Wistar researchers successfully evaluated a simple intervention that could unlock higher anti-tumour potential in T-cell therapies, a strategy known as "cell-based therapy," which uses specifically tailored T cells to combat cancer.
Dr. Hildegund C.J. Ertl, a professor in The Wistar Institute's Vaccine & Immunotherapy Centre, led the team that demonstrated an exciting concept: that the common cholesterol drug fenofibrate can boost T cells' ability to destroy human tumours, as described in their new paper, "Treatment with the PPAR agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma,"
CD8+ T cells work very well in fighting liquid tumors, but for
solid tumors like melanoma, the cell-based therapy approach can stall due to
the physical structure of the cancer.
The T cells infiltrate the tumor, but the cancer adapts and saps the T cells' energy by hijacking the form of metabolism that the T cells use: glycolysis, which turns sugar into energy.
Without energy, the T cells first lose functions and then die, and the cancer continues to grow.
But Dr. Ertl's team has been able to circumvent this problem by forcing T cells to use a different energy source than glucose.
They used fenofibrate because, as a cholesterol-lowering compound, the drug is a PPARa agonist.
When PPARa is upregulated, cellular metabolism is switched from glycolysis to fatty acid oxidation, or FAO.
This mechanism works to improve cholesterol levels in human patients, but for Dr. Ertl's purposes, the fenofibrate-induced switch to FAO provided T cells with a form of energy that cancer couldn't exploit -- which is how Dr. Ertl proved that fenofibrate has been able to boost the killing power of T cells deployed against cancerous cell lines.
In this paper, the authors wanted to see whether this kind of
cancer-killing improvement would have similar effects when deployed against not
just cancer cell lines but solid human tumor fragments -- a more challenging
proposition.
The group treated T cells with fenofibrate, and the hypothesis held: Dr. Ertl's team watched the T cells treated with fenofibrate survive longer and kill more cancer in preclinical models with human solid tumor masses than the T cells that didn't receive the treatment.
"Treating T cells with fenofibrate before using them as a cancer treatment flips a switch of sorts in their metabolism," said Dr. Hildegund Ertl.
"Once that switch is flipped, T cells can destroy the cancer much more effectively. And we've confirmed that this holds for larger human tumor masses."
As a result of these findings, Dr. Ertl and her team think this intervention shows great promise for future anti-tumor therapies. "Melanoma is the most dangerous form of skin cancer. Anything we can do to chip away at the cancer and destroy more of it -- even a simple pre-treatment step like this one -- can make a world of difference."
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