Metabolic Imbalance Associated with Resistance to Checkpoint Inhibitor Nivolumab

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Investigators at the Dana-Farber Cancer Institute, in conjunction with researchers at the Broad Institute of MIT and Harvard, have discovered that a metabolic imbalance in some cancer patients following treatment with a checkpoint inhibitor drug, nivolumab, is associated with resistance to the immunotherapy agent and shorter survival.

Findings from the new study were published recently in Nature Communications through an article titled “Metabolomic adaptations and correlates of survival to immune checkpoint blockade.”

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 PD-1 antibody-drug 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.

“The main message is that metabolic adaptations in cancer immunotherapy may be relevant after immune checkpoint blockade,” explained co-senior study investigator Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School.

Checkpoint blockers such as nivolumab are drugs that release the molecular brakes on the immune response that cancer often uses to escape attack by immune T cells. One such molecular brake is known as PD-1. In some patients and some cancer types, the drugs have proven highly effective in unleashing the T cell attack on tumors, but overall, the drugs help only a minority of patients.

“One of the most important questions in oncology is who responds and who doesn’t to modern PD-1 inhibitors,” Choueiri noted.

Scientists have studied cancer tissue specimens to look for factors that may be associated with the 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 the scientists found in the current study could be measured in the bloodstream—a significant advantage over tissue-based tests.

“This is an attractive option for identifying biomarkers of metabolic changes” related to treatment with checkpoint blockers, said co-senior study investigator Marios Giannakis, MD, PhD, assistant professor of medicine at Dana-Farber and Harvard Medical School. “We know that metabolism is important in immunity, and kynurenine [the chemical found to be elevated in a majority of the patients treated with nivolumab] is known to be immunosuppressive.”

In this study, the researchers analyzed blood samples from three independent immunotherapy trials and measured changes in metabolites [chemicals involved in metabolic reactions] before treatment started and at several points during treatment. In melanoma patients, 78% had increases in the tryptophan to kynurenine conversion and 26.5% had increases of greater than 50% at week four of treatment. In kidney cancer patients, nivolumab treatment was also associated with increases in kynurenine.

“In order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profiled serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1),” the authors wrote. “We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-cancrdioxygenase (IDO/TDO) inhibitors.”

The analysis showed that melanoma and kidney cancer patients with higher levels of tryptophan to kynurenine conversion on 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, 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.

Exactly how treatment with PD-1 checkpoint blockers causes tryptophan to be converted to kynurenine isn’t known. 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 Dana-Farber researchers noted that a randomized clinical trial in which advanced melanoma patients 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 blockers with IDO inhibitors might “benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation.”

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