How CAR T Cell Therapy Works and Why It Carries Unique Risks

CAR T cell therapy takes a patient's own T cells, engineers them in a laboratory to carry a synthetic receptor aimed at a marker on cancer cells such as CD19 or BCMA, and reinfuses them as what one investigator has called a living drug. The same feature that makes it powerful also makes it dangerous. The two signature complications, cytokine release syndrome and a neurologic syndrome now called ICANS, are not incidental side effects. They arise directly from the intense immune activation the treatment is built to unleash.

Engineering a T cell to see cancer

A chimeric antigen receptor, or CAR, is a laboratory-designed protein stitched together from parts that do not naturally occur in one molecule. According to the National Cancer Institute, the receptor spans the T cell membrane, with an external segment built from antibody fragments that latch onto a specific antigen on the tumor surface, and an internal segment that fires the T cell's killing and multiplication machinery once that antigen is bound.

The manufacturing sequence is involved. Clinicians collect a patient's T cells, ship them to a facility where a viral vector inserts the CAR gene, expand the modified cells into the hundreds of millions, and return them for infusion. The National Cancer Institute puts the full process at roughly three to five weeks. Because the receptor recognizes antigen directly, it bypasses the usual requirement for antigen presentation through the major histocompatibility complex, which is part of why the response can be so brisk.

Why CD19 and BCMA

Target choice is the heart of the design. A good CAR target is expressed densely on the cancer and sparingly on tissues the body cannot afford to lose. CD19 sits on the surface of most B cell cancers, which is why it anchors the therapies approved for B cell acute lymphoblastic leukemia and several non-Hodgkin lymphomas. BCMA, or B cell maturation antigen, marks plasma cells and is the target for multiple myeloma.

Six autologous CD19 or BCMA products have reached the United States market. The CD19 group includes tisagenlecleucel, the first approved in 2017 for young patients with acute lymphoblastic leukemia, along with axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel. The BCMA group comprises idecabtagene vicleucel, cleared in March 2021, and ciltacabtagene autoleucel, cleared in February 2022, both for relapsed or refractory multiple myeloma. The label for lisocabtagene maraleucel was extended in December 2025 to include relapsed or refractory marginal zone lymphoma. The trade-off with CD19 and BCMA is that healthy B cells and plasma cells carry the same markers, so the therapy predictably depletes them, leaving patients vulnerable to infection.

Where the risk comes from

The unique dangers of CAR T therapy are best understood as a mechanism running too hot. A 2021 review in the Journal of Experimental and Clinical Cancer Research laid out the chain of events in detail, and it repays close reading because it explains why the harms track so closely with efficacy.

Cytokine release syndrome

When CAR T cells engage tumor cells, they release perforin and granzymes that trigger an inflammatory form of cell death called pyroptosis. Dying cells spill damage signals, molecules such as HMGB1, ATP, and free DNA, into the surrounding tissue. These signals activate macrophages, which the review identifies as the central engine of the syndrome. Activated macrophages pour out inflammatory cytokines, including interleukin-1, interleukin-6, interferon-gamma, and GM-CSF.

Interleukin-6 takes the lead role. It activates the lining of blood vessels through JAK-STAT signaling, and those endothelial cells in turn produce more interleukin-6, creating a feed-forward loop. The clinical result ranges from fever and low blood pressure to organ dysfunction. This mechanism is why the interleukin-6 blocker tocilizumab, borrowed from rheumatology, became a mainstay of management, often paired with corticosteroids.

Neurotoxicity

The neurologic syndrome, immune effector cell-associated neurotoxicity syndrome, tends to follow the peak of cytokine release, which hints at a shared origin. The same review describes systemic cytokines activating the endothelial cells of the brain's vasculature, loosening the tight junctions that form the blood-brain barrier. Once that barrier is compromised, inflammatory cells and mediators reach the central nervous system, and downstream products such as glutamate and quinolinic acid can overstimulate neurons.

There is a target-specific detail here. The review points out that CD19 is expressed on pericytes, the support cells that brace the brain's small vessels, so CD19-directed cells can strike this tissue through an on-target, off-tumor effect. Clinically, ICANS shows up as confusion, difficulty with language, tremor, and in severe cases seizures. The National Cancer Institute lists corticosteroids as the usual treatment, with anakinra, an interleukin-1 blocker, described as an option when steroids do not control the syndrome.

A maturing safety picture

Regulators have watched this therapy long enough to recalibrate. In a safety communication dated June 26, 2025, the FDA eliminated the Risk Evaluation and Mitigation Strategies that had governed every approved CD19 and BCMA autologous product since their launches. The agency stated that adverse-event reporting for cytokine release syndrome and neurologic toxicity had remained stable, and that the risks could be conveyed adequately through current labeling given the hematology and oncology community's experience in recognizing and managing these events. The updated labeling instructs teams to monitor patients for at least two weeks, including daily monitoring for at least one week, to have patients stay within proximity of a healthcare facility for at least two weeks, and to advise patients to avoid driving for two weeks after infusion. The FDA framed the change as a way to reduce burden on the healthcare system while keeping safe administration intact.

None of this makes the risks disappear. It reflects that clinicians have learned to anticipate a set of complications that are, by design, welded to the mechanism. Understanding that link is the point: the intensity that clears refractory cancers is the same intensity that inflames the body, and both flow from the same engineered cell.

This article is educational and is not medical advice. Anyone considering or receiving CAR T cell therapy should discuss their specific situation with their own oncology team.