What Are CAR-T Cells and What Is the American Red Cross Doing About Them?

T-cells play a pivotal role in the immune system’s response to cancer. Unlike B-cells which make antibodies, T-cells act directly in a cell-to-cell fashion. CAR-T stands for chimeric antigen receptor T-cells. The word “chimeric” means having parts from two or more origins. To accomplish this, T-cells are collected from the blood of a patient or donor and genetically modified to bear on their surfaces a receptor protein that binds to a target protein on cancer cells, whose heterogeneous structure greatly enhances targeting and destruction of those cells.

What has revolutionized CAR-T therapy is the precision of these modifications, allowing safe and highly potent tumor-killing capability, coupled with the ability to achieve this in a scalable and efficient manner. In the past, insertion of genes containing useful constructs lacked specificity. Random insertion resulted in side effects and decreased efficacy. Techniques using zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs) allowed more precision, but engineering of proteins for gene editing was costly and inefficient. Clustered regularly interspaced short palindromic repeats (CRISPR) technology, with more efficient RNA-guided gene editing, provided the necessary breakthrough.

CAR-T cell therapies also exploit the ability to target proteins present in abundance on cancer cells that are cell- or tissue- rather than tumor-specific but sufficiently sparing of normal cells and tissues that toxicities are tolerated. For example, CD19 CAR-T cells target the CD19 protein, found on all B-cells but only negligibly on other cells. Thus, hematologic neoplasms of B-cell origin, such as B-cell leukemias or lymphomas, can be targeted. CD19 CAR-T cells will also destroy normal B-cells bearing the antigen, but this is not life-threatening and is ultimately reversible.

When used in the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and certain lymphomas, the strategy has spectacularly led to complete responses in 80% of patients treated.¹

Further investigation has focused on increasing efficacy while reducing side effects and expanding the repertoire of diseases CAR-T cells can effectively treat to include other hematologic malignancies such as multiple myeloma, until recently thought incurable, and solid cancers. Given the challenges of an often insulated and immunosuppressive microenvironment, investigators have looked to bivalent CAR-T cells for greater potency in these neoplasms. Such cells might, for example, contain two chimeric antigen receptors (CARs) specific for relevant tissue antigens,^2,3 or a CAR specific for a relevant tissue antigen and a CD19 CAR to stimulate in vivo expansion of tumor-targeting T-cells.^4,5.

Thus far, CAR-T cell treatment has relied on autologous (patient-derived) sources for cells which has the advantage of avoiding immune system barriers that might result in graft-versus-host (GVH) side effects from, and host destruction of, allogeneic (donor-derived) CAR-T cells. On the other hand, autologous strategies suffer from certain limitations such as cost and complexity, including the need to rapidly manufacture CAR-T cells in a personalized fashion from each patient, limited by the patient’s condition and availability. The ability to utilize donor CAR-T cells or to offer a “universal” off-the-shelf CAR-T cell drug which avoids GVH effects would overcome these obstacles.

The high success enjoyed thus far by available CAR-T cell drugs, and the extraordinary potential of future applications, has resulted in an explosion of interest among academic institutions and in the pharmaceutical industry, with hundreds of clinical trials worldwide. On the other hand, given the complex and emerging nature of these therapies, large medical centers have thus far served as the primary conduit of CAR-T cell therapies to eligible patients, sometimes limiting access because of the distance of such centers from those patients.  However, refinements allowing less severe and less frequent complications, lower costs and operational burden, and less rigorous requirements have begun to allow treatment at other institutions.

The American Red Cross currently uses its extensive apheresis network throughout the United States to assist participating hospitals and biopharmaceutical companies by collecting from patients the T-cells used to make CAR-T cells. The Red Cross hopes that its expertise in blood cell collection and processing and national reach will help catalyze the effort to expand access to more hospitals and patients. In addition, the American Red Cross collects white blood cells from donors (“leukopaks”) vital to research in the field and makes them available to investigators across the country.

References

1. Svoboda J, Landsburg DJ, Gerson J, Nasta SD, Barta SK, Chong EA, Cook M, Frey NV, Shea J, Cervini A, Marshall A, Four M, Davis MM, Jadlowsky JK, Chew A, Pequignot E, Gonzalez V, Noll JH, Paruzzo L, Rojas-Levine J, Plesa G, Scholler J, Siegel DL, Levine BL, Porter DL, Ghassemi S, Ruella M, Rech A, Leskowitz RM, Fraietta JA, Hwang WT, Hexner E, Schuster SJ, June CH. Enhanced CAR T-cell therapy for lymphoma after previous failure. N Engl J Med 2025 May;392(18):1824-1835. https://doi.org/10.1056/NEJMoa2408771
2. Globerson Levin A, Rivière I, Eshhar Z, Sadelain M. CAR T cells: Building on the CD19 paradigm. Eur J Immunol 2021;51(9):2151-2163. https://doi.org/10.1002/eji.202049064
3. De Olivera Canedo G, Roddie C, Amrolia PJ. Dual targeting CAR T cells for B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma. Blood Advances 2025 Feb 9(4):704-721. https://doi.org/10.1182/bloodadvances.2024013586
4. Chen N, Pu C, Zhao L, Li W, Wang C, Zhu R, Liang T, Niu C, Huang X, Tang H, Wang Y, Yang H, Jia B, Jiang X, Han G, Wang W, Chen D, Wang Y, Rowinsky EK, Kennedy E, Lu VX, Cui G, Wu Z, Xiao L, Cui J. Chimeric antigen receptor T cells targeting CD19 and GCC in metastatic colorectal cancer: A nonrandomized clinical trial. JAMA Oncol 2024;10(11):1532–1536. https://doi.org/10.1001/jamaoncol.2024.3891
5. Bagley, S.J., Logun, M., Fraietta, J.A. et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nat Med 30, 1320–1329 (2024). https://doi.org/10.1038/s41591-024-02893-z.