Abstract 3229: Radiation and chemotherapies result in increasing neoantigen intratumor heterogeneity and resistance to nivolumab in a patient with pleomorphic lung cancer

BACKGROUND:Immune checkpoint inhibitors (ICIs) have significantly changed the landscape of cancer treatment, but the response rate of non-small-cell lung carcinoma (NSCLC) to ICIs is less than 30%. Tumor mutational burden (TMB) is the most promising predictive biomarker for NSCLC immunotherapies. However, some NSCLC patients with high-TMB have little response to ICIs. The neoantigen intratumor heterogeneity (ITH), which determined by the ratio of subclonal neoantigen in the tumor, has been verified to be a potential therapeutic biomarker for immunotherapies in some cancer types. Pulmonary pleomorphic carcinoma, a rare subtype of pulmonary sarcomatoid carcinoma, has been shown to respond remarkably to ICIs, but the biomarkers for ICIs in pulmonary pleomorphic carcinoma have not been fully proven. CASE PRESENTATION:A 57 years old female pulmonary pleomorphic carcinoma patient, who underwent surgery, chemotherapy, anti-angiogenic therapy, radiotherapy, and anti-PD1 therapy, with disease relapse at the last, was included in this study. Primary and relapse tumor samples were collected for gene sequencing by a target sequencing panel which covered 811 cancer genes, during ICIs treatment. Peripheral bloods were collected for ctDNA and T cell receptor sequencing every two months. The results showed that the TMB (>10 muts/Mb) was high, but the clonal neoantigen load (1.33 neos/Mb) was low. The neoantigen ITH was increased after chemotherapy and radiotherapy with a score at nearly 0% in the primary tumor but increased to 85.72% in relapse tissues. The clonal neoantigen ratio detected by ctDNA was increased ~0.8 fold, while the high-frequency clonotypes of TCR to neoantigens dropped during ICIs treatment. CONCLUSIONS:Our results indicated that cytotoxic chemotherapy and radiotherapy can induce the subclonal neoantigens production and increase the neoantigen ITH, thus might negatively regulating patients’ response to ICIs therapy. These results highlight that the neoantigen ITH might be an important auxiliary to TMB in predicting patient response to immune therapies. More studies and clinical trials are needed to further validate these results. Citation Format: Xiaohua Hong, Yuting Liu, Yiying Liu, Yue Hu, Qifan Yang, Di Wu, Kai Zhang, Yongchao Li, Jinsong Yang, Jiaqian Wang, Jun Liu, Li Liu. Radiation and chemotherapies result in increasing neoantigen intratumor heterogeneity and resistance to nivolumab in a patient with pleomorphic lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3229.