CAR T cell therapy has become an established treatment for several aggressive blood cancers, with therapies now approved for patients with relapsed or refractory lymphoma, acute lymphoblastic leukemia, and multiple myeloma. For a subset of patients, particularly those with B cell lymphoma, long-term follow-up suggests that a single CAR T infusion can produce durable remissions that may amount to a cure.
But for all its clinical promise, CAR T remains difficult to deliver. Despite nearly seven years of CAR T availability for large B-cell lymphoma in the US, only around two in 10 eligible patients currently receive the therapy. Geography, referral delays, treatment center capacity, workforce shortages, reimbursement, caregiver responsibilities and the logistical demands of treatment can all stand between an eligible patient and an infusion.
These therapies have largely been developed within a paradigm of highly specialized, tertiary-centre care, yet most health systems are not organized to deliver them through coordinated specialist pathways at scale.
—Miguel Perales, Memorial Sloan Kettering Cancer Center
“These therapies have largely been developed within a paradigm of highly specialized, tertiary-centre care, yet most health systems are not organized to deliver them through coordinated specialist pathways at scale,” Miguel Perales, Chief of the Adult Bone Marrow Transplantation Service at Memorial Sloan Kettering Cancer Center, told DDN.
The focus is quickly shifting from proving these treatments work to making them faster, more predictable, and accessible to more patients. But how can it be done?
The challenge of scaling a living medicine
“When Yescarta was approved as one of the very first CAR T cell therapies, it represented an entirely new area of science and a completely novel treatment approach. There was no roadmap for how to manufacture, deliver, or safely administer a living, individualized cell therapy at commercial scale,” Gallia Levy, Global Head of Clinical Development at Kite, a Gilead Company, told DDN.
Since then, Kite, which developed Yescarta and Tecartus, told DDN that the two CAR T therapies have been used to treat approximately 36,000 patients globally through more than 615 authorized treatment centers, with approvals in more than 40 countries.
But scaling CAR T is not simply a matter of producing more doses. “There's a long, precise chain that has to work: collecting a patient's own cells, transporting them to a manufacturing site, engineering and expanding the CAR T cells, and getting that finished, individualized product back to the treatment center in time to be infused into that same patient,” said Levy. This entire process also has to be coordinated around an individual patient's treatment schedule, making reliability just as important as speed.
Laura Alquist, Global Head of Technical Operations at Kite, told DDN that she does expect vein-to-vein times to continue falling over the next five to 10 years through advances in manufacturing technology, automation, analytics and supply-chain coordination. “That said, the goal is not simply to make vein-to-vein time as short as possible,” she emphasized.
A truly scalable CAR T process must be fast, reliable, and predictable, so treatment centers can plan with confidence. “The assurance that a product will be successfully manufactured and delivered when promised is equally as important as shortening cycle times,” Alquist said. That greater predictability “enables treatment centers to plan more effectively, helps patients and caregivers navigate complex logistics with confidence, and ultimately supports a better treatment experience.”
Building the infrastructure
While improving the manufacturing process will help to make CAR T therapies more reliable, it cannot by itself solve the wider access problem. Patients still need to be identified as eligible, referred to an appropriate center, and able to reach that center within the window when treatment can benefit them. Once there, hospitals need trained staff, sufficient capacity, and the financial resources to deliver a complex therapy.
For Perales, these system-level constraints are increasingly important as CAR T moves into earlier lines of treatment and expands into new diseases. “As advanced therapies continue to evolve, success will increasingly depend on aligning scientific innovation with health system readiness rather than treating access as an issue to address after approval,” he said.
Perales is the co-chair of the CAR T Vision Steering Committee, an initiative that aims to address these barriers collectively, bringing together clinicians, patient advocates, providers, health systems, policymakers, and industry around a goal of doubling the proportion of eligible patients receiving CAR T from around 20 to 40 percent by 2030.
One priority is expanding access beyond major academic centers and into community settings, where appropriate. But doing so is not simply a matter of making the therapy available at more hospitals. Community providers would need the expertise, infrastructure, and financial support to identify appropriate patients, coordinate referrals, and manage the treatment and its potential complications.
That makes access a development problem as well as a delivery problem. Rather than waiting until a therapy is approved to consider how it will reach patients, Perales reasoned that developers should be thinking about access as part of therapy development.
“Developers should be considering access and infrastructure requirements from the outset, engaging early with providers, payors, policymakers, healthcare organizations, and patient groups to understand what will be required for successful implementation,” he said.
That means considering not only how CAR T is manufactured and delivered today, but whether the therapy itself could be redesigned to place fewer demands on the systems delivering it. One way to do that could be to move away from the bespoke model, making CAR T easier to manufacture, store, and deliver.
Can CAR T escape its bespoke model?
