Point-of-care manufacturing offers ‘treat it when you need it’ approach to CAR-T
Numerous academic medical centers around the world have demonstrated the ability to develop and produce safe and effective chimeric antigen receptor T-cell therapies.
Point-of-care manufacturing is critical for centers seeking to advance the science of adoptive cell therapies such as CAR-T.
The endeavor still requires considerable investments in time, money and expertise. However, many parts of the process are being automated with the assistance of customized commercial solutions.
Point-of-care capabilities no longer are exclusively for the largest centers. Collaborations with academic and commercial partners allow smaller clinics with cell processing units to provide innovative therapies faster, increasing access to novel therapies for patients with high-risk or aggressive disease who often lack other treatment options.
“We know best which patients need CAR-T today and which patients can wait a few weeks,” Nirav N. Shah, MD, associate professor of hematology and medical oncology at Medical College of Wisconsin, told Cell Therapy Next. This is in contrast with commercially manufactured CAR-T, which is produced as orders are received.
Commercial manufacturers won’t “weigh one patient’s needs over another,” Shah said. “You only have control if you are able to do this in-house.”
Although there always will be a place for commercially produced CAR-T at clinics that offer these therapies, experts with whom Cell Therapy Next spoke envision a future in which a hybrid model of onsite and commercially produced therapies allow them the flexibility to provide treatments tailored toward their patients’ needs.
All About Control
Shah is member of a larger-sized academic center that performs approximately 350 hematopoietic stem cell transplant and CAR-T procedures each year.
His clinic provides commercial CAR T-cell therapy but also uses an automated production system, CliniMACS Prodigy (Miltenyi Biotec), to produce novel CAR T-cell therapies for clinical investigation. The process is efficient and eliminates the time and money involved with third-party shipment of cells.
The greatest advantage point-of-care capability provides is control, Shah said — specifically control of timing and the process.
Having a point-of-care option at a clinic like his requires a commercial partner that can shepherd any novel therapies through the regulatory process, Shah said.
“We’re working with Miltenyi Biotech and hoping that the data we generate one day could lead to a situation where you purchase the ingredients and the materials you need to make the CAR T cells from a company, which then gives institutions the flexibility that we don’t have right now,” he told Cell Therapy Next.
It’s not quite off-the-shelf speed, but Shah said his clinic’s point-of-care manufacturing can produce an autologous therapy within 8 to 10 days, compared with an average of 3 to 4 weeks for commercial CAR-T.
The result is a “treat it when you need it” approach, Shah said.
“We are able to monitor the cells in real time. We’re able to do in-process testing, so that we know the cells are growing and expanding enough to meet our dose level,” Shah said.
The increase in process control includes regimen scheduling, lymphodepletion and final infusion, which becomes more precise using a point-of-care system.
Patient prioritization is another advantage of point-of-care manufacturing, Shah said. Commercial manufacturers do not prioritize according to patient needs; rather, they produce therapies for whomever is next in line.
Beyond process control and speed, point-of-care cell therapy manufacturing could provide new treatment options for rare diseases that pharmaceutical companies often do not prioritize, according to Crystal L. Mackall, MD, Ernest and Amelia Gallo family professor of pediatrics and medicine at Stanford University School of Medicine and founding director of Stanford Center for Cancer Cell Therapy.
Mackall — who has extensive experience with CAR-T research and development — said that academia has an impeccable track record of successfully manufacturing clinically effective CAR T cells. This capability, coupled with a researcher’s motivation to tackle the challenges of treating a condition such as a rare pediatric cancer, means hope for patients with diseases that lack commercial investment.
Incentivizing drug development for rare indications in biotech and biopharma is an ongoing process that has not been fully realized, Mackall said. For cell therapies, where the pace of progress has been rapid, point-of-care manufacturing may enable new cell therapies to reach patients quicker than waiting for prioritization by pharmaceutical companies, which face high costs associated with centralized manufacturing, she added.
“We’ve been able to generate therapies and launch clinical trials without industry partnership, and that means a lot when you are trying to treat rare diseases,” Mackall said. “I hope there’s an option open for tertiary care centers to deliver these treatments in the future. We have a 98% success rate for making products, so there’s no fundamental reason why committed and equipped academic medical centers can’t serve this role.”
As more centers add point-of-care cell manufacturing capability, access to therapies will increase.
“That remains one of the problems with cell therapies: They’re not yet accessible to everyone who needs them,” Mackall said.
A point-of-care model could be adopted by several large centers with extensive experience providing HSCT/CAR-T, Mackall said, but it would be best fit for institutions that already have good manufacturing practice (GMP) facilities or the infrastructure in place to meet GMP requirements.
Ability to pay and maintain product quality also must be considered, Mackall said.
“It would have to be a center that thinks it’s worth the investment in quality systems and expertise,” she said. “This is not going to be available at most community hospitals.”
However, there are examples of medium-sized clinics taking advantage of a point-of-care model by partnering with industry and larger academic centers with more expertise.
Shah’s clinic at Medical College of Wisconsin is one example, and he believes point-of-care technology should not be limited to the largest academic centers.
