From microchips to automobiles, people in the United States are experiencing shortages of all kinds of products, and oncology treatments are no exception. In particular, shortages related to chimeric antigen receptor (CAR) T-cell therapy have been reported, most acutely, for B-cell maturation antigen (BCMA)-directed treatments of multiple myeloma. Some of the same factors affect access to CAR T-cell therapy for patients with leukemia and lymphoma, but supply is closer to demand for these hematologic disorders. To clarify some of the issues causing these shortages, The ASCO Post spoke with several experts in hematologic malignancies.
“At our center—and elsewhere—the biggest shortage [in CAR T-cell therapy] is for BCMA-directed treatments,” stated Krina Patel, MD, Associate Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston.
Two different BCMA CAR T-cell therapies are approved for the treatment of multiple myeloma—idecabtagene vicleucel and ciltacabtagene autoleucel. The manufacturers of these therapies allot a small number of monthly slots at centers for BCMA CAR T-cell treatment. At any given time, according to experts from different centers, the number of patients with multiple myeloma on the waiting list is higher than the number of slots available.
“The two companies that make myeloma CAR T cells have told us that the limited number of slots is due at least in part to the lack of commercial grade good manufacturing process [GMP] viral vectors needed to make the CAR T cells. (The rigor of GMP requirement is more stringent than those used in clinical trials compared to commercial CAR T.) While this is true globally, I am not sure why this access had such critical impact on myeloma CAR T, whereas access for commercial CAR T in leukemia and lymphoma has been minimally impacted,” said Yi Lin, MD, a hematologist-oncologist at the Mayo Clinic, Rochester, Minnesota.
“Now, we have [a CAR T-cell therapy] that achieves unprecedented response rates, and I cannot get this treatment to my patients in a timely manner,” Dr. Patel said.
Supply and Demand
Matthew Frigault, MD, Clinical Director, Cellular Therapy Service, Massachusetts General Hospital, described a similar situation at his institution. “With the growing excitement around cellular therapy, we are seeing an increased demand for these life-saving therapies. Additionally, we are seeing the use of CAR T cells being approved in earlier lines of therapy. With newer indications, especially those in earlier lines of therapy, we are noting increased demand. The manufacturing and delivery of CAR T cells are complicated and take time to scale up. Therefore, we are seeing limited access, more so for the BCMA-directed therapies. Overall, having multiple fantastic CAR T-cell therapies for the same indication will help to improve access,” Dr. Frigault stated.
For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting.— Matthew Frigault, MD
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In Dr. Frigault’s view, two components are mainly responsible for the shortages and delays for patients with myeloma. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting. Manufacturing is extremely complicated and not easily scaled up. That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” he said.
The survival of patients with multiple myeloma while waiting for CAR T-cell therapy is variable and depends on treatment history and aggressiveness of disease. “Our goal is to get every patient who needs it to a CAR T-cell therapy. Unfortunately, not all patients have the time to wait, especially given that some of these patients have multiply relapsed or refractory disease and do have to look to more palliative measures. Getting CAR T cells into earlier lines of therapy will allow us to ‘bridge’ patients more successfully to these exciting treatments,” Dr. Frigault commented.
Frederick Locke, MD, Department Chair, Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, reports the same situation. “We are seeing delays in the manufacturing of CAR T cells, particularly for myeloma, where not enough manufacturing slots are allocated by the pharmaceutical companies. Our myeloma CAR T-cell waiting list is at times more than 100 patients, the majority of whom are not getting CAR T cells in a timely manner, thereby jeopardizing their opportunity for the best outcomes. About 20% of these patients will never get CAR T cells,” Dr. Locke said.
Other Factors
Other issues affecting CAR T-cell treatment delays for patients with myeloma include the following:
- A shortage of the viral vector to deliver CAR T-cell therapy
- Stringent quality control measures for an approved product required by the U.S. Food and Drug Administration (FDA)
- Problems in the viability of patients’ T cells not meeting the criteria set by the FDA
- Amount of time needed to manufacture CAR T cells
- Insurance issues.
Dr. Patel is optimistic that the situation will change over the next year, as the pharmaceutical companies and the oncology community address some of these issues.
“The reasons for the shortages are multifactorial,” said Dr. Locke. “[CAR T-cell therapy] is a gene therapy, whereby T cells are reprogrammed with a chimeric antigen receptor, or CAR, via a gene delivered by a viral vector. They have to be produced in a GMP-compliant manner that is overseen by the FDA. At the end of manufacturing, there are release criteria and specification testing mandated by the FDA that are stricter for commercial use than for the investigational product.”
