Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease ― treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells, and in some cases, they manage to totally eradicate the disease.
About half of patients with leukemia or lymphoma and about a third with myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it.
Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minnesota, and medical director for the cellular therapy program. It was published as an abstract at the recent annual meeting of the American Society of Clinical Oncology, although it was not presented at the meeting.
“We wanted to find out just how widespread this problem is,” she said, adding, “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the US and received responses from 17.
The results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy.
An additional 25% were able to enter a CAR-T clinical trial.
The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage Affecting Mostly Myeloma Patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50 to 60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market ― idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb (BMS). “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022.
While that helped provide centers with a few more slots, it wasn’t sufficient to cut the waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance, Washington.
He noted that, as with other cancer centers, for multiple myeloma, they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex Causes Behind Bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree currently.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Patel told Medscape Medical News. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do,” she explained.
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. The manufacturing and delivery of CAR-T is complicated and takes time to scale up, Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “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, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at the Fox Chase Cancer Center. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the Department of Bone Marrow Transplant and Cellular Therapies. “For Carvykti, there are only 32 certified centers in US, and access is very limited.”
Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR-T products used for lymphomas,” he said.
Pharma Companies Trying to Meet the Demand
Medscape Medical News reached out to the manufacturers of the CAR-T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” said a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility ― our flagship CAR-T manufacturing site ― had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvyki, one of the two approved cell products for myeloma, which launched earlier this year, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Jassen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly Exciting Potential
The supply shortage that myeloma patients are experiencing is all the more poignant and distressing, given the immense potential of CAR T-cell therapy. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, Massachusetts, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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