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Alex S. Woodell
Marathon runners are an interesting breed. In order to complete the grueling 26.2 mile circuit, they must push their mental and physical boundaries to the limit. Seasoned runners possess great strength, focus, resilience, and determination. Each of these qualities is a testament to the intense training schedules they start months or even years in advance. Throughout the course of this training period, athletes must be wary of runner’s burnout. This term collectively refers to a decrease in motivation for running. Overtraining is one of the most common causes of burnout, which often manifests as sluggishness and poor performance. In the first article of this series, we will explore how T cells (like runners) also experience burnout in their race to cure cancer and discuss ways to potentially overcome this limitation in chimeric antigen receptor T cell (CAR-T) therapy.
T cells are specialized lymphocytes that play a key role in cell-mediated immunity. Although numerous subtypes exist, one in particular is primarily responsible for killing tumor cells. These are known as cytotoxic T cells (CTs). Cancer cells express unique molecules on their surface called tumor antigens. CTs can recognize these antigens and subsequently destroy tumor cells by inducing apoptosis, the programmed cell death response.
Recently, scientists have discovered a way to increase the effectiveness of T cells through genetic modification using a strategy called CAR-T therapy. The procedure plays out as follows: (1) T cells are isolated from a blood sample collected from the patient, (2) exposed to a virus carrying genetic material that (3) produces chimeric antigen receptors on the cell surface, (4) expanded into the hundreds of millions, and (5) readministered to the patient. This form of adoptive cell transfer provides patients with new engineered T cells capable of recognizing and killing tumor cells that express the target antigen. However, this novel therapy comes with a hefty price tag. A single dose of Yescarta or Kymriah, two FDA-approved therapies, cost a whopping $475,000 and $373,000, respectively.
In 1998, two groups observed an interesting phenomenon where T cells gradually became dysfunctional and were eventually depleted during chronic viral infections in mice. This phenomenon, commonly referred to as T cell exhaustion or “burnout” appears to be caused by a number of factors including prolonged tumor antigen exposure. This process can be likened to a marathon runner training too hard for a race. Eventually, they just give out. When T cells enter this exhausted state, they begin to express more inhibitory receptors (PD-1, LAG3, and TIM-3). As these receptors grow in number, T cells become progressively less responsive to tumor antigens and lose the ability to transform into CTs. One way to counteract this effect is by using checkpoint inhibitors, molecules that bind to inhibitory receptors on T cells and tone down the immune response. However, it turns out that exhausted T cells also exhibit changes in gene expression which render them ineffective. So where do we go from here?
A group from the University of California in San Diego recently published a paper in Nature showing that transcription factors may be a way to reduce CAR-T burnout. Transcription factors act as genetic switches, turning genes on or off. This allows them to control which molecules are produced within a cell at a given time. The authors identified three transcription factors from the NR4A orphan receptor subfamily that, when removed from CAR-Ts, caused genetic changes that enhanced T cell activation which in turn shrunk tumors and increased the lifespan of tumor-bearing mice. They also noticed a decreased number of inhibitory receptors (PD-1 and TIM-3) in the NR4A-deficient group. The NR4A subfamily is a highly conserved and evolutionarily ancient group of transcription factors that regulate a myriad of cellular processes including differentiation, proliferation, apoptosis, and inflammation. While the exact mechanism for NR4A-mediated T cell exhaustion is unknown, this study highlights a novel approach that uses transcription factors to overcome burnout in CAR-T therapy.
In the next article of this series, we will discuss cytokine release syndrome and it’s life-threatening counterpart, the cytokine storm. This clinical manifestation is the single greatest risk associated with CAR-T therapy.
Chen, Joyce, et al. “NR4A Transcription Factors Limit CAR T Cell Function in Solid Tumours.” Nature, 2019, doi:10.1038/s41586-019-0985-x.
“File:CAR T-Cell Therapy.svg.” Category:Heidentor (Carnuntum) – Wikimedia Commons, Wikimedia Foundation, Inc.