Nivolumab
- PDF / 152,757 Bytes
- 1 Pages / 595.245 x 841.846 pts (A4) Page_size
- 40 Downloads / 147 Views
1 S
Development of resistance in lung cancer: case report An adult man developed acquired resistance to nivolumab during treatment of lung squamous cell carcinoma. The man, at the age of 53-years in November 2011, was referred to a hospital following identification of a mass (3cm) centered in the hilum in the inferior lobe of the right lung and a 0.5cm nodule in the right upper lobe. Subsequently, he was diagnosed with lung squamous cell carcinoma (stage IIIA T4M0N0). Following 4 cycles of chemotherapy including gemcitabine and cisplatin, no recurrence was noted. However, in February 2014, he was hospitalised for left distal femoral pain, where a fluorodeoxyglucose-PET/ CT scan revealed metastasis in distal femur. He received local radiotherapy, which temporarily relieved his symptoms. In June 2015, he underwent knee arthroplasty. In September 2015, as PET/CT scan revealed left inguinal lymph node metastasis, he underwent lyphadenectomy. In November 2016, the PET/CT scan showed a new metastatic lesion. Subsequently, he started receiving IV nivolumab 3 mg/kg every 2 weeks. After 2 cycles of nivolumab treatment, a follow-up PET/CT scan showed a partial response. However, in March 2019, after 28 months of nivolumab treatment, he developed progressive disease. The PET/CT scan showed an increase in the left iliac fossa mass (4.7 x 2.9cm) and a new inguinal lymph node (3.4 x 2.7cm). Therefore, he underwent a left inguinal lymph node biopsy. The histopathologic study of the lesion confirmed the disease relapse. Therefore, tumour genomic profiling analysis of 2 metastatic lymph node specimens obtained from the inguinal lymph node excision (in September 2015) and the lymph node biopsy (in March 2019) was performed. The next-generation sequencing showed cyclin-dependent kinase inhibitor 2(CDNK2) A/CDNK2B gene loss and a copy number reduction in SRY-box transcription factor 2 (SOX2) following development of resistance to nivolumab. The gene copy number of SOX2 was reduced from 19 to 8. Additionally, immunofluorescence showed reduced expression of SOX2 in acquired resistance sample. In the pre-nivolumab and post-nivolumab treated tumour specimens, the tumour mutational burden (TMB) was 8 mutations/Mb and 5 mutations/Mb, respectively. Additionally, some genomic alterations including NFE2L2, KDM5A and MLL2 were noted. As compared with pre-nivolumab-treated tumour specimens, PD-L1 and PD-1 expression was significantly decreased in both tumour cells and immune cells. The nivolumabtreated tumor specimens showed a decreased number of cytotoxic CD8+ T cells and a higher number of regulatory-T cells (Treg) (CD4+ and forkhead box protein P3 [FOXP3+]). It was considered that the gene copy number and the protein expression decrease in SOX2 resulted in a reduction in reactive PD-L1 transcription and the SOX2-specific immune response to anti-PD-1 therapy. This finding was consistent with the decrease in PD-L1 expression after acquiring resistance to nivolumab. It was suspected that the loss of CDKN2A/CDKN2B accompanied by impairments in t
Data Loading...
