The steps in adoptive T-cell therapy. [Medical University of South Carolina]
The steps in adoptive T-cell therapy. [Medical University of South Carolina]

Adoptive cell therapy (ACT) has shown promise for a variety of cancer subtypes, with clinical trial data showing that up to 40% of Stage IV melanoma patients survive 5 years when treated with ACT versus only a 15% survival rate for patients receiving standard treatments. ACT looks to boost a patient's immune responses against cancer by harvesting the patient's T cells, genetically modifying them with a therapeutic T-cell receptor, activating them, and then rapidly expanding them to generate large numbers of T cells for therapeutic reinfusion. Unfortunately, the rapid expansion of harvested T cells before reinfusion—which is essential to produce the appropriate numbers of immune cells to be therapeutically effective—increases their susceptibility to activation-induced cell death (AICD), causing researchers to look for methods to improve overall therapeutic efficiency.   

Now, researchers at the Medical University of South Carolina (MUSC) and Loyola University have demonstrated that culturing T cells in the presence of the peptide N-acetyl cysteine (NAC) before they are infused as immunotherapy improves effectiveness and outcomes in a preclinical model of melanoma. Investigators have long known that factors limiting T-cell persistence also limit ACT efficacy. However, until now, no one knew that something as simple as changing the culture condition by supplementation with NAC could improve survival of the reinfused T cells. 

In the current study, the research team showed that adding NAC to the in vitro T-cell expansion culture prevents increases in the DNA damage marker γH2AX and significantly improves T-cell persistence and immunotherapy outcomes, including reduced tumor growth, and enhanced survival. Moreover, the scientists found that nearly 40% of NAC-cultured T cells were detectable in tumors after transfer compared to approximately 1.2% of standard culture T cells. They also found that mice receiving NAC-cultured cells experienced significantly delayed tumor growth compared to mice receiving standard-culture cells.

“We were really surprised by the number of adoptively transferred T cells we saw in the tumor,” remarked senior study investigator Christina Voelkel-Johnson, Ph.D., associate professor of microbiology and immunology at MUSC's Hollings Cancer Center. “Given the harsh environment T cells encounter within tumors, we did not expect that the number of NAC-cultured T cells would be 33-fold higher than T cells not cultured in NAC.”

The findings from this study were published recently in Cancer Research in an article entitled “Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death.”

The researchers surmise that the addition of NAC to existing protocols should pose little risk to patients as the compound is already in clinical use for many indications and the culturing of T cells in NAC would occur outside of the patient. “The only difference would be a change to the cell culture protocol in an effort to generate cells with an improved phenotype,” noted Dr. Voelkel-Johnson.

This is the first study showing that expanding therapeutic T cells in the presence of NAC prior to adoptive transfer improves their ability to resist AICD. Most importantly, using these “AICD-resistant” T cells improves therapeutic outcomes in a preclinical model by enhancing T-cell persistence, increasing tumor control, and improving survival.

“Now we are looking at studies to help us understand exactly how NAC changes the phenotype of T cells,” Dr. Voelkel-Johnson stated. “How does it make these cells survive? How is trafficking to tumors improved? There may be benefits to culturing T cells in NAC aside from generating AICD resistance that we haven't yet recognized.”








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