Steps to Address Shortages
According to Dr. Frigault, manufacturers are working to expand manufacturing suites, increase the supply of critical resources such as lentiviral and retroviral vectors, and decrease the time needed to manufacture cells with newer platforms.
In addition to CAR T-cell shortages, there have been shortages of tocilizumab during the pandemic, because it is used to treat COVID-19. Patients treated with CAR T cells can develop cytokine-release syndrome, and tocilizumab is needed to treat that.
“At Massachusetts General Hospital, we have been planning for the shortage of tocilizumab since the beginning of the pandemic and have been fortunate always to have stock available for patients,” Dr. Frigault explained.
More recently, fludarabine shortages have also been reported. Fludarabine is used for high-dose chemotherapy conditioning regimens.
Dr. Lin mentioned that longer-term solutions may include several innovative technologies with CAR T-cell manufacturing. One example is using nonviral vectors, which are cheaper and more readily available. This approach is being studied.
Another advance would be allogeneic off-the-shelf CAR T cells. “Preliminary studies suggest that these are not actually better than autologous CAR T cells, but may be just as good. Longer follow-up is needed to assess safety and efficacy,” Dr. Lin said.
In the meantime, there are more rapid manufacturing methods to significantly shorten the turnaround time to within 1 to 2 days. This is being tested in clinical trials by pharmaceutical companies at a central manufacturing facility and also in different trials by treatment centers on site.
“Faster turnaround times make it more likely that more patients can remain clinically stable enough to receive their CAR T-cell product. Another interesting observation is that the CAR T cells made with shorter manufacturing appear to be more potent, and fewer cells are needed to dose,” Dr. Lin said.
Fine-tuning the regulatory process could also improve patient access. ”Each autologous CAR T-cell product is essentially a single-batch manufacturing of a drug. The science of setting the appropriate regulatory balance to account for this individual variability is evolving with new generations of CAR T-cell trial data. Current release criteria for FDA-approved CAR T cells are always narrower than what was allowed in the registration study. When the criteria become very different, a larger percentage of patients would get products that fail commercial product criteria than the rate of manufacturing failure seen on study,” Dr. Lin said.
Currently, both FDA-approved BMCA-directed CAR T-cell therapies are indicated for patients who have received four prior lines of therapy. “We tell providers not to wait until the patient has received four prior lines of therapy. A patient on second- or third-line therapy should be referred to the waiting list. This may increase the chance that the wait is shorter for that patient by the time his or her myeloma has progressed through the fourth line of therapy,” Dr. Lin said.
Prioritizing Access to CAR T-Cell Therapy
Dr. Lin was coauthor of a survey on shortages of idecabtagene vicleucel presented at the 2022 ASCO Annual Meeting.1 She and her co-investigators surveyed 17 centers and found that the median wait time for a slot was 7 months, during which time the cancer can progress to a point where CAR T-cell therapy will no longer be beneficial. The investigators estimated a median of 25% of patients died waiting for a slot.
“How you prioritize patients with multiple myeloma for CAR T cells is taking a toll on providers. We want to do the right thing. There are only so many slots. We need a better crystal ball to select which patients are more likely to attain durable remissions. This is a topic for research. We need to be smarter about selecting patients for CAR T-cell therapy,” Dr. Lin commented.
“Our survey showed that at the end of the day, there is a lot of variability in how we select patients for the available slots. Over time, it has become clear that the sickest patients are not necessarily the ones who will have the best outcomes. If their T cells are not fit, there’s a higher risk that it is not even possible to successfully manufacture their CAR T cells,” she explained. “Many providers are shifting to selecting the healthiest patients.”
Insurance Issues and Leukemia
Two CAR T-cell therapies are FDA-approved for the treatment of acute lymphoblastic leukemia (ALL): tisagenlecleucel and axicabtagene ciloleucel.
“There has been poor penetration [of CAR T-cell therapies] in leukemia because of all the burdens we face. We don’t have a shortage, but we have other problems affecting access. For one thing, with relapsed leukemia, we don’t have the luxury of time to collect T cells and plan CAR T-cell therapies,” noted Elias Jabbour, MD, Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center.
