Abstract
A 2022 survey found that only about 25% of patients with multiple myeloma who were waiting for CAR T-cell therapy received the treatment. Manufacturing bottlenecks, such as shortages of viral vectors, limited supply. New approaches for manufacturing and testing the cells could improve their availability, but demand could also soar if they are approved for earlier use in treatment regimens.
Last year, Yi Lin, MD, PhD, of the Mayo Clinic in Rochester, MN, surveyed 20 of the nation's top cancer centers to find out how long patients with multiple myeloma waited for chimeric antigen receptor (CAR) T-cell therapy. The 17 responses painted a stark picture: Just 25% of patients on waiting lists received CAR T cells as part of standard therapy—and then only after a median delay of 6 months. Another 25% joined clinical trials to access the treatment, and 50% elected to enroll in clinical trials of different therapies, entered hospice, or died.
But the situation “has changed in the last few months,” says Lin. Manufacturers of idecabtagene vicleucel (ide-cel; Abecma; Bristol Myers Squibb [BMS]) and ciltacabtagene autoleucel (cilta-cel; Carvykti; Janssen/Legend Biotech), two BCMA-targeting CAR T-cell therapies for multiple myeloma approved in 2021 and 2022, respectively, have worked to increase availability. Some oncologists say they have seen reductions in the vein-to-vein time—how long it takes to harvest, genetically modify, expand, and reinfuse a patient's T cells. Alfred Garfall, MD, of the University of Pennsylvania in Philadelphia, says that his patients with multiple myeloma now typically wait 6 to 10 weeks to receive their cells.
That's longer than for some other, less recently approved types of CAR T cells for treating different blood cancers. The median vein-to-vein time for axicabtagene ciloleucel (Yescarta; Kite Pharma), an option for patients with large B-cell lymphoma, is 31 days, per a study led by Frederick Locke, MD, of the Moffitt Cancer Center in Tampa, FL. The delays influence oncologists’ decisions about which patients with multiple myeloma should receive the therapy. “You have to be able to keep the patient's disease under control” until their cells are ready, says Garfall.
Despite the recent improvements, many patients still aren't getting the therapy. Before a cancer center can dispatch a patient's cells for engineering, it must obtain a manufacturing slot. Companies offer a limited number of slots, and some cancer centers aren't able to book them. CAR T-cell treatment is also out of reach for patients who can't travel to hospitals that offer it, says Locke. “These are really important treatments, so we need to figure out manufacturing and access.”
BMS and Janssen/Legend Biotech acknowledge they initially could not meet demand. One bottleneck was the scarcity of the viral vectors needed to engineer patients’ T cells. The COVID-19 pandemic also led to shortages of viral and nonviral starting materials and clean-room capacity, says Ulrike Köhl, MD, PhD, director of the Fraunhofer Institute for Cell Therapy and Immunology in Leipzig, Germany.
Legend's CEO also told investors in 2022 that a major difficulty was manufacturing products that met FDA standards.
The upshot? Only a few manufacturing slots were available initially. For ide-cel, BMS started with 40 per month and then doubled the number in 2022. Lin's survey, which largely reflects ide-cel's availability, showed that each center received a median of one slot per month. Cilta-cel's subsequent approval boosted the overall supply of CAR T cells, but Janssen and Legend offered just 40 slots at first.
Both manufacturers are trying to crank up production. This year, BMS received the FDA's go-ahead to make CAR T cells at a facility in Massachusetts to supplement output from its New Jersey plant. Janssen and Legend have invested $500 million in their cilta-cel manufacturing facility and plan to produce their own viral vectors instead of using outside suppliers.
Some oncologists say the companies are largely keeping up with demand. Locke says his center delivered CAR T cells to about 80% of the 120 patients initially on its waiting list. “We don't have a big difficulty obtaining slots,” Garfall adds. The approval of three bispecific T-cell engagers for multiple myeloma has also provided an alternative and “taken away a lot of the anxiety” about deciding who can receive CAR T-cell therapy, Garfall says.
Other approaches may also ease manufacturing pressure. Pfizer is testing a new procedure—in which CAR T cells are expanded mainly in a patient's body, not a lab—that could slash the manufacturing time. Another promising approach involves engineering cells from healthy donors instead of patients. These allogeneic products could be available off-the-shelf, eliminating the delays associated with personalized therapies.
In addition, streamlining potency and quality control testing, which can add weeks to the turnaround time, could speed manufacturing, notes Mohamed Abou-el-Enein, MD, PhD, of the Keck School of Medicine of the University of Southern California in Los Angeles. For instance, rapid sterility tests are gaining wider use. “Despite their advantages, these tests require extensive validation data before the FDA allows their use for product release,” he says.
Even if these methods succeed, it may be years before they increase the availability of CAR T cells. Yet demand for the agents is likely to soar if, as oncologists expect, they are approved for use earlier in the course of treatment instead of after the current minimum of four previous therapies. And if CAR T-cell treatment expands to solid tumors and autoimmune diseases, demand for raw materials and production facilities would increase further, potentially leaving manufacturers again scrambling to meet the needs of patients with multiple myeloma.
“I don't think companies are ready for the numbers of patients” that would follow, says Locke. –Mitch Leslie
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