the manufacturing site close to Amsterdam, Hallard said the company has filed an application to the EMA for a change in the EU marketing authorization for Axi-cel, requesting the use of fresh material as well as cryopreserved cells for the treatment approach in Europe.