A metabolic imbalance in some patients with cancer, following treatment with the checkpoint inhibitor nivolumab, may be associated with resistance to immunotherapy and shorter survival, according to scientists from Dana-Farber Cancer Institute, in collaborative work with the Broad Institute of Massachusetts Institute of Technology and Harvard, according to a news release from Dana-Farber Cancer Institute.
The chemical change, which the investigators say reflects an “adaptive resistance mechanism” by cancer cells or the immune system, in response to treatment with the programmed cell death protein 1 (PD-1) antibody nivolumab, was linked to worse survival in patients with advanced melanoma and kidney cancer. The greater the change—the conversion of the amino acid tryptophan to a metabolite called kynurenine—the larger the impact on survival.
Scientists have studied cancer tissue specimens to look for factors that may be associated with greater or lesser effect of checkpoint inhibitors; among them are the number of cancer-related mutations found in the tumors’ DNA and other genetic “signatures” associated with response to checkpoint blockers. The metabolic alteration observed in the current study could be measured in the bloodstream—a significant advantage over tissue-based tests.
In this study, the researchers analyzed blood samples from three independent immunotherapy trials and measured changes in metabolites before treatment started and at several points during treatment. In the patients with melanoma, 78% had increases in tryptophan-to-kynurenine conversion and 26.5% had increases of greater than 50% at week 4 of treatment. In the patients with kidney cancer, nivolumab treatment was also associated with increases in kynurenine.
The analysis showed that patients with melanoma and kidney cancer who had higher levels of tryptophan-to-kynurenine conversion while receiving nivolumab had worse survival: 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, whereas those with decreases in this ratio had a median survival of more than 39 months (the respective numbers for patients with kidney cancer were 16.7 vs 31.3 months).
Exactly how treatment with PD-1 checkpoint inhibitors causes tryptophan to be converted to kynurenine is not known. However, an enzyme known as IDO, which has been implicated in many types of cancer, plays a major role in synthesizing kynurenine from tryptophan. The Dana-Farber researchers noted that a randomized clinical trial in which patients with advanced melanoma were treated with IDO inhibitors alone did not yield positive results. However, that study did not look at the kynurenine levels of these patients. The researchers said their results suggest that combining checkpoint inhibitors with IDO inhibitors might “benefit a selected group of patients with checkpoint inhibition–triggered kynurenine pathway activation.” ■