NEW YORK – Even though drugmakers are looking to automate manufacturing of CAR T cells in the hope of easing production bottlenecks, for autologous therapies significant technology advances are still needed to bridge the gap between supply and demand.
Five autologous CAR T-cell therapies are currently approved by the US Food and Drug Administration for second- or later-line treatment of hematologic malignancies, and hundreds of clinical trials are underway in an expanding list of blood and solid cancer indications. According to a report from market research firm McKinsey and Company, the addressable patient population for CAR T-cell therapies was 450,000 in 2019, and is expected to grow to 2 million within the next two to seven years. Meanwhile, doses of approved CAR T-cell therapies produced per year number in the low thousands.
The production backlog creates a significant barrier to access for patients. In a survey of cancer centers in the US, the median wait time for CAR T-cell therapies for patients with relapsed or refractory multiple myeloma was six months, with only 25 percent of patients eventually receiving the treatment. Another 25 percent entered a CAR T-cell clinical trial, and the remaining 50 percent died or entered hospice care without ever getting a shot at a cell therapy. Each site had up to four slots per month to administer treatment, with anywhere from five to 100 patients on the waiting list.
Bristol Myers Squibb acknowledged that in the first half of 2022 it struggled with ramping up manufacturing capacity for its cell therapies, including for its newly launched multiple myeloma product Abecma (idecabtagene vicleucel) and the large B-cell lymphoma therapy Breyanzi (lisocabtagene maraleucel). BMS reported $107 million in sales for Abecma in the third quarter of 2022. Using the drug's list price of $419,500 as a metric, roughly 255 patients received Abecma.
Legend Biotech, which markets the CAR T-cell therapy Carvykti (ciltacabtagene autoleucel) for relapsed and refractory multiple myeloma in partnership with Janssen, reported $55 million in revenues for the third quarter of 2022 in an October SEC filing. Based on its $465,000 list price, an estimated 118 patients received the drug in Q3. About 34,000 new cases of multiple myeloma are diagnosed each year in the US, according to the American Cancer Society. The majority will experience relapse and some will be refractory to treatments.
These numbers illustrate the steep cliff drugmakers must climb to meet patient demand for CAR T-cell therapies. And the incline will only get steeper if sponsors are successful in garnering approval for their products in earlier treatment lines and additional indications — ambitions drugmakers are pushing to quickly achieve.
The access delays are primarily due to the fact that it takes so long to produce autologous CAR T cells. The process begins at the patient's bedside with collection of the lymphocyte-rich mononuclear cell layer of blood through leukapheresis. The cells are then sent to a facility where T cells are enriched, activated, and modified to produce a tumor-specific chimeric antigen receptor (CAR). These CAR T cells are expanded and harvested, tested for quality, and shipped back to be re-infused into the patient. Patients are then monitored to track how their immune systems react to the treatment.
On the Carvykti website, Legend and Janssen state that this process from cell collection to infusion takes about four weeks, referred to in the industry as "vein-to-vein" time. Novartis' and BMS's promotional materials for Kymriah and Breyanzi both indicate about a three-to-four-week turnaround time from leukapheresis to infusion.
Because CAR T-cell therapy is a personalized medicine product made to order for one patient at a time, it is not possible to scale up the process, and make, for example, a hundred or a thousand products per run. Instead, manufacturers hope to "scale out," or add capacity to produce more individualized CAR T-cell products at the same time. Automation, particularly closed end-to-end automation, is viewed as a potential means of scaling out production by increasing the number of products that can be processed simultaneously.
Meeting demand in other ways
Kite Therapeutics, a Gilead company, is certainly embracing automated CAR T-cell manufacturing, but the company is looking to automation technology for efficiencies rather than to increase production. In 2019, it broke ground on a new 275,000-square-foot facility in Frederick County, Maryland, dedicated to automated manufacturing of its CAR T-cell therapies Yescarta (axicabtagene ciloleucel), Tecartus (brexucabtagene autoleucel), and other cell therapies. In April of this year, the FDA approved commercial production of those therapies at the new site.
Added to the company's existing cell therapy manufacturing facilities in El Segundo, California, and Amsterdam, the new facility increased Kite's cell therapy production capacity by 50 percent. Kite has previously reported that its facility in Amsterdam can produce cell therapies for 4,000 patients per year. In October, it also added a retroviral vector manufacturing facility in Oceanside, California, to support its cell therapy production.
Chris McDonald, global head of technical operations for Kite, said the company is "in the middle" of automating its cell therapy manufacturing process. According to McDonald, Kite is meeting demand among refractory lymphoma and leukemia patients for Yescarta and Tecartus with its existing network, including its new automated manufacturing facility, and has the infrastructure to meet "all future patient demand."
Yescarta is approved for patients with relapsed or refractory large B-cell lymphoma. Kite and Gilead have estimated that about 7,500 patients with DLBCL will be eligible for it each year, whereas the number of DLBCL cases is expected to grow to more than 32,000 by 2025 in the US. If the companies are successful in winning market approval for Yescarta as a first-line DLBCL treatment, as the results of the Phase II ZUMA-12 trial suggest, this could significantly increase demand.
