The metabolic imbalance in some cancer patients after treatment checkpoint inhibitor, nivolumabom associated with resistance to the immunotherapeutic agent and reduced survival. This was reported by scientists from the Institute of Cancer Dana-Farber and the Broad Institute in «Nature Communications» magazine.

Chemical changes which, according to the researchers, reflect the adaptive mechanism of resistance of cancer cells and the immune system in response to treatment with anti-PD-1 monoclonal antibody nivolumabom were associated with poorer survival in patients with advanced melanoma and renal cell carcinoma. The more changes - the transformation of the amino acid tryptophan metabolite kynurenine - the greater the impact on survival.

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"The main message of the study is that the metabolic adaptation to cancer immunotherapy can be relevant after the blockade of immune checkpoints" - reported the scientists. Metabolic Processes - these are chemical reactions in the body that are necessary to sustain life, such as the conversion of food into energy to trigger cellular processes.

Inhibitors of checkpoint, such as nivolumab, free molecular "brake" the immune response to cancer is often used to avoid the immune attack T-cells. One such brake molecular known as PD-1. In the case of some patients and some types of cancer, these drugs show high efficacy in enhancing T cell attack on the tumor, but in most cases the treatment does not help. One of the most important issues in oncology - which patients are responsible and which are not, for the treatment of PD-1 inhibitors.

Scientists studying cancerous tissue samples to find factors associated with greater or lesser effect checkpoint inhibitors, e.g., the number of cancer-related mutations found in tumor DNA, and other genetic "signature" associated with the response to inhibitors of control points. Metabolic changes detected by scientists in this study, can be measured in the bloodstream. This is a significant advantage compared with tests on cancerous tissues.

"This is an attractive option for the identification of biomarkers of metabolic changes associated with the treatment of inhibitors of control points - the scientists noted. - It is known that the metabolism is important for immunity, and kynurenine (chemical, the level of which is increased in the majority of patients receiving nivolumab) is an immunosuppressive agent. "

In this study, researchers analyzed blood samples from three independent trials of immunotherapy and measured changes in metabolites (chemicals involved in metabolic reactions) before treatment and at some stages of therapy. Among patients with melanoma, 78% was an increase in the conversion of tryptophan to kynurenine, and 26.5% of this increase was more than 50% in the fourth week of treatment. In patients with kidney cancer treatment nivolumabom also associated with increased levels of kynurenine.

The analysis showed that in patients with melanoma and renal cancer and an increased conversion of tryptophan to kynurenine levels, survival was worse. In particular, patients with melanoma, in blood analyzes which revealed more than a 50% increase in the ratio of tryptophan and kynurenine, median survival was 15.7 months while those in whom this ratio decreased, the median survival was more than 39 months. The same trend was observed in patients with kidney cancer - appropriate figures were 16.7 versus 31.3 months.

Not yet known exactly how using checkpoint inhibitors PD-1 occurs converting tryptophan to kynurenine. However, enzyme IDO, which is involved in many forms of cancer, plays an important role in the synthesis of tryptophan kynurenine. Scientists have noted that a randomized clinical trial in which patients with advanced melanoma treated only IDO inhibitors, has not produced positive results. However, this study did not consider the kynurenine levels in these patients.

Results of the study indicate that the combination of inhibitors of control points with IDO inhibitors may "benefit selected patients with kynurenine pathway activation initiated by inhibition of the control point."


Date of publication: 
Thursday, September 26, 2019