CAR-T: The Cancer Therapy That Saves Lives But Messes With The Mind

Cancer immunotherapies, such as CAR-T cell therapy, are very effective, but they can cause side effects in the brain, affecting memory and attention. Studies in animals and humans show that this may occur due to inflammation in the brain, activating cells called microglia. The good news is that scientists have already found ways to reverse these effects in the laboratory, which may help protect patients' minds in the future.

With advances in medicine, immunotherapy, a type of treatment that stimulates the immune system to fight cancer, has saved many lives. A notable example is so-called CAR-T cell therapy, which has been highly effective in treating some types of blood cancer and, more recently, has been tested for aggressive brain tumors in children.

However, despite the benefits, concerns are beginning to arise about the possible long-term side effects of this type of treatment, especially on the brain and cognitive function, our ability to think, remember, pay attention, and learn.

Many cancer survivors report persistent cognitive difficulties after treatment, such as problems with memory, attention, organization, and thinking speed.

This phenomenon, known as cancer therapy-related cognitive impairment (CRCI), was more common after chemotherapy and radiation therapy, but there is now evidence that immunotherapy may also cause similar, albeit more subtle, effects.

CAR T Cells Attack Cancer Cells

Respiratory infections like COVID-19 and the flu can cause problems with memory, attention, and mental clarity, something that closely resembles what some people experience after undergoing cancer treatments, a condition called "brain fog." These infections activate defense cells in the brain called microglia.

Microglia are a type of immune system cell that lives in the brain. When activated by cancer therapies or infections, microglia can enter a "reactive" state, affecting the proper functioning of neurons, the formation of new connections, and even the production of new brain cells.

In the case of CAR T cell therapy, studies have shown that even after acute treatment and tumor elimination, the brain can remain inflamed.

In experiments with mice, scientists observed that this inflammation involved the activation of microglia in the brain's white matter (areas rich in nerve connections), an increase in inflammatory molecules in the fluid that bathes the brain (cerebrospinal fluid), and a reduction in the production of myelin (the substance that insulates and protects neurons).

Furthermore, the formation of new nerve cells in the hippocampus, a region essential for memory, was also impaired.

These changes weren't limited to the biological level: the animals also had poorer cognitive performance on attention and memory tests. In humans, brain tissue analyses showed similar patterns of inflammatory activation after CAR T-cell therapy.

Sequencing studies of human frontal lobes from patients with and without prior CAR T-cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes after treatment. Oligodendrocytes are cells responsible for the speed of conduction and communication between neurons.

Interestingly, when researchers temporarily blocked microglial activity or interfered with certain inflammatory pathways (such as the CCR3 receptor), memory deficits and brain changes were reversed in the animals, after the oligodendroglial deficits were restored.

These findings are important because they show that, although immunotherapy is extremely effective against cancer, it can cause side effects in the brain that affect patients' long-term quality of life.

The good news is that we are now beginning to understand the mechanisms involved, which paves the way for the development of treatments that can prevent or reverse these cognitive problems without compromising the effectiveness of cancer therapy.

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Immunotherapy-related cognitive impairment after CAR T cell therapy in mice

Anna C. Geraghty, Lehi Acosta-Alvarez, Maria C. Rotiroti, Selena Dutton, Michael R. O’Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani,  Karen Malacon, Pamelyn J. Woo, Naiara Martinez-Velez, Theresa Pham, Noemi N. Reche-Ley, Gabriel Otubu, Enrique H. Castenada, Kamsi Nwangwu, Haojun Xu,  Sara B. Mulinyawe, Daniel B. Zamler,  Lijun Ni, Kevin Cross, Justin Rustenhoven, Jonathan Kipnis,  Shane A. Liddelow,  Crystal L. Mackall, Robbie G. Majzner, and Michelle Monje

Cell. Volume 188, Issue 12P3238-3258.E25June 12, 2025

DOI: 10.1016/j.cell.2025.03.041 

Abstract: 

Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.