Cancer has been winning the arms race agains the immune system for too long, but scientists are developing plenty of new weapons to try to turn the tide. One key technique is to supercharge T-cells – the foot-soldiers of the immune system – to better detect and kill tumors, and a new trial at the Children's Research Institute has delivered promising results, keeping cases of Hodgkin's lymphoma at bay for years at a time.
Normally, T-cells protect us from infection by patrolling the body, seeking out specific protein signatures that indicate invading bacteria, viruses or cancer cells, and then rallying more T-cells together to attack the threat. At least, that's how it would work in a perfect world. In our imperfect world, tumors have developed workarounds that ensure their survival.
A signaling protein known as transforming growth factor beta (TGF-β) usually controls the growth of healthy cells, but tumors have TGF-β mutations that allow the cancer to spread to neighboring cells. At the same time, excess TGF-β can deactivate attacking T-cells, allowing the tumor to avoid detection by the immune system.
To counter that defense mechanism, the team at the Children's Research Institute engineered a new type of T-cell. The researchers modified LMP-specific T-cells (LSTs) to express a dominant-negative TGF-β receptor type 2 (DNRII). The resulting T-cells were called DNRII-LSTs, and they were designed specifically to fight Epstein Barr virus-positive Hodgkin's lymphoma.
By expressing DNRII, the engineered T-cells are able to survive in the hostile environment around the tumor and continue their usual seek-and-destroy mission. In this case, they would target proteins associated with the Epstein Barr virus, which the tumors would express.
In the study, the researchers administered the engineered T-cells to eight patients with Epstein Barr-positive Hodgkin's lymphoma. Doses ranged from two to 12, and the amount in each ranged from 2 x 107 to 1.5 x 108 cells/m2. The results were promising, with the treatment working to keep the illness at bay for years. Even better, the technique doesn't require the unpleasant "pretreatment" of chemotherapy.
"DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their ability to kill the cancer cells," says Catherine Bollard, lead author of the study. "After infusion, the signal from the genetically modified T-cells in the peripheral blood increased up to 100-fold. DNRII-LSTs persisted for up to four years. Four of the seven patients with active disease achieved clinical responses that were complete and ongoing in two patients for more than four years, including in one patient who achieved only a partial response to unmodified tumor-directed T-cells."
With only eight subjects, the study may be small, but it's an encouraging finding nonetheless. The research was published in the Journal of Clinical Oncology.
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