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Immune checkpoint inhibitors in clinical trials

Immune checkpoint inhibitors in clinical trials Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called “immune checkpoints.” These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibody- based therapies targeting cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development. Key words Immune checkpoints, PD-1, PD-L1, CTLA4, immunotherapy, immune modulators [2] Immune checkpoints refer to regulatory pathways in the pathogens as evidenced by T-cell exhaustion in these conditions . immunome that inhibit a portion of an active immune response Cancer, however, arises from within the host. While some immune [1] against a specific target or set of targets . Immune checkpoints checkpoints are engaged to avoid immune-mediated eradication, are therefore seen as a normal part of the immune system’s others are merely a part of the normal immune response to stimuli. regulatory cascade and necessary to modulate and maintain immune We are only beginning to understand these pathways. homeostasis. These regulatory pathways are redundant, multi- As a therapeutic class, drugs that inhibit these co-inhibitory faceted, and complex (Figure 1). Their presence and evolutionary signaling pathways, also known as immune checkpoint inhibitors, development are thought to reflect the fact that a normal immune have emerged as a mainstay in melanoma therapy, with potential response can also be potentially deadly to a host if not properly roles in the treatment of renal cell carcinoma (RCC), non–small cell regulated, as evidenced by autoimmune disease. lung cancer (NSCLC), urothelial cancer, head and neck cancer, [3-11] As immunotherapy has gained a foothold in the anticancer ovarian cancer, and various lymphomas . In fact, ClinicalTrials. a r m a m e n t a r i u m , t h e r e i s a c o m m o n l y h e l d b e l i e f a m o n g gov now lists dozens of trials with immune checkpoint inhibitors in a oncologists that cancers thwart these regulatory mechanisms to broad range of indications. As the targets of therapy are components evade immune detection and continue their growth and spread. of the immune system, there is currently no theoretical reason However, the whole picture is more complex. In many chronic to exclude any potential histologies or tumor types from clinical infections, immune checkpoints are exploited by parasitic and viral evaluation. However, from a drug development perspective, this can be a challenge, as the resources are constantly constrained. It will Authors′ Affiliations: Cancer Therapy Evaluation Program, Division of be important to optimize the development of strategies to efficiently Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, explore the therapeutic potentials. MD 20892, USA; Medical Oncology Service, Center for Cancer While a variety of agents could be deemed to interact with Research, National Cancer Institute, Bethesda, MD 20892, USA. immune checkpoint inhibitors, the focus of this review are limited Corresponding Author: Elad Sharon, 9609 Medical Center Drive, 5W502, Bethesda, MD 20892, USA. Tel: +1-240-276-6565; Fax: +1- to the most advanced agents in clinical trials, those targeting the 240-276-7894; Email: sharone@mail.nih.gov. cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 doi: 10.5732/cjc.014.10122 www.cjcsysu.com Chinese Anti-Cancer Association 434 CACA Elad Sharon et al. Immune checkpoints in cancer clinical trials [14] (PD-1), and programmed cell death ligand 1 (PD-L1) pathway. The lymphocyte-activation gene 3 (LAG3) , T-cell membrane protein 3 [15] [16] early trials involving CTLA4- and PD-1/PD-L1-targeting agents have (TIM3) , signal transducer and activator of transcription 3 (STAT3) , shown how the addition of just one blocking antibody can reveal glucocorticoid-induced tumor necrosis factor receptor (TNFR) family- [17] a hidden immune response, with potentially massive therapeutic related protein (GITR) , and agents against the human inhibitory benefit for patients. Immune modulators targeting other mechanisms killer IgG-like receptor (anti-KIR) targeting natural killer (NK) cells [12,13] [18-20] ( Ta b l e 1 ) , s u c h a s i n d o l e a m i n e 2 , 3 - d i o x i g e n a s e ( I D O ) , have also entered the clinical trials arena . Figure 1. Regulatory pathways in immuno-oncology. The immune system has multiple levels of co-stimulatory (shown in green) and co-inhibitory (shown in red) pathways, helping to maintain immune homeostasis in the midst of responding - - to antigenic stimulation. Antibodies blocking cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD 1), and programmed cell death ligand 1 (PD-L1) have shown remarkable clinical activity and further development is underway. Agonist antibodies, which directly interact with co-stimulatory pathways such as 41BB and CD40, are also in clinical development. Other means