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Immunologists have made great strides in enlisting the body’s own immune cells to fight cancers and infections. In particular, they have developed techniques to extract so-called killer T cells from the blood, re-engineer them by providing new T cell receptors that allow them to target tumors or microbes, and re-introduce them into the body.
Now, St. Jude researchers led by Terrence Geiger, MD, PhD, Pathology, have created a promising new technique to precisely engineer and re-target T cells.
The scientists also discovered subtle side effects of such T cell engineering that they say raise questions in the field. Even small changes in a T cell that target it to cancer, for example, could also aim it at other targets, including the body’s own tissues. Thus, although T cell engineering remains highly promising, such immunotherapies must be extensively tested to avoid hitting the wrong targets.
Geiger and his colleagues published their findings in the April issue of the Journal of Immunology.
T cells attack invading microbes and other threats when triggered by distinct protein fragments of invaders such as viruses or bacteria. These proteins, called antigens, are transported and presented to T cells by the immune machinery. They engage receptors on the T cell surface, like a key fitting a lock.
While naturally occurring T cells are powerful protectors of the body, they have their limitations as weapons against specific microbes or tumors. For example, the process of educating T cells during their development to prevent them from attacking the body’s own tissues limits the antigens to which T cells can respond. T cells operate under powerful controls to prevent them from overreacting and from attacking the body’s own tissues—a process called self-reactivity.
Researchers have sought to overcome limitations in the ability of T cells to respond to antigens by genetically altering and re-introducing their T cell receptors to render them sensitive to the distinctive antigens from cancers or microbes.
In their approach to engineering T cells to recognize such antigens, Geiger and his colleagues concentrated on altering the small region within the T cell receptor that an antigen plugs into. The researchers used genetic techniques to alter or mutate single amino acids, the smallest building block of this antigen-recognizing segment of the T cell receptor. The investigators produced a large number of such mutations and screened them for receptors that showed a greater sensitivity for their test antigen.
“We found that by this selective targeting we could create T cell receptors with a hundred times greater sensitivity for the test antigen,” Geiger said. “However, we found that in some cases incredibly subtle mutations, in addition to generating increased sensitivity, profoundly altered how antigen was recognized and also led to new self-reactivity. It’s as if we adjusted one little tumbler on a lock to make it fit a key better, but we found this adjustment changed how the whole key worked in the lock.”
These surprising findings offer a lesson for immunologists and clinicians exploring the use of immune therapy with T cells modified to express new T cell receptors.
“It is possible to make these targeted receptors, but even the most subtle change can have a dramatic impact on how a T cell recognizes antigen, and what it recognizes,” Geiger said. “The findings mean that if scientists casually make these mutations in T cell receptors without cautiously validating them in pre-clinical studies, there is the potential for trouble. Those T cells could be triggered by antigens that didn’t trigger them before, and this could be harmful when they are tested clinically.”
Geiger said even if such engineered T cells were only tested for their effects on blood cells, for example, scientists might miss unwanted reactivities in other types of cells, such as brain or heart cells.
In further St. Jude studies, the researchers are refining their technique to learn to engineer T cell receptors to have optimum affinity for target antigens, while minimizing unwanted new antigen reactivities.
Other St. Jude authors of this paper are Rajshekhar Alli, PhD, and Phuong Nguyen, both of Pathology; and Akshata Udyavar, formerly of St. Jude.
This research was sponsored in part by the National Institutes of Health and ALSAC.