Cognitive Impairment After CAR T Cell Therapy

Many cancer survivors experience a problem known as cancer therapy-related Cognitive Impairment (CRCI). This condition makes it hard for them to remember things, pay attention, process information quickly, multitask, and use higher-level thinking skills. While this issue is often seen after traditional cancer treatments like chemotherapy, recent studies show that newer treatments, like immunotherapies, could also lead to these cognitive problems.

Some cancer treatments, including radiation therapy to the head and certain drugs like methotrexate, can cause changes in the brain's immune cells, specifically a type called microglia. When these microglia become reactive, they can disturb the balance of myelin, which is essential for proper brain function. This disruption might damage the brain’s ability to create new nerve cells, especially in an area important for memory called the hippocampus. Other conditions, such as respiratory infections, can also lead to similar cognitive problems by affecting microglial activity and disturbing brain functions.

Given that immunotherapy often uses Inflammation to fight cancer, researchers want to find out if it can also result in brain inflammation and cognitive issues.

#CAR T Cell Therapy

One significant advancement in treating some types of blood cancers is CAR T cell therapy. This treatment has been a game-changer for patients with hard-to-treat cancers, including certain leukemias. Recently, researchers found that CAR T cells targeting a protein called GD2 might be helpful for treating some aggressive childhood brain tumors. While CAR T therapy can effectively clear tumors, it may also cause immediate neurological problems known as immune effector cell-associated neurotoxicity (ICANS). However, the long-term effects of CAR T therapy on brain function are still not well understood.

To study the effects of CAR T cell therapy beyond the immediate impact on tumors, researchers tested its long-term effects on brain health and cognitive function using mouse models.

#Cognitive Impairment in Mice After CAR T Cell Therapy

In their research, scientists wanted to see if mice that received CAR T cell therapy showed any issues with memory or awareness. They used specific mouse models that had been engineered to develop different types of tumors, including a type of brain tumor (DIPG), a type of leukemia, and two types of bone tumors (osteosarcomas). These different models helped control for various factors like the location of the tumor and the type of CAR T cells used.

After the treatments, the researchers found that mice given effective CAR T cells showed signs of cognitive impairment in tests designed to measure attention and short-term memory. Conversely, mice receiving mock T cells or off-target CAR T cells generally performed well on these cognitive tests, indicating that the issues were linked to the tumor-clearing treatment rather than the cancer presence itself. Interestingly, in one model where the cancer was cleared rapidly, the mice did not show any cognitive problems, suggesting that the effectiveness of treatment might influence cognitive outcomes.

#Persistent Changes in Brain Chemistry

To investigate the underlying changes in the brain after CAR T cell therapy, researchers collected samples of cerebrospinal fluid (CSF) a month after the treatment. In several mouse models, they found higher levels of certain inflammatory chemicals known as cytokines in the CSF of mice treated with tumor-clearing CAR T cells. These elevated cytokines appeared to be linked to the cognitive deficits observed in these models. However, in the rapid-clearing osteosarcoma model, the scientists did not see these elevated markers, which pointed to a potential connection between how the cancer was treated and brain health.

#Microglial Changes After CAR T Cell Therapy

Microglia are immune cells in the brain that can become activated in response to various disturbances. In the study, researchers looked at microglial activity after CAR T cell therapy. They evaluated microglial numbers and their level of reactivity in different regions of the brain. After treatment, there were increased numbers of reactive microglia in certain brain areas associated with cognitive performance, particularly in the subcortical white matter and hippocampus.

However, in the rapid-clearing osteosarcoma model, the researchers did not see any increase in microglial presence or activity, suggesting that the immune response triggered by the cancer treatment significantly impacted brain health.

#Disruption of Oligodendrocytes and Myelin

The study also looked at oligodendrocytes, which are cells that help produce myelin, the protective covering for nerve fibers. Researchers found that following CAR T cell treatment, there was a noticeable decrease in both oligodendrocyte precursor cells and mature oligodendrocytes in certain brain areas. This decline in healthy oligodendrocytes could lead to issues with myelin integrity.

In the rapid-clearing osteosarcoma model, the researchers did not observe any changes in oligodendrocyte populations, once again indicating that a successful and thorough tumor clearance via CAR T therapy may not disrupt brain health in the same way as treatments that trigger stronger immune responses.

#Impaired Neurogenesis in the Hippocampus

Neurogenesis refers to the process of forming new nerve cells, which is crucial for memory and learning. The study revealed that after CAR T treatment, the production of new nerve cells in the hippocampus was significantly lower in certain mouse models. This decrease in neurogenesis was linked to elevated levels of inflammatory markers and reactivity of microglia.

However, in the rapid-clearing model, the level of neurogenesis remained stable, suggesting that successful tumor clearance might help protect against cognitive decline.

#Effects of Anti-Cytokine Treatment

Given that some patients experience neurological issues after CAR T cell therapy, researchers tested the potential of a drug called Anakinra, which blocks certain inflammatory signals. They hoped that this treatment would help reduce the cognitive deficits observed in the mouse models after CAR T therapy. However, the results showed that Anakinra did not have any effect on the cognitive or cellular problems following CAR T treatment, indicating that simply blocking one inflammatory signal might not be enough to resolve the broader issues.

#Microglial Depletion and Cognitive Recovery

To better understand the role of microglia in cognitive impairment, scientists tested a different approach that involved depleting these cells using a drug called CSF1R inhibitor. This treatment significantly reduced the number of microglia in certain brain regions, leading to improved cellular health in terms of oligodendrocyte populations and cognitive performance in memory tests.

The results suggested that reactive microglia were central to the cognitive issues faced by the mice after CAR T cell therapy. With the reduction of these immune cells, both the brain health and cognitive function improved, showcasing the potential for targeted therapies to support brain health in patients receiving CAR T cell treatment.

#Conclusion

The research highlights significant concerns regarding cognitive health in cancer survivors, particularly those treated with CAR T cell therapy. The study shows a clear connection between inflammation in the brain and cognitive impairment. While CAR T therapy has transformed cancer treatment, it is crucial to consider the potential long-term effects on brain function and overall quality of life for survivors.

As we continue to explore these connections, it becomes increasingly clear that the immune response, along with the interactions between different cell types in the brain, plays a pivotal role in cognitive outcomes following cancer treatment. Understanding these mechanisms will be essential in developing supportive therapies that can help mitigate cognitive decline in cancer survivors, ultimately enhancing their quality of life.