of affecting the immune responses are being explored, including direct actionon regulatory T (Treg) cells and natural killer (NK) cells. MHC, major histocompatibility complex; TCR, T-cell receptor. Table 1. Other immunotherapeutic agents in development Target Name Indication(s) Company Phase Clinical Trials.gov identifier (selected trials) B7.1 Galiximab Lymphoma Biogen Idec Phase II NCT00516217 B7H3 MGA271 Solid tumors Macrogenics Phase I NCT01391143 LAG3 IMP321 Solid tumors Immuntep Phase I/II NCT00349934 BMS-986016 Solid tumors Bristol-Myers Squibb Phase I NCT01968109 CD137 BMS-663513 Solid tumors Bristol-Myers Squibb Phase I/II NCT00309023 PF-05082566 Lymphoma Pfizer Phase I NCT01307267 KIR IPH2101 Myeloma, AML Innate Pharma (BMS) Phase II NCT01248455 NCT01256073 CCR4 KW-0761 ATL, CTCL Kyowa Kirin Phase I/II NCT00920790 CD27 CDX-1127 Solid tumors & Heme CellDex Therapeutics Phase I NCT01460134 Ox40 MEDI-6469 Solid tumors MedImmune/AZ Phase I NCT02205333 CD40 CP-870,893 Pancreatic Genentech Phase I NCT01456585 Heme, hematologic tumors; ATL, acute T-cell leukemia; CTCL, cutaneous T-cell lymphoma; AML, acute myeloid leukemia. www.cjcsysu.com Chin J Cancer; 2014; Vol. 33 Issue 9 435 Elad Sharon et al. Immune checkpoints in cancer clinical trials (FDA) and the European Medicines Agency for the treatment CTLA4 Inhibition and Human Cancers of metastatic melanoma following research showing improved [29] survival . Ipilimumab is a fully humanized immunoglobulin (Ig) G1 CTLA4 background kappa monoclonal antibody that antagonizes CTLA4 and prevents [30] CTLA4 is one of several co-inhibitory molecules that aid in ligand binding . modifying the T-cell response to antigen activation. The primary role A phase III combination study of ipilimumab at 3 mg/kg with a of CTLA4 is to modify T-lymphocyte response to stimuli. CTLA4 glycoprotein 100 (gp100) peptide vaccine was conducted with 676 regulates the clonal burst size during priming and secondary patients with stage III or IV unresectable melanoma, randomized in expansion, which is thought to be proportional to the activation a 3:1:1 ratio. The results showed the median overall survival (OS) in strength of the complex formed by the T-cell receptor major the ipilimumab plus gp100 group was 10.0 months [95% confidence histocompatibility complex (TCR-MHC complex), both in terms of interval (CI), 8.5 to 11.5 months], as compared with 6.4 months binding affinity and co-stimulation by accessory signals. CTLA4, (95% CI, 5.5 to 8.7 months) in the gp100 alone group [hazard ratio also known as cluster of differentiation (CD) 152, is an inhibitory (HR) for death, 0.68; P < 0.001]. The median OS in the ipilimumab molecule found on T cells, and its counterpart is CD28. CD28 is a co- alone group was 10.1 months (95% CI, 8.0 to 13.8 months; HR for stimulatory signal, but it is important to note that CTLA4 has higher death with ipilimumab alone as compared with gp100 alone, 0.66; avidity for its ligands than CD28, which suggests a dominance of P = 0.003). Grade 3 or 4 immune-related adverse events occurred inhibitory signals in immune activation. The ligands for both CD28 in 10% to 15% of patients treated with ipilimumab and in 3% of and CTLA4 are known as B7 proteins, which are found on antigen- patients treated with gp100 alone. The investigators concluded that presenting cells (APCs). There are two types of B7 proteins: B7-1 (also ipilimumab, with or without a gp100 peptide vaccine, as compared [21,22] known as CD80) and B7-2 (also known as CD86) . with gp100 alone, improved OS in patients with previously treated In normal circumstances, T lymphocytes are thought to express metastatic melanoma. Adverse events can be severe, long-lasting, or CTLA4 on their surface immediately upon response to antigenic both, but most are reversible with appropriate treatment, particularly [29] stimulation of TCR. Because a blocking antibody would attenuate corticosteroids . the inhibitory signal, an anti-CTLA4 antibody would appear to have a Another supportive study in metastatic melanoma involved 502 clear role in enhancing antitumor immunity, as the interaction of B7 patients in a 1:1 randomized trial of ipilimumab at a dose of 10 mg/kg with CD28 would thereby be enhanced. Indeed, in preclinical models, plus dacarbazine at a dose of 850 mg/m of body surface area versus [23] this is exactly what was seen . However, B7 is rarely present in the dacarbazine and placebo. The OS was longer in the group receiving tumor microenvironment, leading to a second hypothesis for how anti- ipilimumab-dacarbazine therapy than in the dacarbazine-placebo [22] CTLA4 antibodies may enhance immune-mediated tumor rejection . arm (11.2 months vs. 9.1 months). Survival rates were also higher CTLA4 is differentially expressed among separate T-lymphocyte for the ipilimumab-dacarbazine arm at 1 year (47.3% vs. 36.3%), subsets. Indeed, higher levels of surface expression of CTLA4 