Influence of Vitamin D in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab

Abstract

Nivolumab is one of the most commonly used monoclonal antibodies for advanced non-small cell lung cancer treatment, to the extent that the presence of its anti-antibody is considered a negative prognostic factor. Vitamin D (VD) modulates expression of the genes involved in drug metabolism and elimination. Immune system regulation and immunodeficiency is frequent in non-small cell lung cancer patients. To date, no data have been reported about the relationship between nivolumab and VD. The aim of this study was to quantify plasma 25-hydroxyVD (25-VD) and 1,25-VD, nivolumab, and its anti-antibody before starting treatment (baseline) and at 15, 45 and 60 days of therapy. VD-pathway-associated gene single nucleotide polymorphisms (SNPs) were also evaluated. Molecules were quantified through enzyme-linked immunosorbent assay, and SNPs through real-time PCR. Forty-five patients were enrolled. Median nivolumab concentrations were 12.5 μg/mL, 22.3 μg/mL and 27.1 μg/mL at 15, 45 and 60 days respectively. No anti-nivolumab antibodies were found. Correlations were observed between nivolumab concentrations and 25-VD levels. Nivolumab concentrations were affected by VD-pathway-related gene SNPs. VDBP AC/CC genotype and baseline 25-VD < 10 ng/mL predicted a nivolumab concentration cut-off value of <18.7 μg/mL at 15 days, which was associated with tumor progression. This is the first study showing VD marker predictors of nivolumab concentrations in a real-life context of non-small cell lung cancer treatment.

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

“…25-VD inactivation in calcitroic acid (24,25-VD) is performed by CYP24A1 [38]. 1,25-VD stimulates the expression of DNA-damage-inducible transcript 4 protein (DDIT4), also known as a regulator in the development and response to DNA damage 1 (REDD1), which acts as a negative regulator of mTOR [39,40]. The combination of vitamin D and mTOR inhibitors inhibits osteoclast differentiation and their function in inflammatory conditions by increasing NFATc1 and decreasing cathepsin K expression [41].…”

Diet, Microbiome, and Cancer Immunotherapy—A Comprehensive Review

“…Vitamin D, in addition to its classic effects on the skeletal and muscular-nervous system, has a significant effect on the immune system [ 100 ]. Vitamin D plays a role in the activation of the immune system, mainly T cells.…”

“…In addition, some vitamin deficiencies are more likely in people who follow a vegetarian, vegan, or fruit-based diet; therefore, supplementation is recommended in these cases [ 56 ]. Research shows that vitamin D affects cancer immunotherapy, for example, 25-hydroxyvitamin D affects nivolumab concentration [ 100 ]. 25-hydroxyvitamin D concentration is influenced by the polymorphism of the gene encoding of the vitamin D binding protein (VDBP).…”

“…Assessment of the 25-hydroxyvitamin D level and rs7041 VDBP genotype before and during nivolumab treatment allows for adequate supplementation of vitamin D to achieve better treatment results, by reducing the risk of cancer progression. Higher risk of more severe adverse events has been observed in patients diagnosed with vitamin D deficiency before starting immunotherapy [ 100 ]. Studies on patients with advanced metastatic melanoma have shown that both a low initial value and poor supplementation of vitamin D are associated with a worse prognosis [ 105 ].…”

Predictors of the response to nivolumab immunotherapy in the second or subsequent lines for metastatic non‑small cell lung cancers

“…It is interesting to note that the serum level of nivolumab at 14, 45 and 60 days after the beginning of treatment correlates with the plasma level of 25-hydroxycholecalciferol (12).…”