“If your center has that framework in place, then it has a cell processing suite, it knows how to handle cells, and it has the space and the environment to do this work,” he said.
Robert-Bosch-Krankenhaus (RBK) in Stuttgart, Germany, is a medium-sized hospital with stem cell transplant and processing units.
RBK is part of a consortium known as the ProCell for Patient project, a collaboration with Optima Pharma and Universitätsklinikum Heidelberg (UKHD) to develop an automated production system for CAR T-cell therapies.
Walter E. Aulitzky, MD, chief physician in the department of oncology, hematology and palliative medicine at RBK, told Cell Therapy Next it would be unfeasible to bring an automated CAR-T production unit to his clinic without the partnerships they have established for the project, including the contributions of Andrea Traube, PhD, at Optima and Michael Schmitt, MD, at UKHD.
A system prototype is scheduled to be installed at RBK by summer 2022. Optima will provide the equipment. The process of generating CAR T cells has been established in cooperation with the GMP core facility headed by Schmitt at Heidelberg University Hospital and has already gone through the regulatory approval process.
“It’s close to impossible for us to proceed in this project without automation of parts of the process, because the regulatory requirements are so enormously high that they pose barriers to us providing this therapy,” Aulitzky said.
“We can fulfill these requirements only when we have successfully automated large parts of process,” he added. “Otherwise, we will never have the flexibility to justify point-of-care manufacturing of these products.”
Many of the advantages that apply to a cell therapy point-of-care manufacturing model are relevant when examining the drawbacks of a centralized, industrial-based system, Aulitzky said.
“Cell therapy like CAR-T is personalized in such a significant way because the patient is the source of the product,” he said. “The time it takes for a centralization of the process makes it more difficult and a key disadvantage.”
Aulitzky, like the other experts with whom Cell Therapy Next spoke, cited downsides of a centralized model. These include lack of flexibility within the treatment regimen, lack of dosage control and an inability to provide repeat doses.
All of these are open research questions, Aulitzky said. Having a point-of-care capability would allow investigators to develop novel CAR T cells, adjust a cell dose, or provide multiple doses on a preestablished schedule based on a patient’s disease type and characteristics. This ability to adapt to patient needs is “one of the primary motivations” behind bringing a point-of-care capability to RBK, but doing so alone would pose too many challenges from a regulatory perspective, Aulitzky said.
“This is not a quick process; it takes enormous amounts of money and time,” he explained. “In the end this has to be delivered with an industrial partner and could not be achieved by smaller centers or academia itself.”
Despite the potential benefits, a point-of-care model still would require partnerships with industry, according to Rupa Pike, PhD, global director of enterprise science and innovation partnerships with Thermo Fisher Scientific.
Pike is a cell biologist by training and former director of cell manufacturing with the program for advanced cell therapy at University of Wisconsin Carbone Cancer Center, where she helped establish the institution’s new program for advanced cell therapies — including the infrastructure, staffing and GMP training.
“Most hospitals are not set up to do any commercial manufacturing,” she told Cell Therapy Next, adding centers that do have onsite manufacturing capabilities are not typically equipped to bear the financial burden and meet the regulatory requirements to commercialize a new therapy.
“You need a financial partner or sponsor, and such a partner typically will be a biotech or a biopharma,” Pike said. “Most hospitals have never done this before on their own, so the regulatory landscape is still evolving.”
As the technology advances, the regulatory landscape will need to keep pace.
Commercialized point-of-care manufacturing of CAR-T may require point-of-care regulation, Aulitzky said. Having an array of approved viral vectors and processes approved for each center would allow a point-of-care system to deliver patient-specific CAR T cell therapy that targets one or multiple antigens and produces a therapy faster.
“It would take years before this could happen, but this is the direction that regulation should follow,” he said.
Mackall said she shares a similar vision, especially because large centers have a proven track record of manufacturing CAR T-cells suitable for clinical trials. She contemplated a future with a regulatory model that included separately approved viral vectors, reagents and processes for producing a CAR-T, but with manufacturing of the final commercial product done at the point of care at approved centers.
“Something like that might prove to be very helpful in some rare diseases because biotech and pharma are not as focused on those populations,” Mackall said. “I hope a path like this remains open because I think it might solve a lot of problems.”
Shah also expressed concerns about what the regulatory mechanism would look like in a commercialized point-of-care manufacturing model. Key questions include which entities in a partnership would be tasked with compliance and how it would be maintained, Shah said.
“I think the sponsor companies would have to certify each site and probably do an annual follow-up,” he said. “Some sort of accountability would have to occur to make sure that sites are following the process exactly as specified.”
An Alternate Path
Unlike HSCT, which is regulated as a product according to the Public Health Service Act, CAR T cells are regulated as drugs under their current regulatory framework.
The addition of the CAR to the cells is considered more than minimal manipulation, which means it is subjected to more rigorous FDA approval requirements.
A commentary on drug pricing in JAMA Health Forum by Chalasani and colleagues examined the cost and access issues related to CAR T-cell therapy. The authors concluded the current regulatory framework for the commercialization of these products favors pharmaceutical companies because they have greater resources to negotiate the approval process.
