Exploring the Use of CAR-T Therapy Beyond Oncology

March 2020 - Vol. 9 No. 3 - Page #12
Q&A with Suzanne Thibodeaux, MD, PhD
Assistant Professor
Department of Pathology and Immunology
Washington University School of Medicine
St. Louis, Missouri
Medical Lab Management: Can you provide a brief update on the functions and current clinical applications of CAR-T cell therapy?

Suzanne Thibodeaux: It is a very exciting time in the world of chimeric antigen receptor (CAR)-T cells, as they have shown immense promise as an anti-cancer immune therapy. These cells—T cells that have been genetically modified to express a protein containing the target recognition specificity of a B cell antibody and the killing function of a cytotoxic T cell—can be utilized as a dynamic living drug that can not only attack cells in a targeted manner, but also proliferate and maintain a presence in the patient’s blood after treatment. In order to function in this capacity, CAR-T cells need to recognize targets that are as specific as possible to the targeted cell, and the target antigen needs to be “visible” to the CAR-T cell.

CAR-T cells represent a unique class of therapeutics by the manner in which they are manufactured; a patient’s own T cells are harvested, genetically modified by insertion of the CAR, grown outside of the body, and then infused back into the patient. Currently, two CAR-T cell therapies have been approved for clinical use by the US FDA: Tisagenlecleucel and axicabtagene ciloleucel. Both of these drugs target the B-cell antigen CD19 and are used to treat B-cell malignancies. Tisagenlecleucel has been approved for relapsed or refractory-B acute lymphoblastic leukemia in pediatric and adult patients and relapsed or refractory large B-cell lymphoma in adults. Axicabtagene ciloleucel has been approved for adult patients with relapsed or refractory large B-cell lymphoma.

Several other CAR-T cell-based therapies targeting additional molecules are progressing through the clinical development pipeline, so it is becoming increasingly important to be familiar with CAR-T cells and their potential impact on clinical laboratory medicine.

MLM: What efforts are being made to expand CAR-T applications beyond cancer care?

Thibodeaux: There are a multitude of efforts seeking to expand applications of CAR-T cells beyond the field of oncology and cancer therapeutics, including numerous diseases that are impacted by dysfunctional cells and have the potential to be targeted for destruction by a CAR-T cell. Manipulation and optimization of T-cell function likewise holds the potential to target dysfunctional nonmalignant cells, such as specific immune cells contributing to autoimmunity and/or transplant rejection, as well as for infectious diseases.

MLM: What are the specific impacts of CAR-T on infectious diseases?

Thibodeaux: The impact of CAR-T cell therapy on various infectious disease could be substantial and it will be very interesting to see how they develop. The potential applicability to other diseases essentially operates under the same principles used for cancer: The antigen should be as specific to the target as possible, “visible” to the CAR-T cell and, ideally, not be expressed on non-targeted cells (or expressed in a predictable way that minimizes risk to the patient).

One example of an infectious disease being targeted by CAR-T cell therapies currently in clinical trials is HIV. There are two clinical trials actively recruiting patients for participation involving CAR-T therapy of HIV and these will be closely watched to see if the results can help chart the progress of developing new therapies against HIV.1,2 Other infections, such as hepatitis and aspergillus, also are theoretically targetable by CAR-T cell therapies and preclinical studies have been published on the potential for treatment of these diseases.3

MLM: Describe the role of the clinical laboratory in CAR-T cell therapy applications.

Thibodeaux: As the potential (and realized) applications of CAR-T cell therapies continue to expand, it becomes increasingly important for those in the clinical laboratory to be familiar with the affected patient population(s). Various clinical labs might see patient samples at any point in the CAR-T cell treatment process and many circumstances would not necessarily dictate differentiation of these patients’ samples or specimens from any others. However, some circumstances could benefit from additional context of CAR-T cell therapy. For example, a peripheral blood smear review of a patient who recently received CAR-T cells could contain both malignant cells and nonmalignant but activated CAR-T cells, and this is useful information to those interpreting the results.

MLM: What laboratory workflows should be developed to enable CAR-T therapy?

Thibodeaux: The production of CAR-T cell therapies now involves a few different manufacturers developing in parallel, so some processes are individualized to each CAR-T cell, while others might be applicable to many. Consider that the two FDA-approved CAR-T cell products previously mentioned target the same antigen (CD19), so it follows that monitoring for treatment effects are similar.

However, identifying an individual CAR-T cell could prove difficult since the CARs are distinct. Further, CAR-T cells directed toward different antigens could result in a different treatment plan (and adverse effect profile). For example, a CAR-T cell directed toward mesothelin, a protein expressed on some solid tumors, could be monitored differently than for CAR-T cells directed against CD19.

Collaborative workflows, including coordination between the patient teams, apheresis services (harvesting cells for manufacturing), and the cellular therapy laboratory that prepares the cells for shipment and transport, are quite useful in fostering successful CAR-T cell therapeutic programs. Many institutions offer multiple CAR-T cell therapies as FDA-approved treatments and/or as part of clinical trials, either developed internally or by third party manufacturers. Approaching the complex framework in which CAR-T cell therapy occurs, from patient screening to follow-up after administration, could help ensure a strong foundation on which to build in the future that incorporates all parties whose services contribute to a successful CAR-T cell treatment.