Similarly, Kite and Gilead have said that about 1,000 patients are treated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia per year, but eligible patients for Tecartus could expand to more than 6,000 in the US alone with an early-line approval.
For Kite, automation is more about ensuring sterility of cell therapy manufacturing through a closed process and minimal human handling steps than about increasing production capacity. Kite's automation system, which it has not detailed to date, uses multiple pieces of equipment to automate different portions of the process. The company claims it has achieved end-to-end automated processing, meaning that all steps, starting with the arrival of patient cells at the facility through final analysis of the finished CAR T cells, are carried out in an automated fashion. According to McDonald, the company is also working on automating quality control testing of cell therapy products.
Kite touts a 96 percent success rate for its cell therapy production process. When asked how often the company has experienced contamination events in the past, McDonald said, "We have an extremely high sterility success rate. We've had a few sterility positives over thousands of batches. There's an opportunity for loss, but we're not seeing that."
One challenge, McDonald pointed out, in meeting patient demand for CAR T-cell therapy is that the demand is uneven, with periodic spikes and dips. "Normally in a biotech or pharmaceutical product, you would have inventory, and you're selling out of that inventory that covers those peaks and valleys," he said. "Here, you really need to have the capacity in place to capture the peaks, and that's what we've been able to do."
Ultimately, Kite acknowledges that it is not relying on automation to increase its manufacturing capacity for CAR T-cell therapies. "Kite has continued to increase its manufacturing network capacity to meet increasing demand, ensuring scheduling availability to meet the needs of physicians and their patients, which is not necessarily tied to automation," said McDonald.
While most of the major players in the CAR T-cell therapy space have not disclosed their manufacturing methods, Miltenyi, the manufacturer of the automated CliniMACS Prodigy cell therapy manufacturing platform, said that the system is widely used by industry customers at all phases of development from clinical research to commercial manufacturing. However, some drug developers are taking a more cautious approach.
"I'm not a big fan of [end-to-end] automation," said Knut Niss, chief technology officer for Mustang Bio. The Worcester, Massachusetts-based company is developing a pipeline of CAR T-cell, gene, and oncolytic viral therapies, including a Phase I product, MB-101, for glioblastoma and MB-106 for non-Hodgkin lymphoma. Mustang is also preparing to file an investigational new drug application to study MB-101 with the oncolytic virus product MB-108 in glioblastoma and has begun a Phase I/II trial of MB-106 in advanced lymphoma and leukemia.
Instead of an end-to-end automation approach, Mustang is using a hybrid process to manufacture its CAR T-cell therapies that incorporates Miltenyi's CliniMACS Prodigy system. Mustang automates what it calls the day zero operations. That generally involves platelet and red blood cell depletion followed by washing of the cells. Some CAR T cells will also undergo specific cell isolation on day zero, such as CD3 selection. Niss said that approximately 50 percent to 60 percent of the cost and operator time is spent on these day zero operations. The subsequent steps, including activating, transducing, and expanding the T cells, require significantly less hands-on time, with lengthy incubations in between.
"If you have a $270,000 machine and you turn it 95 percent of the time into just an incubator, you basically have a very expensive incubator," said Niss. "If you look at the hours the cells are not spending in the incubator, meaning somebody is working with them, that's less than 12 hours in seven days."
As for concerns about contamination, Niss hasn't seen this cause major delay in standard CAR T-cell manufacturing processes. "Where you see it is in trials where the process is not [fully developed], or where there are still a lot of open steps," he said. "Our process for CAR T is almost entirely closed. The risk of contamination is very low. We have never seen [contamination losses]."
Niss, who before Mustang worked for Novartis at its Morris Plains, New Jersey, site developing the manufacturing process for the drugmaker's CAR T-cell product Kymriah (tisagenlecleucel), also questioned the staffing benefits of end-to-end automation. "I have not seen any automation that is truly walkaway, meaning somebody sets it up and comes a few days later and it's monitored from outside the clean room," said Niss.
And whether the system is truly "walkaway" or not, he pointed out, the typical failure rates of automated systems are around 5 percent. In Niss' view, that means the additional labor for rescuing cells from a failed automated process and finishing them manually chips away at any potential savings. "I've not seen that there's a significant reduction in labor using automation, mainly because you still need people monitoring, you still need people on standby," he said.
Niss said that in establishing the process for Mustang's CAR T-cell products, the company aimed to minimize interactions with the operator. He said in order to produce "a few thousand" CAR T-cell treatments per year, the company will need a significant-sized facility and workforce.
But Mustang is not only building out more space and personnel for producing CAR T cells but is also working to solve capacity problems with "smarter" facility design. "When you look at a biologics facility, there's a giant clean room, with different workstations. The design of the facility is not set up in a way that is specific to the CAR T process," Niss explained.
To illustrate, he said that in comparison to the space needed for day-zero operations, starting on day three, when the lentiviral vector is brought in for transduction of the cells, the process can be carried out in an 80-square-foot room. By laying out the space more strategically, Niss said, the facility is "smarter" and can produce more products for patients in the same amount of space.