“A regulatory shift could eliminate the burden of FDA approval, lower barriers to entry for entities such as hospitals, and enable such entities to commercialize, manufacture and deliver CAR-T therapies directly at the point of care, thereby increasing access and potentially lowering costs,” Chalasani and colleagues wrote.
Proliferation of point-of-care CAR T-cell therapies would require some type of regulatory shift.
Such a framework is not unprecedented, they said, adding that in the EU “cell and gene therapies are exempt from certain regulatory requirements if they are for use in a hospital, prepared on a nonroutine basis according to specific quality standards, and used within the same member state in a hospital under the exclusive professional responsibility of a medical practitioner.”
Switzerland is implementing a point-of-care manufacturing model, and centers there are anticipating offering CAR T-cell therapy at half the price of commercial therapies in the U.S., Chalasani and colleagues noted.
“A more permissive regulatory landscape would enhance competition within the CAR-T therapy market, with multiple health care systems and hospitals taking therapies from bench to bedside, like other hospital services,” they wrote. “This competition, coupled with elimination of the costs of premarket approval, could lower the prices of CAR-T therapies.”
In an article published in 2018 in The New England Journal of Medicine, former FDA Commissioner Scott Gottlieb, MD, and Peter Marks, MD, the current director of the FDA’s Center for Biologics Evaluation and Research (CBER), suggested an alternate regulatory pathway for gene and cell therapies.
The current biologics licensing involves manufacturing a product at a single facility that is then used at one or more clinical trial sites. Approved products then receive a biologics license for a single product.
The proposed alternate licensing procedure would involve multiple manufacturers using the same protocol to make the product at the point of care and, if approved, site-specific biologics licenses would be issued.
“Such a pathway toward licensure may be well suited to groups of investigators or small firms that are able to consistently follow a common manufacturing and clinical protocol but that may not have access to the patient populations or infrastructure needed to conduct separate development programs,” Gottlieb and Marks wrote. “The approach may be particularly well suited to the development of products that involve manufacturing that is not highly complex yet is more than minimal manipulation and to clinical applications amenable to trials of relatively simple design.”
When Cell Therapy Next asked the FDA if it was considering an alternate regulatory pathway to accelerate the development and manufacturing of CAR T-cell therapies, the agency issued a statement saying, “Facilitating the development of innovative therapies to address unmet medical needs is a high priority.”
The FDA’s primary concern is safety, and CBER has plans to develop draft guidance on the development of CAR T-cell therapies on its 2021 agenda, the statement said.
CAR T-cell therapies began as a point-of-care treatment in their investigational phase, and point-of-care manufacturing capabilities are likely to grow in numbers as more researchers enter the field.
A key question is whether the point-of-care model will play a larger role in clinical care going forward at the expense of centralized manufacturing.
“We haven’t seen it yet — all of the commercial [CAR-T] products right now have a centralized model,” Pike said.
Because there is no example of a decentralized manufacturing product on the market, it is difficult to predict whether the approach would be successful for providers.
The “decentralized model with centralized control” suggested by Gottlieb and Marks still would require an industry partner because of the expense involved, Pike said. Sponsors also may be hesitant to partner with centers that have limited exposure to providing these therapies, she added.
“[Point-of-care] is not going to be feasible at smaller hospitals in rural regions,” she said. “It’s going to be at the centers of excellence, with people who understand the complexity and have the necessary experience.”
Mackall foresees an active yet limited role for point-of-care cell therapies. She is hopeful that a path for these can be cleared to treat diseases that are often seen as unattractive by pharmaceutical companies because they lack profitability under a centralized manufacturing model.
“Given that the technological advances for manufacturing these have been so impressive, and the fact that some large academic medical centers have invested heavily in this area, there may be a path forward in the future for special cases — such as rare diseases — where it might make financial sense for point-of-care manufacturing,” she said.
The future of CAR-T and its production will require numerous solutions to overcome the current buffet of challenges that exist, Aulitzky said. Having more than one option to provide effective treatments would be beneficial clinically, he added.
“For me, it’s still an open question whether point-of-care manufacturing of these cells is preferred over commercial-based options,” he said. “Both ways have advantages and disadvantages and, in the end the market will decide.”
Shah said a clinic like his has a large enough support staff to execute a point-of-care strategy that allows his institution to innovate and test new CAR-T constructs. Conversely, smaller clinics that only provide CAR-T to a dozen or so patients a year would find it more reasonable to purchase from commercial manufacturers, he said.
“It is a laborious process to make your own genetically modified products,” Shah said. “I think there’s room for all these different models of care, because it really isn’t a one-size-fits-all program.”
- Chalasani R, et al. JAMA Health Forum. 2020;doi:10.1001/jamahealthforum.2020.0868.
- Marks P and Gottlieb S. N Engl J Med. 2018;doi:10.1056/NEJMsr1715626.
- For more information:
- Walter E. Aulitzky, MD, can be reached at firstname.lastname@example.org.
- Crystal L. Mackall, MD, can be reached email@example.com.
- Rupa Pike, PhD, can be reached at firstname.lastname@example.org.
- Nirav N. Shah, MD, can be reached at email@example.com.