MLM: What are the forthcoming regulatory issues, FDA input, or manufacturing standards affecting the process of implementing CAR-T therapy?

Thibodeaux: The process by which CAR-T cells are vetted and deemed suitable for clinical use can vary based on the geographical region in which they are developed, due in part to regulatory oversight. In the United States, the FDA provides regulatory oversight for novel therapeutics, including CAR-T cells. In this context, a few of the unique characteristics of CAR-T cell products can be considered from the regulatory perspective.

One major distinction between CAR-T cell therapy and other therapeutics is the fact that these cells have been genetically modified with foreign DNA (the genetic material carrying the information for the CAR) that was not present in the cells before the manufacturing process. Furthermore, the system used to deliver the genetic material can vary and could potentially use viral vectors. For instance, of the two FDA approved CAR-T cell therapies, one uses a lentiviral vector and the other uses an adenoviral vector to deliver the genetic material. As the technologies that are used to develop CAR-T cells continue to advance, so will the regulatory framework.

Keep in mind that CAR-T cell therapies are living drugs that continue to proliferate and function after being administered to the patient, and could continue to target and attack cells over time. Detection of CAR-T cells long after infusion has been reported and patient studies continue in order to further ascertain the safety of these cells over long periods of time. These are the kinds of issues facing clinicians, regulatory agencies, and manufacturers.

Another unique attribute of CAR-T cells that is of great importance in preclinical and clinical development is their potential to exert on-target/off-tumor effects. The CAR-T cell is directed to attack cells that express a specific antigen, no matter what cell type it is. An example of an on-target/off-tumor effect is B cell aplasia in patients who receive CAR-T cells directed against CD19. Since CD19 is expressed on normal and many malignant B cells, CAR-T cells attack them regardless of their malignant or non-malignant status. However, this side effect was anticipated during clinical development and accounted for by already available medical management strategies. As a result, on-target/off-tumor effects, both expected and unexpected, must be accounted for during clinical development to ensure the safest CAR-T cell product is developed and optimized for clinical use.

Regulatory oversight will continue to be a factor that helps shape the future of CAR-T cell product availability and the way in which these products are manufactured and delivered to patients. Regulatory oversight also will evolve as CAR-T cell products expand in their clinical applications and new technologies are developed.

MLM: What are the cost-related challenges tied to CAR-T cell therapy?

Thibodeaux: Currently, the cost of a CAR-T cell product is substantial, with a per-treatment list price greater than $350,000 for each of the two FDA-approved CAR-T cell therapies. However, cost analyses continue to be undertaken to determine whether CAR-T cell products are cost effective. One consideration is that, given the dynamic nature of the drug, CAR-T cell therapies are potentially a one-time treatment if successful.

Another consideration is the current manufacturing paradigm for CAR-T cell products; since each CAR-T cell is specific to the patient/disease being treated, each CAR-T cell product must undergo an individualized manufacturing process at a centralized manufacturing site. Therefore, the future of CAR-T cell harvesting could have a substantial impact on the eventual cost of this therapy. If, for example, “universal” CAR-T cells (cells that can be safely made from a healthy donor and then be expanded for provision to multiple patients) can be developed, these advances could drive down the cost of manufacturing. Regardless, this is an exciting therapeutic breakthrough and with many such breakthroughs, a combination of further research, wider adoption and application, and lower cost will set the stage for a powerful agent against cancer, and other challenging disease states.


  1. Guangshou 8th People’s Hospital. The Effect of Chimeric Antigen Receptor (CAR)-T Cell Therapy on the Reconstitution of HIV-specific Immune Function. ClinicalTrials.gov Identifier: NCT03240328 Accessed: 3.1.20. https://clinicaltrials.gov/ct2/show/NCT03240328?term=chimeric+antigen+receptor+T+cells&cond=HIV&draw=2&rank=1
  2. University of Pennsylvania. CD4 CAR+ ZFN-modified T Cells in HIV Therapy. ClinicalTrials.gov Identifier: NCT03617198. Accessed 3.1.20. https://clinicaltrials.gov/ct2/show/NCT03617198?term=chimeric+antigen+receptor+T+cells&cond=HIV&draw=2&rank=2
  3. Seif M, Einsele H, Loffler J. CAR T Cells Beyond Cancer: Hope for Immunomodulatory Therapy of Infectious Diseases. Front Immunol. 2019;10:2711. doi: 10.3389/fimmu.2019.02711.

Suzanne Thibodeaux, MD, PhD, serves as medical director of the cellular therapy laboratory and assistant medical director of transfusion services at Barnes-Jewish Hospital, and as laboratory medical director at Barnes-Jewish West County Hospital in greater St. Louis, Missouri. Her clinical and research interests focus on improving cellular therapies from the clinical laboratory perspective, apheresis and transfusion medicine as it relates to cellular therapy, and medical education. Suzanne earned her advanced degrees at the University of Texas Health San Antonio, after which she completed a residency in clinical pathology and a fellowship in blood banking and transfusion medicine at The Hospital of the University of Pennsylvania. She then joined the faculty in the Department of Pathology and Immunology at Washington University School of Medicine in St. Louis.


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