CAR-T Memory Cells May Enhance the Efficacy of Cancer Therapy

Although chimeric antigen receptor (CAR) T cells can effectively fight B-lineage malignancies, disease relapse is common in patients after CAR, and the therapeutic efficacy for other tumors is very limited. These challenges may be solved by controlling the function of CAR-T cells through reasonable manipulation.

Recently, in a research report entitled "Antigen experience history directs distinct functional states of CD8+ CAR T cells during the antileukemia response" published in the international journal Nature Immunology, scientists from the University of Colorado Anschutz Medical Campus and other institutions found through research that some CAR-T cells used to fight cancer and other diseases may carry memories of past encounters with bacteria, viruses and other antigens. This research finding may prompt scientists to make cells in a more precise and targeted way.

In the article, the researchers focused on CAR-T cells, which are an effective therapy to fight cancer, especially leukemia and lymphoma. As a type of immune cell, T cells can be removed from the patient's blood, then modified to target cancer and reinfused back into the patient. Now, researchers have found that some of these cells have long-lasting memory. They found that even after extensive engineering to insert the CAR into the cell, CAR-T cells that had been exposed to an antigen in the past behaved differently than cells that had never been exposed.

"Unlike most drugs, the product of CAR-T cells is not uniform. We knew there would be variation, but the nature of that variation may only be beginning to be understood. What is surprising is that past interactions with antigens may leave a lasting imprint on the cell," said Terry Fry, MD, PhD.

The researchers found that "memory cells" that had previous antigen experience may kill cancer cells quickly but also become exhausted quickly and reproduce more slowly, which may open the door to potential relapse. At the same time, the researchers found some favorable disease resistance capabilities, such as the powerful expansion and tolerance to exhaustion of innate cells, which also have no antigen experience. By directly comparing the two cell types, the researchers were able to identify specific gene targets that regulate and improve the cells' function. They found that innate cells can be specifically enhanced by targeting genes such as RUNX2, and these cells also live longer and reproduce faster than memory cells.

Figure 1. Antigen experience history directs multiple aspects of in vitro function of mouse CAR8 T cells. (DeGolier K R, et al., 2025)

These epigenetic differences may be used to identify specific genes that can be manipulated to modify their function. The study was first conducted in mouse models and then in human cells. T cells were derived from vaccinated and unvaccinated subjects. Cells from the vaccinated model were altered after encountering the vaccine antigen in the lymph nodes, and subsequently responded quickly to leukemia cells because they had a memory of previous exposure to the antigen. However, they were also exhausted more quickly than innate cells. Although innate T cells lack the disease-fighting imprint of memory cells, they became more effective and lived longer when RUNX2 was added. The gene protected them from exhaustion and enabled them to continue fighting cancer.

This balance is determined by the cell's previous history, and adding RUNX2 to innate cells made them more effective at killing cancer. The study also generated a large dataset of other proteins that the researchers were able to explore in depth along with RUNX2. This research finding may promote scientists to more precisely engineer CAR-T cells and enable them to attack cancer more effectively, while potentially reducing some of the side effects of therapy, including strong inflammatory responses. Understanding this difference may help guide scientists to develop new methods to manipulate specific cell properties, and the effect of RUNX2 in limiting exhaustion programs may also be further explored. Especially in the context of solid tumors, exhaustion plays a major role in limiting anti-tumor T cell responses. In summary, the results of this study indicate that the previous antigen experience of CAR-T cells may determine the functional enhancement and susceptibility mediated by transcription factors.