Beyond processing, personnel, and smart space design considerations, drugmakers will need to address quality control to resolve bottlenecks in CAR T-cell production, Niss pointed out. And this is where automation might help — something Kite has also recognized. "Believe it or not, the cost of quality control is probably roughly the same as the processing," Niss said. "The QC element of making a CAR T product is actually where I am missing automation the most."
Addressing cost with automation
While there are upsides and downsides to automation, scaling out CAR T-cell production can stand to significantly lower costs, some experts say. This, in turn, can create more product supply and make these treatments more financially accessible to patients. The price of CAR T-cell therapies start at $150,000 and range higher, presenting a significant barrier to access.
"To get these products to be first-line [options], you can't have products that cost hundreds of thousands of dollars per patient. It would be very difficult to make those products widely available," said Ori Biotech CEO Jason Foster. Ori is developing an automated cell therapy processing platform that it hopes will decrease the costs of CAR T-cell production by 80 to 90 percent. With those lower production costs, Foster claimed, the corresponding costs for patients receiving second-line CAR T-cell therapy would be price-competitive with multiple rounds of chemotherapy or a transplant.
Such an automated platform would employ robotics technology to process the cells and incorporate sensing capabilities to observe the cells as they progress through the system. Foster said Ori is adding robotics where they are relevant and removing people from the process "so we can get highly repeatable, highly scalable, high-throughput, high-quality, and low-cost processes."
London-based Ori has invented its own fluid handling system, combining aspects of bag-based and cartridge-based processes. It also offers the ability to weld sterile tubing at large scale in an automated manner. These capabilities decrease the variability in the development process, Foster said, making them more amenable to scaling out from the early stages of development to commercial production. The company claims its system has a smaller footprint in being able to fit more productivity into a given manufacturing space.
For comparison, Foster noted that while Kite's 117,000-square-foot manufacturing facility in the Netherlands can produce CAR T-cell therapies for 4,000 patients per year, "with the Ori platform, we'll be able to produce 4,000 doses in 4,000 square feet, so that's a 95 percent reduction in the amount of … square footage you need [in a Good Manufacturing Practices facility] to deliver these products."
While Kite and Ori don't have a business relationship and Foster was just using publicly available data to illustrate the advantages of Ori's technology, the company's platform is currently being tested by five partners through an early-access program. (Ori hasn't yet disclosed who the partners are.) The firm will also begin a clinical trial using the system late in 2023 and hopes to introduce it for broader research use around that time or in early 2024.
The company doesn't yet know what the failure rate of its system will be because it is still in beta testing. "In case of an instrument failure, the operator would just remove the consumable and put it into a different Ori device — an operation that should take no more than 30 seconds, with no risk to the final drug product," said Foster.
A Miltenyi spokesperson said that it is also possible to rescue cells from the CliniMACS Prodigy system in the event of automated process failure.
Cellares is another company developing a next-generation end-to-end automation system for CAR T-cell therapies. Cellares' Cell Shuttle is a "factory" in a room-sized box about 15 feet by 18 feet by 9 feet. It's capable of processing 16 batches simultaneously, and requires one-tenth of the number of human operators needed for manual processing.
Inside the Cell Shuttle, a robot moves single-use cartridges from one bioprocessing instrument to the next. "You load the cartridge into the Cell Shuttle, then the Cell Shuttle executes the entire manufacturing process fully automatically from start to finish," said Cellares Cofounder and CEO Fabian Gerlinghaus.
He added that in addition to the advantages of a multiplexed process, the Cell Shuttle reduces the risk of contamination, which Gerlinghaus believes is higher than the 5 percent risk estimate often cited by pharma companies. According to him, operator error and contamination are the two primary sources of process failure. "We have had conversations with several industry leaders who have shared with us that they believe the manufacturing failure rates are higher than publicly acknowledged and may be as high as 20 percent for some products," said Gerlinghaus. "However, they all agree that automation can and will help address this challenge."
Cellares is aiming to lower the failure rate to less than 5 percent using a closed, fully automated process. In case of system failure, the South San Francisco, California-based firm has a couple of options for users. First, every consumable is equipped with sterile connections that can be used to manually rescue cells. However, depending on the specific type of failure, it might also be possible to transfer the cells completely automatically within the Cell Shuttle from the consumable cartridge into a sterile liquid transfer device.
"The current paradigm requires highly trained operators performing highly complex manufacturing processes, spending up to two weeks in very expensive clean rooms, executing around 50 manual processing steps that require 80 hours of touch time, generating up to 500 pages of documentation, all to produce one product at a time," said Gerlinghaus. "It is not reasonable to expect perfection from humans."
However, he noted that much more can be expected from an automated system like the Cell Shuttle, which has already demonstrated a fourfold reduction in process failure rates.
Cellares expects its system will reduce manufacturing costs by more than 50 percent, while enabling commercial scale manufacturing and resolving the bottleneck for patients. "I fully anticipate that as manufacturing costs go down over time, drug pricing will come down as well," said Gerlinghaus. The Cell Shuttle is expected to be available for the commercial and research market in 2024.