Addressing the CAR-T Supply Challenge
It’s a Matter of Life or Death for Multiple Myeloma Patients
Demand has quickly grown for chimeric antigen receptor T-cell (CAR-T) therapies used to treat a variety of blood cancers, including lymphomas, leukemia, and multiple myeloma. Newer indications and impressive clinical results leading to the use of these medications as earlier lines of therapy have significantly increased the number of patients eligible for CAR-T treatments.
Usually, this would be considered good news. Except, when supply can’t keep up with the 31,000 new cases of multiple myeloma diagnosed annually1. It is for this reason J&J and Legend have taken a phased approach to Carvykti’s launch, gradually scaling up availability and the number of treatment centers based on constrained manufacturing capacity.
Shortages Cause Painful Triage Choices
Shortages of CAR-T therapies, particularly for patients with multiple myeloma, have required oncologists to make impossibly difficult decisions about which of their patients will receive the treatment. Hospitals may have up to 100 patients who could benefit from the therapy but are often only given one or two cell-manufacturing treatment slots a month. For example, MD Anderson Cancer Center estimates 20% of their patients die while waiting to start their CAR-T therapy2.
To choose which patients should get those limited slots, doctors weigh several factors, including how many other treatments have failed, how those treatments may have affected the patient’s T-cells and the patient’s current condition, balancing the patient’s disease progression where it is critical for them to get treatment with the patient’s ability to survive the treatment at that stage. Given the uncertain progress of the disease and that patients can rapidly deteriorate, it often feels like a guessing game.
Currently, there are two FDA approved CAR-T cancer therapies for multiple myeloma and an additional four for lymphoma and leukemia. These commercially available therapies have already moved to second line course of treatment after chemotherapy, exponentially increasing the number of patients that qualify for the treatment. That said, the global CAR-T pipeline is expansive. At present there are more than 750 active CAR-T therapies in development worldwide representing over a 50% increase from 2019. The majority of these are in early clinical development, predominantly Phase I, with oncology accounting for over 95% of the active CAR-T trials.
Factors Slowing Supply of CAR-T Therapies
There is a myriad of reasons for autologous CAR-T therapy shortages, beginning with the complex and time-consuming manufacturing process. Every CAR-T cell dose uses the individual’s own T-cells, in which a chimeric antigen receptor is expressed and infused back into the patient’s body to attack and kill the cancer cells that host the target antigen. The vein-to-vein time – the process of collecting the T-cells, genetically transforming them in the lab and treating the patient with CAR-T — currently can take as much as eight weeks, twice as long as it took in 2020.
Among the hurdles manufacturers face is the availability of good manufacturing practices (GMP) lentiviral vector capacity. There simply is not enough supply of these critical components used in the gene-modification of CAR-T therapies to meet burgeoning demand. Lack of qualified and trained staff with the skills required to produce these customized treatments combined with supply chain disruptions due to the COVID-19 pandemic are causing further challenges for manufacturers.
Additionally, since CAR-T therapies are made in batches of one, both the manufacturing steps and the capturing of data are critical to the safety of the product. While some facilities still conduct these processes manually, which are prone to error, manufacturing facilities such as CBM have moved to a new digitally enabled approach which uses closed and automated cell processing technology to reduce manufacturing costs by 70%. Additionally, the manufacturing engineering system (MES) enables parallel batch processing that decreases manual entry and review by 50-70%.
Another complication is the high batch-failure rate, particularly disastrous given the limited treatment slots available to these patients. Because CAR-T is not approved as a first, and in many cases even a second-line therapy, patients must endure multiple treatments before they are eligible for CAR-T therapy, including harsh chemotherapies that can impair the long-term functionality of their T-cells – increasing the odds of a batch-failure.
Leading the Charge to Increase Supply
The Center for Breakthrough Medicines (CBM) is moving quickly to increase CAR-T therapy supply, recently accelerating our plans to build additional capacity to support cell therapy manufacturing on our existing 200-acre campus. Once online, this new facility will enable, at minimum, an additional 50,000 batches of autologous drug products each year. In-process, release, and safety capabilities located across the hall from manufacturing reduces the typical seven-day sterility timeline down to a single day.
We are also making substantial investments in infrastructure and digital platforms to streamline operations and increase efficiencies, including forward engineering our GMP facilities to accommodate future technical advances in the science (and art) of cell therapy manufacturing. We are also installing world-class Manufacturing Execution and Quality systems to minimize manufacturing glitches while streamlining efficiency.
To protect against supply chain bottlenecks CBM, like many CDMO’s, has incorporated a multi-sourcing strategy, having built strong relationships among reliable suppliers for key equipment and reagents.
Finally, we are executing against a five-year strategic roadmap that will deliver CBM-exclusive platform processes to reduce vein-to-vein time as well as costs, benefiting both our patients and clients. These include game-changing advances such as “reduced harvest” manufacturing processes using lentiviral vectors that have been shown to decrease CAR-T engineering time to 24-48 hours, rather than the usual two-week timeframe, without negatively affecting T-cell potency.
By April 2023, when our first wave of our cell therapy suites are fully qualified, CBM will begin cGMP cell therapy manufacturing followed by another set of suites in the third quarter and the final set by year-end to complete our phase one expansion. This will make operational 28 new suites with the capacity to produce ~ 2,400+ autologous doses per year.
CAR-T therapies may be the only treatment that can extend the life, for months and even years, of multiple myeloma patients who have not responded to other treatments. Increasing the supply of this highly effective treatment is a top priority for CBM, so doctors don’t have to make heart-wrenching choices and patients don’t grow too sick to benefit from treatment.
1 American Cancer Association
2 ‘How do you decide?’: Cancer treatment’s CAR-T crisis has patients dying on a waitlist, Stat, June 2022