are 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%), with seen in regulatory T cells (Treg cells) as compared with effector an HR for death at 0.72 (P < 0.001). Grade 3 or 4 adverse events T cells (Teff cells). Researchers have established that higher Teff/ were recorded in 56.3% of patients in the experimental arm and only [31] Treg ratios in both CD4-positive and CD8-positive tumor-infiltrating 27.5% in the control arm . These findings further support the use of lymphocytes are associated with enhanced tumor eradication when ipilimumab in metastatic melanoma. [24,25] CTLA4 blockade is employed in tumor models . The preliminary results of the first adjuvant trial were reported Other mechanisms of action involving Treg cells have been at the 2014 Annual Meeting of the American Society of Clinical hypothesized. For example, Treg cells are known to reduce B7 Oncology (ASCO). The European Organization for Research and [26] expression on both human and animal APCs . While B7 is thought Treatment of Cancer (EORTC) conducted a trial with 951 patients to directly signal CTLA4, leading to its co-inhibitory effect, the reverse, with stage III melanoma following complete resection (EORTC 18071, or CTLA4 signaling to APCs via B7, also occurs. CTLA4 reverse NCT00636168). Patients were randomized to receive ipilimumab at signaling via B7 can lead to increased expression of IDO. IDO leads a dose of 10 mg/kg versus placebo every 3 weeks for 4 doses. The to a reduced level of local tryptophan stores in the microenvironment, median relapse-free survival was 26.1 months for the ipilimumab arm [27] which inhibits T-lymphocyte activation and proliferation . Lastly, and 17.1 months for the placebo arm, with an HR of 0.75 (95% CI, recently discovered alternatively spliced mRNA molecules encode 0.64 to 0.90; P = 0.001). The adverse event profile was thought to soluble CTLA4 molecules lacking transmembrane domains. These be generally consistent with that seen in advanced melanoma, but a [32] soluble inhibitors could also mediate immune suppression, either by higher incidence of endocrinopathies were reported . down-regulating B7 expression as noted above or by blocking the While the results were largely seen as positive, there are still [28] potential interaction of B7 and the co-stimulatory molecule CD28 . unresolved issues that may limit the ability of regulatory agencies to approve ipilimumab in the adjuvant setting. In particular, patients with stage III melanoma have the option of high-dose interferon, Ipilimumab [33] which is the standard of care in the United States . In addition, as The first anti-CTLA4 agent in clinical development, ipilimumab, noted above, the dose chosen in EORTC 18071 trial was 10 mg/kg was approved by the United States Food and Drug Administration of ipilimumab, higher than the dose used in the metastatic setting. Chinese Journal of Cancer 436 Chin J Cancer; 2014; Vol. 33 Issue 9 Elad Sharon et al. Immune checkpoints in cancer clinical trials [37] Another large adjuvant trial, E1609 (NCT01274338), addresses the 0.0011) . Regardless, the study failed to demonstrate a statistically questions of the optimal dose of ipilumumab and its comparative significant survival advantage of treatment with the investigational effectiveness to high-dose interferon. In this trial, conducted by the drug over standard-of-care chemotherapy. Eastern Cooperative Oncology Group (ECOG) under the sponsorship While the results were disappointing, there was a possibility that of the United States National Cancer Institute (NCI), 1,500 patients the dosing schedule of tremelimumab (once every 3 months) was with stage III or IV melanoma that has been fully resected are insufficient to achieve results similar to that of ipilimumab. As a result, randomized to three arms: high-dose interferon, ipilimumab at 3 mg/ ongoing efforts with tremelimumab as a monotherapy have used more [30] kg, and ipilimumab at 10 mg/kg . The trial is close to completing frequent dosing. The preferred dose and schedule for tremelimumab accrual and the outcome data are eagerly awaited. for ongoing trials has generally been 10 mg/kg intravenously, every Other indications with ipilimumab are still under clinical 4 weeks for 6 months. A phase II, single-arm study of tremelimumab d e v e l o p m e n t . O n C l i n i c a l Tr i a l s . G o v, a s e a r c h w i t h t h e t e r m as a second-line treatment was conducted with 29 patients with “ipilimumab” returns 191 trials, over 100 of which remain open. Much malignant mesothelioma. Results showed a partial response in 4 of the attention in ipilimumab clinical development has moved to patients (13.8%) and stable disease in 11 patients (37.9%), with OS [38] combination therapy, particularly with the anti-PD-1 agent nivolumab. of 11.5 months . As a result, a phase III, double-blinded, randomized [39] The development of ipilumumab brought up interesting ques- trial