The role of ipilimumab is also being investigated in small cell lung cancer (“type”:”clinical-trial”,”attrs”:”text”:”NCT01331525″,”term_id”:”NCT01331525″NCT01331525, “type”:”clinical-trial”,”attrs”:”text”:”NCT01450761″,”term_id”:”NCT01450761″NCT01450761, “type”:”clinical-trial”,”attrs”:”text”:”NCT02046733″,”term_id”:”NCT02046733″NCT02046733). Tremelimumab, a monoclonal antibody much like ipilimumab has been studied inside a phase II study of pre-treated individuals with advanced stage NSCLC [37]. 0.05), whilst in the early arm, no improvement in irPFS was seen (5.5 vs 4.6 months HR = 0.81; = 0.13). In the delayed group, a non-statistical improvement in OS was also seen (12.2 vs 8.3 months HR = 0.87; = 0.23). Although not statistically significant, individuals with squamous histology experienced longer OS (HR = 0.55, 95% CI, 0.27C1.12). The side effects reported were rash, pruritus and diarrhea. Grade 3/4 irAE was 20% for the early phase, 15% for the delayed phase and 6% for the control group. One death from toxic epidermal necrolysis was attributed to ipilimumab. A larger phase III trial is being conducted, aiming specifically at the squamous subtype NSCLC (“type”:”clinical-trial”,”attrs”:”text”:”NCT01285609″,”term_id”:”NCT01285609″NCT01285609). Ipilimumab is also being studied in combination with EGFR and ALK tyrosine kinase inhibitors (“type”:”clinical-trial”,”attrs”:”text”:”NCT01998126″,”term_id”:”NCT01998126″NCT01998126). The role of ipilimumab is also being investigated in small cell lung cancer (“type”:”clinical-trial”,”attrs”:”text”:”NCT01331525″,”term_id”:”NCT01331525″NCT01331525, “type”:”clinical-trial”,”attrs”:”text”:”NCT01450761″,”term_id”:”NCT01450761″NCT01450761, “type”:”clinical-trial”,”attrs”:”text”:”NCT02046733″,”term_id”:”NCT02046733″NCT02046733). Tremelimumab, a monoclonal antibody similar to ipilimumab has been studied in a phase II study of pre-treated patients with advanced stage NSCLC [37]. Patients were randomized Goat polyclonal to IgG (H+L)(HRPO) into two arms-tremelimumab or best supportive case after 4 cycles of a platinum doublet chemotherapy regimen of investigators choice. The ORR was 5% and there was no difference in PFS. 2.2. PD1 PD-1 receptor is usually expressed on CD4 and CD8 lymphocytes, Tregs, B lymphocytes and NK cells [13]. Known ligands of PD-1 include PD-L1 (or CD274, B7-H1) and PD-L2 (CD 273, B7-DC). The binding of PD-1 with PD-L1 or PD-L2 leads to decreased cytokine production, reduced proliferation and cell lysis. In many tumors, PD-1 is usually up regulated in tumor infiltrating lymphocytes (TILs), while many tumors have increased PD-L1 expression [38]. It is proposed that through this mechanism, tumors can induce T cell anergy and avoid the processing tumor antigens by APCs that lead to recognition. PD-1 antagonists include PD-L1 antibodies such as nivolumab (BMS936558), lambrolizumab (MK-3475), and pidilizumab (CT-011) and the fusion protein AMP-224. Nivolumab (BMS-936558, MDX-1106, ONO-4538) is usually a fully human IgG4 monoclonal antibody without detectable antibody-dependent cellular cytotoxicity (ADCC). In a phase I study of patients with advanced stage solid tumors [39], escalating doses of nivolumab biweekly were given for up to 12 cycles (2 years). In the NSCLC cohort (= 129) the majority of patients were heavily pretreated, with 55% receiving at least 3 prior lines of therapy. The ORR was 17% with a median duration of response of Eniporide hydrochloride 74 weeks (range, 6.1C133.9 weeks). The median survival was 9.9 months with one and two year survival rates of 42 and 24%, respectively. The median PFS was only 2.3 months. Nivolumab was generally well tolerated with skin toxicities (20%), gastrointestinal (15%) and pulmonary (9%) being the most commonly observed adverse events (AEs). A lower frequency Eniporide hydrochloride of gastrointestinal toxicities was seen: 2% (grade 3/4) as compared to 20% with ipilimumab. Pneumonitis was reported in 6% (8/129) of patients with two deaths [40]. Biomarker analysis for PD-L1 expression was performed in 49% (63/129) patients. PD-L1 positive cases, defined as expression in at least 5% of tumor cells on immunohistochemistry (IHC), were seen in 49% (31/63) of patients. The ORR in patients with PD-L1 positive and PD-L1 unfavorable tumors was 16% and 13%, respectively [41], suggesting that in a pretreated group, archival tumor tissue may not be ideal for assessing PD-L1 status. Phase III trials of nivolumab versus docetaxel in patients with either squamous NSCLC (“type”:”clinical-trial”,”attrs”:”text”:”NCT01642004″,”term_id”:”NCT01642004″NCT01642004) or non-squamous NSCLC (“type”:”clinical-trial”,”attrs”:”text”:”NCT01673867″,”term_id”:”NCT01673867″NCT01673867) have completed accrual and results are eagerly awaited (Table 3). Table 3 Selected ongoing studies of immune checkpoint mediators. = 1) and grade 3 pulmonary edema (= 1) were reported. In the tumor biomarker studies, new pre-treatment tumor biopsies were obtained. Tumor PD-L1 expression by IHC was a predictor of response with the ORR of 67% (6/9) and 4% (1/24) in PD-L1 positive and negative tumors, respectively. Based on these results, a randomized phase II/III trial of lambrolizumab vs docetaxel in patients with PDL1 positive advanced Eniporide hydrochloride NSCLC is being conducted (“type”:”clinical-trial”,”attrs”:”text”:”NCT01905657″,”term_id”:”NCT01905657″NCT01905657) (Table 3). 2.3. PDL1 Programmed death receptor ligand 1 (PD-L1, B7-H1), the ligand for PD-1, is usually a member of the B7 superfamily, is involved in the negative regulation of immune response [44]. PD-L1 is usually expressed in T and B cells, macrophages and dendritic cells and is up regulated in a range of solid tumors.