Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to evade immunosurveillance and escape effective innate and adaptive immune responses. 19,20,21 Current immunotherapy efforts attempt to br eak the apparent tolerance of the immune system to tumor cells and anti gens by either introducing cancer antigens by therapeutic vaccination or by modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process involving the integration of numerous positive as well as negative co-stimulatory signals in addition to antigen rec ognition by the T-cell r eceptor.22Collectively, these signals govern the balance between T-cell activ ation and tolerance. PD-1 is a member of the CD28 family of T-cell co -stimulatory receptors that also includes CD28, CTLA-4, ICOS, and B- and T-lymphocyte attenuator (BTLA).23PD-1 signaling has been shown to inhibit CD-28-mediated up-regulation of interleukin (IL)-2, IL-10, IL-13, interferon- γ (IFN-γ) and Bcl-xL. PD-1 expression also been noted to inhibit T- cell activation and expansion of previously activated cells. Evidence for a negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a variety of autoimmune phenotypes.24These results suggest that PD-1 blockade has the potential to activa te anti-self T-cell responses, but these responses are variable and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self-antigens. In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the binding of PD-1 to its ligands programmed death ligand-1 (PD-L1) and programmed Revised Protocol No.: 04 Date: 31-May-2019 44 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS death ligand-2 (IC50 1.04 nM and 0.97 nM, respectively). Nivolumab binds specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both proliferation and IFN- γ release in the mixed lymphocyte r eaction. Using a cytomegalovirus (CMV) re-stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall response indicates that nivolumab augmented IFN- γ secretion from CMV-specific memory T cells in a dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-tumor immune response and results in tumor r ejection in several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02). 25 3.2.3.2 Clinical Pharmacology and Safety of Nivolumab The PK of nivolumab were studied in participants over a dose range of 0.1 to 10 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric mean (coefficient of variation [CV]%) CL was 9.5 mL/h (49 .7%), geometr ic mean volume of distribution at steady state was 8.0 L (30.4%), and geometric mean elimination T-HALF was 26.7 days (101%). Steady-stat e concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks (Q2W), and systemic accumulation was approximately 3-fold. The exposure to nivolumab increased dos e proportionally over the dose range of 0.1 to 10 mg/kg administered Q2W. The clearance of nivolumab increased with increasing body weight. The population phar macokinetic (PPK) analysis suggested that the following factors had no clinically important effect on the CL of nivolumab : age (29 to 87 years), gender, race, baseline lactate dehydrogenase, PD-L1, solid tumor type , baseline tumor size, and hepatic impairment. Although Eastern Cooperative Oncology Group (ECOG) status, baseline glomerular filtration rate (GFR), albumin level, and body weight had an effect on nivolumab CL, the effect was not clinically meaningful. When nivolumab is administer ed in combination with ipilimumab, the CL of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab. Additionally, PPK and exposure response analyses have been performed to support use of 240 mg Q2W dosing in addition to the 3 mg/kg Q2W regimen. Using the PPK model, exposure of nivolumab at a 240-mg flat dose was ident ical to a dose of 3 mg/kg for par ticipants weighing 80 kg, which was the approximate median body weight in nivolumab clinical studies. Full details on the clinical pharmacology aspects of nivolumab can be found in the nivolumab IB. 17 3.2.4 Ipilimumab 3.2.4.1 Pharmacology and Mechanism of Action of IpilimumabCTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 immunoglobulin (Ig) superfamily that competes with CD28 for B7. CTLA-4-mediated signals are inhibitory and turn off T- cell-dependent immune responses. 26Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human and nonhuman primates. The proposed mechanism of action for ipilimumab is interference of the Revised Protocol No.: 04 Date: 31-May-2019 45 Approved 5.0 v Approved 1.0 v Clinical Protocol CA021002 BMS-986226 anti-ICOS interaction of CTLA-4 with B7 molecules on APCs , with subsequent blockade of the inhibitory modulation of T-cell activation promoted by the CTLA-4/B7 interaction. Additional details are provided in the current version of the ipilimumab IB.18 3.2.4.2 Clinical Pharmacology and Safety Phase 3 programs are ongoing in melanoma, PRC, and lung cancer. The safety profile of ipilimumab is generally consistent across these st udies with (a) the majority of AEs being inflammatory in n ature, which is consistent with the proposed mechanism of action of ipilimumab; (b) the same types of such immune-mediated events in the gastrointestinal (GI) tract, skin, liver, and endocrine system being reported; and (c) most of these events being manageable with immune suppressive therapies. In addition, a completed, large, Phase 2 study (Study CA184041) has investig ated the addition of ipilimumab to carboplatin and paclitaxel using 2 d ifferent schedules (concurrent and phased) in participants with NSCLC or small cell lung cancer.Ipilimumab offers a clinically meaningful and stati stically significant survival benefit to participants with pretreated a dvanced melanoma (as 3 mg/kg monotherapy compared with the melanoma peptide v accine gp100) and previously untreated a dvanced melanoma (at 10 mg/kg in combination with dacarbazine [DTIC] compared with DTIC alone), and there was evidence of clinical activity in randomized studies in other tumor types. The PK of ipilimumab has been extensively studied in participants with melanoma at the 3- and 10-mg/kg dose administered as an IV infusion.