The Challenge With CAR T? It’s Not the Drug, It’s the Delivery

When FDA approved the first chimeric antigen receptor (CAR) T-cell therapy in August 2017, experts hailed its arrival as leap forward for patients with certain blood cancers who had lost hope. According to data published in 2020,¹ clinical trials for tisagenlecleucel, or tisa-cel (Kymriah) demonstrated 83% remission rates, and soon patients with leukemia and lymphoma who met the criteria were lining up to try this miracle treatment or one approved months later, axicabtagene ciloleucel (axi-cel, Yescarta).²

Yet, for the 7 years that CAR T-cell therapies have been approved, the number of patients treated has never kept pace with those who could benefit, according to a new review published in Frontiers in Bioengineering and Biotechnology.² Authors from Monash University School of Business in Australia approach the challenges of CAR T-cell therapy not only from a scientific point of view but also from supply chain perspective, calling for improved collaboration among all stakeholders and at all levels—including the primary clinical caretakers, the regulators, and the manufacturers—making these lifesaving therapies more available to those in need.

Since 2017, FDA approved brexucabtagene autoleucel, or brexu-cel (Tecartus) in 2020; lisocabtagene maraleucel, or liso-cel (Breyanzi), in 2021; idecabtagene vicleucel, ide-cel (Abecma), in 2021; and ciltacabtagene autoleucel, or cilta-cel (Carvykti), in 2022. Prices for therapies, not including administrative or hospital costs, range from $375,000 to $475,000, according to data gathered by the authors.

There is both a shortfall in the number of patients receiving CAR T-cell therapy and disparities in who has access, according to the authors. They cited data showing only 2500 patients received treatment form 2016 to 2020 (including trials), even though approximately 3000 were eligible every year in North America. Patients in Latin America, Asia-Pacific, and Africa face particular hurdles receiving treatment due to supply chain issues, notably the long distances that cells collected from patients must travel to manufacturing sites. The authors noted that until a site was approved in Australia, cells for patients in that country had to make it all the way to New Jersey and back before being administered to a patient.

Breaking down stakeholder levels. The authors delineate primary, secondary, and tertiary stakeholders and explain the role of each one in the supply chain. First and foremost, the chief primary stakeholder is the patient. Other primary stakesholders are the clinical facility, the logistics company that ferries the cells from the patient to the manufacturer and the finished product back to the clinic, and the manufacturer itself.

Secondary stakeholders include regulators, insurers, and key suppliers in the process—from cell tracking systems to makers of reagents to companies that make frozen storage equipment. Finally, there are tertiary groups: patient advocates, research organizations, and advocacy groups.

Each of these entities has a role to play, the authors explain, but thus far, “most of the existing literature on the cell therapy supply chain has a narrow focus, analyzing the challenges faced by primary stakeholders in isolation.”

They found that most challenges in the supply chain were due to issues with the product itself—namely around safety—regulatory challenges, or infrastructure barriers. For good reason, companies, medical centers, and individuals involved in the process, including the transportation of patient cells or newly manufactured treatment, must meet strict quality, safety, and chain-of-custody requirements. And this can create challenges, the authors write, not only from regulators but industry officials enforcing their own standards.

The specialized nature of this work may mean there aren’t even spaces or people to do it. For example, clinicians have warned that the United States is running short of leukapheresis slots due to rising numbers of patients receiving CAR T-cell therapy as well as others participating in clinical trials.

Capacity issues. The authors highlight how CAR T-cell therapy still sees variability in demand and capacity bottlenecks, which can be caused by many factors—from equipment issue to the need for highly skilled personnel. Automation may provide some solutions, but not all.

Reimbursement. The authors describe in detail the many issues that the US reimbursement landscape presents in CAR T-cell therapy. First, it can take up to 30 days to gain approval for coverage of therapy, and in that time patients may deteriorate, causing them to miss the window where treatment will work. Second, the authors explain that Medicare funds CAR T-cell in outpatient settings through patient copayments that are based on daily services, capped at $1408 per day; this offers better coverage than if the patient were to remain in the hospital; however, it relies on a round-the-clock caregiver to manage the patient’s support and limit toxicity-related events.

Here, the need for collaboration is vital.

“The quality of patient cells directly impacts the ability of the manufacturing center to produce sufficient and high-quality products. The responsiveness and policies that surround reimbursement from private and public insurance schemes dictate the level of deterioration of the patient, and ultimately the quality of the starting material,” the authors write.

“Additionally, the incidence of toxic events determines whether the patient is treated in an in-patient or out-patient facility, which then has an impact on reimbursement for the patient.”

References

1. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020;20(11): 651–668. doi:10.1038/s41577-020-0306-5
2. Holland SM, Sohal A, Nand AA, Hutmacher DW. A quest for stakeholder synchronization in the CAR T-cell therapy supply chain. Front Bioeng Biotechnol 2024;12:1413688. doi: 10.3389/fbioe.2024.1413688