Department of Pathology and Immunology
Washington University School of Medicine
For our initial discussion of CAR T-cell therapies from the clinical laboratory perspective, see the March 2020 issue of MedicalLab Management.
Q: In early 2020, we discussed the use of CAR T-cell therapy beyond oncology applications. Where does your facility stand now in terms of this technology?
Thibodeaux: In 2022, all approved CAR T-cells are for use with hematologic malignancies. That said, there are numerous clinical trials currently exploring the application of cellular therapy to non-hematologic and non-oncologic indications. Our cellular therapy laboratory is involved in dozens of clinical trials using a variety of other types of cell therapy products for many diseases with an upward trajectory. Examples of target indications include solid tumors, sickle cell disease, stroke, and viral infections, to name a few.
Q: At that time of our initial Q&A, there were two CAR T-cell therapies approved for clinical use by US FDA— Tisagenlecleucel and A. ciloleucel—how has that number changed?
Thibodeaux: There are currently 6 CAR T-cell therapies approved by the FDA for clinical use, so the number of these products obtaining FDA approval has tripled. Furthermore, the number of additional prospects under clinical development has grown exponentially. As of May 23, 2022, a search for “chimeric antigen receptor T-cells” at clinicaltrials.gov yields 1107 clinical studies. Undoubtedly, this number will continue to grow as will the number of approved therapies and the number of affected diseases.
Q: Has progress been made in applying CAR T-cell therapy to transplant rejection and/or infectious disease (eg, HIV) management?
Thibodeaux: CAR T-cell therapy applications to transplant rejection and infectious disease remains largely in the research realm, but progress is being made every day and clinical laboratory stakeholders are quite excited to monitor these developments.
Q: Have there been further developments in using CAR T-cells for treating other infections such as hepatitis and aspergillus?
Thibodeaux: Along with CAR T-cells under clinical development, other types of cellular therapy are being studied and developed to help combat infections, including viral-specific cytotoxic T lymphocytes. The T-cells from a donor who has had this type of infection can then be utilized to fight that infection and pathogen in another patient. Those T-cells can be harvested and encouraged to expand outside of the body with cytokines and antigen exposure, and then administered to a recipient with the same kind of infection. The expectation is that the donor T-cells will fight the infection when the recipient’s own immune system is not strong enough to do so on its own.
Q: How have state and federal regulations evolved in the last two years governing the development and use of CAR T-cell therapies?
Thibodeaux: In March 2022, the FDA released 2 guidance documents regarding cell and gene therapy: one that provides guidance on applying for an investigational new drug (IND) application for human gene therapies,1 and one that specifically provides guidance for development of CAR T-cell therapies.2 These guidance documents can help anyone involved in the development and application of these novel therapies to optimize the potential for success in a way that is aligned with FDA regulations.
Q: How has the technology used to harvest, manipulate, and administer CAR T-cell therapies changed in recent years and what is the future trajectory?
Thibodeaux: CAR T-cell production has largely followed a central manufacturing model, where the initial material is collected from a patient and transported to a manufacturing facility. The therapeutic product is produced and then transported back to the patient location for infusion. The entire process can take a few weeks.
The initial material used to create CAR T-cell products is almost exclusively collected by a process called apheresis, where blood is continually separated into components based on density by centrifugation so that the target cells can be removed, and the remaining blood be reinfused into the patient. Since CAR T-cells are mostly autologous, the donor is the patient with disease who will receive the cells after manufacturing. Thus, exploring methods to optimize the harvesting of initial material could help ensure the success of CAR T-cell manufacturing.
Introduction of genetic material into the target cells is an area of heavy recent research. Currently, the CAR T-cells with FDA approval use a viral vector to insert the genetic material into cells. However, other options include RNA electroporation, which is a method to temporarily introduce genetic material into target cells. Another method of genetic material delivery involves CRISPR technology, which is promising and is primed to for interesting developments in the near future.
It is worth noting that CAR T-cells can undergo on-site manufacturing if a given facility has the capability and regulatory clearance to do so for a given product. There are devices that can manufacture a CAR T-cell product, such as next generation automated cell processors, but those are limited to a single product at a time.
Q: Have there been further developments in understanding on-target/off-tumor effects?
Thibodeaux: Since on-target/off-tumor effects are specific to each individual CAR T-cell therapy, it is important to characterize any on-target-off/tumor effects of new CAR T-cell therapies as they are developed for clinical use, and find ways to manage them medically, if possible.
Perhaps the most well-known and characterized on-target/off-tumor effect of CAR T-cells targeting CD19 for B cell malignancies is B cell aplasia, where normal B cells, which also express CD19, are bystander casualties of appropriate CAR T-cell function. Patients with dysfunctional B cells can be managed with medical support (eg, intravenous immunoglobulins) demonstrating that some on-target/off-tumor effects may be an acceptable tradeoff for life-saving therapy.3
Q: How has the cost burden of adopting CAR T-cell therapy been affected since being introduced?
Thibodeaux: CAR T-cell therapies remain expensive, but one could also say that cost could be offset by the cost of care for the disease if treated by other means. Regardless, the process of manufacturing CAR T-cells has remained largely manual—one that requires substantial resources to scale up—so it will be interesting to see what engineering developments will help streamline the process.
Q: Have there been developments in producing “universal” CAR T-cells?
Thibodeaux: Yes, and there are several of these developments currently in clinical trials. Universal CAR T-cells have the potential to be significantly meaningful as these would allow for the donor to be someone other than the patient. Expanding the potential donor pool to otherwise healthy individuals could allow for opportunities at several stages in the CAR T-cell manufacturing process. For one, the chances of collection success would likely increase because donors could be chosen who have not been exposed to medications that could affect T-cell function or quality, such as chemotherapies.
One of the major reasons that CAR T-cell manufacturing is currently defined as one product manufactured by one person or device at a given time is owed to the critical importance of ensuring chain of identity such that the correct donor receives the intended product. The concept of universal CAR T-cells would reduce that concern because they would not have the cellular expression unique to a T cell, so they could be manufactured en masse and infused into anyone who needs CAR T-cells against the target, should the recipient meet the criteria for treatment. If successfully applied clinically, universal CAR T-cells could greatly influence the availability of this treatment as a therapeutic option.
Q: What case can be made for non-cancer-center institutions to implement CAR T-cell therapy?
Thibodeaux: As of now, centers must be certified to implement CAR T-cell therapy, and this is required to ensure that the cell therapy products can be infused under appropriate conditions and with appropriate supervision to monitor for development of potential adverse events. Since optimizing patient safety is of paramount importance, development of clear processes to allow for centers to identify whether they have or can obtain the appropriate resources to manage patients receiving CAR T-cell therapy will be essential in expanding availability to other health care centers.
Suzanne Thibodeaux, MD, PhD, serves as medical director of the cellular therapy lab and assistant medical director of transfusion services at Barnes-Jewish Hospital, and as lab medical director at Barnes-Jewish West County Hospital in St. Louis, Missouri.