Photo credit: www.sciencedaily.com
Researchers at the University of Colorado Anschutz Medical Campus have made a significant advancement in CAR-T cell therapy, uncovering that certain CAR-T cells engineered for combating cancer carry with them memories of previous encounters with pathogens. This discovery could lead to more precise and targeted approaches in the manufacture of these cells.
The findings, published in the journal Nature Immunology, center on chimeric antigen receptor (CAR)-T cells, which have shown considerable effectiveness in treating various cancers, particularly leukemia and lymphoma. The therapy involves extracting T cells from a patient’s blood, modifying them to target cancer, and reintroducing them into the patient.
In their study, researchers noted that some CAR-T cells possess enduring memories. They established that these memory cells, which had encountered antigens before their modification, exhibited distinct behaviors compared to those without any prior antigen exposure, even after undergoing extensive manufacturing processes.
“Unlike many conventional medications, CAR-T cell products are not uniform. While we recognize that variability exists, the understanding of this variability is still evolving,” explained Terry Fry, MD, the senior author of the study and a professor at the University of Colorado School of Medicine. He is also the executive director of the Gates Institute at CU Anschutz, which is involved in CAR-T cell production. “It was particularly surprising to see how deeply past interactions with antigens imprinted on these cells.”
Fry, along with lead author Kole DeGolier, PhD, discovered that memory T cells effectively targeted and destroyed cancer cells rapidly; however, these cells also faced fatigue sooner and replicated at a slower rate, which raises concerns about potential relapses in treatment. In contrast, naïve T cells—those without prior exposure to antigens—showed promising defensive capabilities, including strong expansion and enhanced resistance to fatigue. The comparative analysis of these two types of cells allowed the researchers to pinpoint specific genetic targets that could be manipulated to enhance their performance. Notably, naïve cells could be effectively increased by focusing on genes such as RUNX2, which not only facilitated faster reproduction but also led to a longer lifespan compared to memory cells.
“These epigenetic variations provide avenues to identify genes that can be targeted to improve cell function,” DeGolier stated.
The research began using mouse models before transitioning to human cells. T cells harvested from both vaccinated and unvaccinated individuals revealed notable changes in the vaccinated group after they encountered vaccine antigens in the lymph nodes. These memory cells were equipped to respond quickly and efficiently against leukemia cells thanks to their prior antigen exposure, though they did exhibit quicker exhaustion compared to naïve T cells.
Despite their lack of the experienced imprinting of memory cells, naïve T cells displayed enhanced effectiveness when targeted with RUNX2, which protected them from fatigue and extended their efficacy against cancer.
“There exists a balance influenced by the cell’s history. By adding RUNX2 to a naïve cell, we observed improved cancer-killing capabilities,” Fry noted. “Our research also produced a substantial dataset on various proteins that may warrant further investigation alongside RUNX2.”
The implications of these findings could pave the way for more refined CAR-T cell engineering, enhancing their ability to combat cancer while potentially minimizing adverse effects, including severe inflammatory responses associated with the therapy.
“Grasping these differences will inform the development of strategies to intelligently tweak specific cell attributes,” the authors concluded. “Further exploration of RUNX2’s impact on preventing exhaustion, particularly in solid tumors where cellular fatigue significantly hampers T cell responses to cancer, is essential.”
Source
www.sciencedaily.com