Scientists Discover How T Cell Memory Influences CAR-T Cell Effectiveness

Researchers at the University of Colorado Anschutz Medical Campus have made a significant discovery that could improve the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy, a promising immunotherapy for various cancers. This breakthrough focuses on the phenomenon of “memory” within CAR-T cells, showing that some of these cells carry the memory of previous encounters with pathogens such as bacteria, viruses, and other antigens. This finding could allow scientists to develop more targeted and precise CAR-T cell therapies, potentially enhancing the treatment’s effectiveness and reducing side effects.

CAR-T therapy involves modifying a patient’s T cells—key immune cells that fight infections and cancer—so that they can specifically target and attack cancer cells. The process begins with extracting T cells from the patient’s blood, then engineering them in the laboratory to express a chimeric antigen receptor (CAR), which enables the cells to recognize cancer cells. These modified T cells are then infused back into the patient, where they can seek out and destroy cancer cells. CAR-T therapies have shown remarkable success, particularly in treating leukemia and lymphoma, and have been used to treat patients who have not responded to other treatments.

While CAR-T therapy has been groundbreaking, scientists have long known that there is variability in the effectiveness of CAR-T cells between patients. However, the reasons behind this variability have remained poorly understood. This study, published in Nature Immunology, sheds light on a crucial factor: the memory of past antigen encounters within the CAR-T cells themselves. The research revealed that, even after undergoing extensive manufacturing processes to insert the CAR into the T cells, some of these engineered cells carried “memory” of prior interactions with antigens.

This memory appears to be imprinted onto the cells in such a way that those with prior antigen exposure behave differently from those that have never encountered an antigen. These “memory cells” are able to kill cancer cells more rapidly, but they become exhausted more quickly and reproduce more slowly. This could open the door to potential cancer relapse, as exhausted T cells may be less effective at sustaining a prolonged anti-cancer response.

In contrast, the study also uncovered the advantages of “naïve” cells, which have never encountered an antigen. While naïve T cells lacked the disease-fighting imprinting of memory cells, they exhibited more favorable disease-fighting capabilities. The researchers found that naïve cells were more robust in their expansion and were less prone to exhaustion compared to memory cells. These findings were particularly notable as they suggested that naïve cells could be manipulated to perform better in the context of cancer treatment.

The research team, led by Terry Fry, MD, professor of pediatrics, oncology, and hematology at the University of Colorado School of Medicine, and Kole DeGolier, Ph.D., an immunology researcher, identified specific gene targets that could be used to modulate the behavior of both memory and naïve CAR-T cells to enhance their function. One of the most promising gene targets identified was RUNX2, a gene that appears to play a crucial role in boosting the performance of naïve T cells. When RUNX2 was introduced into naïve cells, they not only lived longer but also reproduced more quickly, making them more effective at fighting cancer. These results suggested that manipulating RUNX2 could provide a way to optimize CAR-T cell function, making them more durable and less susceptible to exhaustion.

To verify their findings, the researchers conducted experiments first using mouse models and then with human T cells. They found that T cells from vaccinated individuals—those who had been previously exposed to antigens—changed after encountering the vaccine antigens in the lymph nodes. These cells exhibited the characteristic “memory” response, quickly and effectively targeting leukemia cells. However, they also experienced faster exhaustion compared to naïve T cells, highlighting the trade-off between rapid effectiveness and long-term durability.

The study also showed that by manipulating the RUNX2 gene in naïve T cells, they could overcome some of the limitations associated with memory cells. The modified naïve T cells showed better cancer-killing abilities, with a longer lifespan and increased resistance to exhaustion. These findings suggest that enhancing the function of naïve cells through genetic manipulation could result in more effective CAR-T therapies, potentially offering a solution to one of the major challenges of cancer immunotherapy.

The discovery of these epigenetic differences between memory and naïve CAR-T cells opens up new avenues for research into how to optimize the use of CAR-T therapies. By targeting specific genes like RUNX2, scientists may be able to develop methods to modify CAR-T cells in ways that improve their anti-cancer capabilities while minimizing side effects such as the severe inflammatory responses that are sometimes triggered by the therapy.

The potential applications of these findings are significant. In particular, researchers believe that manipulating CAR-T cells to enhance the longevity and effectiveness of naïve cells could lead to more durable and long-lasting responses in patients. This could be especially beneficial for patients with solid tumors, where T cell exhaustion has been a major barrier to effective treatment. Exhaustion is a state where T cells become less effective over time, rendering them unable to mount a sustained attack against the tumor. The research suggests that by manipulating certain genes, including RUNX2, it may be possible to prevent or delay exhaustion, thereby enhancing the ability of CAR-T cells to fight solid tumors.

Additionally, this study could help address the variability in CAR-T cell therapy outcomes. By better understanding how the prior history of a T cell influences its performance, researchers can begin to develop more personalized therapies. For example, scientists could engineer CAR-T cells with specific modifications to suit individual patient needs, improving the likelihood of a successful response.

The study also underscores the importance of further exploration into the role of epigenetics—the chemical changes that regulate gene expression—in shaping the behavior of CAR-T cells. The findings suggest that epigenetic modifications could be leveraged to create CAR-T therapies that are more finely tuned and optimized for specific patient populations and cancer types.

The implications of this research extend beyond the realm of CAR-T therapy. It may also pave the way for broader applications in immunotherapy, where understanding the cellular history and memory of immune cells could lead to more effective treatments for a range of diseases, including autoimmune disorders, infections, and potentially even aging-related conditions. By harnessing the memory and adaptability of immune cells, scientists could develop therapies that are not only more effective but also safer, with fewer side effects.

The study also opens up exciting possibilities for combining CAR-T therapy with other immunotherapeutic strategies. For instance, combining the targeted manipulation of genes like RUNX2 with checkpoint inhibitors or other immune-boosting treatments could create powerful combination therapies that enhance the immune system’s ability to recognize and destroy cancer cells. This approach could help overcome some of the limitations of current cancer treatments, particularly in solid tumors, where the immune system often struggles to maintain a prolonged and effective attack on the tumor.

Reference: Kole R. DeGolier et al, Antigen experience history directs distinct functional states of CD8+ CAR T cells during the antileukemia response, Nature Immunology (2025). DOI: 10.1038/s41590-024-02034-1