Metabolic Imbalance Linked to Immune Checkpoint Inhibitor Resistance

According to a report by Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard, metabolic imbalance in some patients with cancer following treatment with the checkpoint inhibitor nivolumab is associated with resistance to the immunotherapy agent and shorter survival.

The study, published in Nature Communications, reported that the conversion of the amino acid tryptophan to a metabolite, called kynurenine, in cancer cells is a response to treatment with nivolumab, a PD-1 antibody. This chemical change was linked to worse survival in patients with advanced melanoma and kidney cancer, according to the study.

Checkpoint inhibitors halt the immune response that cancer cells often use to escape attack by immune T cells. In some patients and certain cancer types, the drugs have proven highly effective in unleashing the T cell attack on tumors, but overall, checkpoint inhibitors help only a minority of patients.

Researchers analyzed blood samples from 3 independent immunotherapy trials and measured changes in metabolites before treatment started and at several points during treatment. In patients with melanoma, 78% had increases in the tryptophan to kynurenine conversion and 26.5% had increases of greater than 50% at week 4 of treatment. In patients with kidney cancer, nivolumab treatment was also associated with increases in kynurenine.

The analysis showed worse survival in patients with melanoma and kidney cancer, who had higher levels of tryptophan to kynurenine conversion on nivolumab. In particular, individuals with melanoma whose blood tests showed a greater than 50% increase in the kynurenine and tryptophan ratio had a median survival of 15.7 months, while those with decreases in this ratio had a median survival time of more than 39 months, whereas the respective number for patients with kidney cancer were 16.7 versus 31.3 months.

It is not entirely known how treatment with PD-1 checkpoint blockers causes tryptophan to be converted to kynurenine. However, an enzyme known as IDO, which has been implicated in many forms of cancer, plays a major role in synthesizing kynurenine from tryptophan.

The researchers note that their results suggest that combining checkpoint blockers with IDO inhibitors might benefit a selected group of patients with checkpoint inhibition-triggered kynurenine pathway activation.

Reference

• Resistance to immune checkpoint blocker drug linked to metabolic imbalance [press release]. Dana-Farber Cancer Institute website. Published September 25, 2019. https://www.dana-farber.org/newsroom/news-releases/2019/resistance-to-immune-checkpoint-blocker-drug-linked-to-metabolic-imbalance/. Accessed September 26, 2019.