In the first phase II trial of nivolumab, grade 1 or 2 2 pneumonitis in 6 of 296 patients was reversible upon discontinuation of treatment and administration of glucocorticoid, but 3 of 296 patients (1?%) died of pneumonitis. future. Clinical applications of PD-1 inhibitors in cancer In light of fundamental research, clinical studies using PD-1 pathway inhibitors against treatment-resistant solid tumors were initiated in the United States in 2006 . To date, at least 200 such clinical studies have been carried out using nine types of antibody in at least 20 types of cancer, including both solid and hematological tumors; the total number of subjects worldwide is usually more than 20,000 (Table?1). Table?1 Programmed death (PD)-1 inhibitors (anti-PD-1 antibodies and Pimavanserin anti-PD-L1 antibodies) in clinical testing antigen-presenting cell Snyder et al. performed whole-exome sequencing of tumors from 64 melanoma patients who had been treated with the anti-CTLA-4 antibody ipilimumab or tremelimumab. The results revealed durable clinical efficacy in 11 subjects, and the mutation levels in these patients were significantly elevated . Because neither of these factors is sufficient as a predictive marker for treatment, genome-wide somatic cell neo-epitope analysis and HLA analysis were carried out, resulting in identification of a neo-epitope candidate that is Pimavanserin specifically expressed in tumors against which anti-CTLA-4 antibodies are therapeutically effective. This neo-epitope was validated in a dataset comprising 39 melanoma patients. In addition, the neo-epitope activated T cells derived from patients who received ipilimumab, demonstrating the usefulness of mutation analysis by whole-exome sequencing, as well as neo-epitope analysis, in predicting the therapeutic efficacy of anti-CTLA-4 antibodies. In addition, Rizvi et al. carried out whole-exome sequence analysis of tumors in NSCLC patients treated with the anti-PD-1 antibody pembrolizumab. The results revealed that when numerous non-synonymous mutations were present, there were correlations between response to treatment, durable clinical benefit (i.e., partial response or stable disease for at least 6?months), and recurrence-free survival rate . Similarly, correlations were observed between therapeutic efficacy and a set of genes that is upregulated in smokers, neo-antigen count, and mutations in the DNA-repair pathway, all of which are linked to the mutation level. Furthermore, some studies have described patients who exhibit neo-antigen-specific T-cell immune responses that increase with tumor contraction upon treatment with pembrolizumab. Therefore, it is possible that the efficacy of pembrolizumab treatment against lung Pimavanserin cancer is determined by the genomic scenery of the cancer. In addition, Le et al. found that in a phase II tremelimumab study carried out previously in CRC patients, 1 of 47 subjects exhibited a partial response. In addition, in a phase I study in which the anti-PD-L1 antibody MPDL3280A was administered to 20 subjects, 1 CRC patient with deletion of a mismatch repair (MMR) gene exhibited a partial response . Therefore, the anti-PD-1 antibody pembrolizumab was administered to three cohorts, A, B, and C, respectively, comprising 25 CRC patients with MMR deletion, 25 CRC patients with normal MMR, and 21 patients with cancers other than CRC with MMR deletion. The therapeutic efficacy was very high in the CRC patients with MMR deletion, with a Pimavanserin response rate of 62?% and a disease-control rate of 92?%. By contrast, in the 25 CRC patients with normal MMR, the efficacy was very low, with a response rate of 0?% and a disease-control rate of 16?%. Furthermore, in the subjects with non-CRC cancers with MMR deletions, the response rate Rabbit Polyclonal to ME3 and disease-control rate were 60?% and 70?%, respectively, suggesting the possibility that MMR deletion is usually a predictive factor for the therapeutic efficacy of anti-PD-1 antibody, pembrolizumab. In the manner already described, a search for biomarkers was recently carried Pimavanserin out via comprehensive mutation analysis of the cancer genome using next-generation sequencing technology. This approach is usually termed mutanome analysis when it involves genome-wide mutation analysis of cancer cells, and immunome analysis when it involves a comprehensive exploratory analysis related to tumor immunology; the latter includes diversity analysis of a T-cell repertoire, microarray analysis, and protein analysis. By making extensive use of these techniques, high-throughput extraction of markers can be carried out more effectively, and rapid progress is being made in.