Today's approved autologous CAR T therapies are manufactured from a patient's own T cells, meaning every treatment follows its own journey from cell collection to infusion. Two emerging approaches could eventually break that link between the patient and the manufacturing process: in vivo CAR T, which aims to engineer T cells directly inside the body, and allogeneic or induced pluripotent stem cells (iPSC)-derived CAR T, which could produce cells in advance for use in multiple patients.
Both approaches are still under development, but they offer a tantalizing possibility. If CAR T cells could be manufactured in batches — or generated inside the patient — much of the logistical complexity that currently limits access could be removed.
In vivo CAR T cell engineering is a fast-growing sector, with several large companies exploring the approach. By using viral or nanoparticle vectors to directly engineer CAR T cells inside the patient, the strategy could eliminate the need for apheresis, personalized cell manufacturing, and lymphodepleting chemotherapy.
Kite has already entered this emerging field through its acquisition of Interius Biotherapeutics, but Levy cautioned that in vivo CAR T remains at a very early stage compared with the ex vivo therapies already used in the clinic.
While the field is still young, initial clinical results have been promising. In an early clinical study of Kelonia Therapeutics’ KLN-1010, an in vivo therapy for multiple myeloma (MM), all six patients with relapsed or refractory MM reached minimal residual disease negativity in the bone marrow one month after treatment. Similarly, MagicRNA’s HN2301 generated CD19-targeting CAR T cells inside the body in five patients with treatment-refractory systemic lupus erythematosus, completely depleting circulating B cells and significantly reducing disease activity after three months.
However, both studies also revealed safety challenges, including cytokine release syndrome and other treatment-related adverse events.
Another possibility is to move away from the patient's own cells altogether.
Building CAR T in advance
Researchers at the Center for Regenerative Medicine at Boston Medical Center and Boston University are exploring whether iPSCs could provide a renewable starting material for an off-the-shelf CAR T therapy.
Unlike mature T cells collected from an individual patient, iPSCs can be maintained and expanded in culture. Genetic modifications can also be made at the stem-cell stage, allowing researchers to create a defined starting population that could eventually be used to generate large batches of therapeutic cells.
If we can make T cells out of iPSCs and have them ready with the CAR frozen, the moment the patient needs it, we can take them out of the freezer and inject them.
—Gustavo Mostoslavsky, Boston University
“If we can make T cells out of iPSCs and have them ready with the CAR frozen, the moment the patient needs it, we can take them out of the freezer and inject them,” Gustavo Mostoslavsky, stem cell biologist and co-Director of the Center for Regenerative Medicine at Boston Medical Center and Boston University, told DDN.
Mostoslavsky's latest work addresses a particular limitation of iPSC-derived T-cell therapies: generating CD4+ helper T cells. CD4+ cells help coordinate the immune response, reducing the risk of severe adverse reactions in CAR T treatments.
“CAR T cells can produce large amounts of cytokines, which can trigger an excessive immune response known as a cytokine storm and, in severe cases, can be life-threatening,” said Mustoslavsky. “Recent studies have highlighted the potential role of CD4+ helper T cells, which produce cytokines that can help regulate or dampen this response.”
This is something that ex vivo CAR T therapies are already working towards by optimizing the ratio of CD4+ and CD8+ cells that are infused into the patient. Mostoslavsky’s team is now working toward testing combinations of its iPSC-derived CD4+ and CD8+ cells in tumor-bearing mice to determine whether the cells perform as intended in vivo.
The longer-term goal is not simply to make CAR T cells in advance, but to make them potentially usable across patients. One of the key problems with allogeneic therapies right now is that cells generated from an unrelated donor are generally recognized as foreign by the recipient's immune system. Researchers are therefore exploring additional genetic modifications to make the cells hypoimmunogenic, or less visible to the patient's immune defenses.
For Mostoslavsky, an off-the-shelf CAR T product is still several years away. The cells still need to be tested in vivo, and researchers need to determine how to scale their production while preserving the characteristics that make them therapeutically useful.
But if those hurdles can be overcome, the approach could fundamentally change the economics and logistics of CAR T. Instead of manufacturing a new product around every patient, developers could produce defined cell populations in advance, store them, and select a ready-made therapy when a patient needs it. That could reduce the manufacturing time, variability, and patient-specific logistics that currently constrain access to autologous CAR T.
More than one route to scale
All of these approaches are aimed at solving the same problem: Can CAR T therapies be made easier to manufacture, deliver, and access without compromising their effectiveness or safety?
The answer is unlikely to come from a single technological breakthrough. Faster manufacturing can shorten the wait for treatment, while in vivo and off-the-shelf approaches could eventually remove some of the logistical constraints of personalized cell therapy. But these advances will need to be matched by changes in the healthcare systems that identify, refer, and treat patients.
CAR T Vision is aiming to double the proportion of eligible patients receiving CAR T by 2030. Reaching that goal will require developers, healthcare providers, payors, policymakers, and patient groups to address the problem together.
Getting there may require not one breakthrough, but several — in manufacturing, healthcare policies, and the underlying biology of cell therapy itself.