“Insurers often won’t cover CAR T cells and have to be convinced. Then, there is sometimes a very high copay. CAR T-cell therapy has been viewed as a bridge to transplantation, but when you submit for insurance, they say you have to choose one or the other, which is a Catch-22,” Dr. Jabbour said. “CAR T-cell therapy is most effective in patients with minimal disease. We should use the best regimen upfront and give CAR T cells afterward, but insurers will find any loophole to deny coverage.”
Dr. Jabbour estimated that at his institution, about 80% of patients with leukemia who are candidates for CAR T-cell therapy are currently getting the treatment. “From the first day I see a patient with relapsed/refractory ALL, I have a roadmap and start the process of ordering CAR T cells. By the time the tumor is controlled, I use [CAR T-cell therapy] for consolidation to offer the best chance of cure,” he said.
Importance for the Oncology Community
Elizabeth Lihua Budde, MD, PhD, Executive Medical Director, Immune Effector Cell Program and Associate Professor, Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, said there is definitely a shortage of BCMA-directed CAR T-cell therapy at her institution. She also mentioned the fludarabine shortage impacting all CAR T-cell delivery.
“We do feel the impact of the shortage. We have a weekly meeting to discuss each case and recommend CAR T-cell therapy, or if that option is not immediately available, then we recommend other treatment alternatives. We have City of Hope-led and other clinical trials that may be suitable for particular patients. Our goal is to deliver the best therapy to the patient. Sometimes waiting is not the best strategy,” she stated.
Dr. Budde believes that community oncologists may not be fully aware of the shortage of BCMA-directed CAR T-cell therapy for patients with myeloma. “The academic community knows about the shortage, but the oncology community as a whole needs to be aware of this. If community oncologists are referring patients to a comprehensive cancer center, they should be aware of the CAR T-cell shortages. But there are other options, including more than 50 CAR T-cell clinical trials that are offered at City of Hope, either our own or pharmaceutical-sponsored trials.”
DISCLOSURE: Dr. Patel is a consultant for Janssen, Pfizer, Bristol Myers Squibb, Legend Biotech, Arcellx, Merck, Oncopeptides, and Karyopharm. Dr. Lin is a consultant for Kite/Gilead, Celgene BMS, June/BMS, Bluebird Bio, Janssen, Legend Biotech, Gamida Cell, Novartis, Iovance, Takeda, Fosun Kite, and Pfizer; has received institutional grants or research support from Kite/Gilead, Celgene/BMS, Bluebird Bio, Janssen, Legend Biotech, Merck, Takeda, and Boston Scientific; and has served on a data safety monitoring board for Sorrento; a data review committee for Pfizer, and a scientific advisory committee for NexImmune. Dr. Frigault is a consultant for BMS, Novartis, Kite/Gilead, Iovance, and Johnson & Johnson; and has received research funding from Kite/Gilead, Novartis, and Arcellx. Dr. Locke is a consultant or advisor to A2 Bio, Amgen, Bluebird Bio, Bristol Myers Squibb/Celgene, Calibr, Cellular Biomedicine Group, CERo, Cowen, Daiichi Sankyo/UCB Japan, EcoR1 Capital, Gerson Lehrman Group, Iovance Biotherapeutics, Janssen, Kite/Gilead, Legend Biotech, Novartis, Sana Biotechnology, Takeda, and Umoja Biopharma; has received institutional research funding from CERo, Bluebird Bio, Bristol Myers Squibb/Celgene, Kite/Gilead, and Novartis; has been reimbursed for travel, accommodations, or other expenses by Kite/Gilead; and holds the following institutional patents, royalties, or other intellectual property: CAR T Cells With Enhanced Metabolic Fitness, Double Mutant Survivin Vaccine, Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR T-Cell Therapy, Methods of Enhancing CAR T-Cell Therapies. Dr. Jabbour has been a consultant or advisor to or has received research funding from AbbVie, Adaptive Biotechnologies, Amgen, BMS, Genentech, Pfizer, and Takeda. Dr. Budde is a consultant for ADC Therapeutics, BeiGene, Genentech, Gilead, Novartis, and Roche; and has received research funding from Amgen, AstraZeneca, Merck, and Mustang Bio.
REFERENCE
1. Kourelis T, Bansal R, Patel KK, et al: Ethical challenges with CAR T slot allocation with idecabtagene vicleucel manufacturing access. 2022 ASCO Annual Meeting. Abstract e20021.