is currently underway using tremelimumab in mesothelioma . tions about the best endpoints of efficacy assessment for this class Tremelimumab is also being tested in various combinations in a of agents. In the phase III melanoma trials with ipilimumab described variety of other tumor types. above, improvements in OS seen in the metastatic setting were not accompanied by significant radiographic responses to therapy. This - - PD 1/PD L1 Inhibition and Human has complicated efficient drug development, as response rate is Cancers less likely to serve as a readout of efficacy, at least when ipilimumab is used as a monotherapy. Monotherapy is still being explored in PD-1/PD-L1 background various settings, however. In one example, in a single institution case series, 5 patients with recurrent glioblastoma multiforme (GBM) Compared to the limited development with CTLA4, there is who were treated with ipilimumab were followed. Patients had time an immense level of interest and investment by pharmaceutical to progression ranging from 1 to 6 months, and 1 patient remains companies in the PD-1/PD-L1 pathway (Table 2). Seven major recurrence-free 19 months after therapy, suggesting penetration of companies have entered the fray, with multiple phase III registration [34] this drug across the blood-brain barrier . trials already underway in a variety of malignancies, most notably Currently, there are no biomarkers to predict which patients or melanoma, RCC, and NSCLC (Table 3). This enthusiasm is justified, tumor types are more likely to respond to anti-CTLA4 therapies. as clinical trial results thus far confirm that targeting the PD-1/PD- Some analysis suggested that a high mutational load may be L1 pathway represents the most exciting opportunity for advancing associated with a clinical benefit from ipilimumab. In particular, cancer immunotherapy to date. one group of researchers has focused on identifying a “neoantigen Whereas CTLA4 is involved in central tolerance and control, the signature” that correlates with benefit. Findings are preliminary, PD-1 receptor is critical in peripheral tolerance. PD-1 is expressed on but this suggests that tumor genetics might explain the divergent T lymphocytes during thymic development. Similar to CTLA4, PD-1 [35] outcomes among patients treated with ipilimumab . becomes expressed on CD4- and CD8-positive T lymphocytes during antigenic stimulation, serving as a co-inhibitory signal. In addition, Tremelimumab PD-1 is expressed on numerous other immune cells, including natural killer T cells, B cells, monocytes, and certain dendritic cell [40,41] Tremelimumab (formerly CP-675,206) is a human IgG2 subsets . PD-1 has two main ligands, namely PD-L1 (also known monoclonal antibody specific for CTLA4. In a large, single-arm phase as B7-H1) and PD-L2 (also known as B7-DC). While PD-L2 has a II trial, 241 response-evaluable patients with advanced refractory or much higher affinity for PD-1, it is expressed chiefly on activated relapsed melanoma were treated at a dose of 15 mg/kg intravenously dendritic cells, macrophages, certain B-cell subsets, and other every 3 months. Objective responses were observed in 6.6% of those immune cells. PD-L1 is more widely expressed on hematologic and [36] [1] patients, which led to a phase III trial in a similar patient population . non-hematologic tissues . In the phase III trial in advanced melanoma, 655 patients were As a co-inhibitory signal, PD-1 engagement results in reduced [41] enrolled and randomly assigned to treatment with tremelimumab or cytokine production, cytolytic activity, and lymphocyte proliferation . chemotherapy. Median OS by intent to treat was 12.6 months (95% PD-1 is up-regulated in T lymphocytes following viral infections and CI, 10.8 to 14.3 months) for tremelimumab and 10.7 months (95% down-regulated following viral clearance. In chronic viral infections, CI, 9.36 to 11.96 months) for chemotherapy (HR, 0.88; P = 0.127). however, CD8-positive T lymphocytes express PD-1 constitutively, Of note, while objective response rates were similar in the two arms likely through gene demethylation, contributing to what has been (10.7% in the tremelimumab arm and 9.8% in the chemotherapy termed a T-cell exhaustion phenotype. In human immunodeficiency arm), duration of response was significantly longer among patients virus (HIV) infection, for example, high levels of PD-1 expression treated with tremelimumab (35.8 months vs. 13.7 months, P = allow for persistent interaction between PD-L1 expressed by APCs www.cjcsysu.com Chin J Cancer; 2014; Vol. 33 Issue 9 437 Elad Sharon et al. Immune checkpoints in cancer clinical trials Table 2. Agents targeting PD-1/PD-L1 in clinical development Company Agent targeting PD-1 Agent targeting PD-L1 Bristol-Myers Squibb BMS-936558/MDX-1106 BMS-936559/MDX-1105 (fully human IgG4 mAb) Nivolumab (fully human IgG4 mAb) CureTech CT-011 N/A Pidilizumab (humanized IgG1 mAb) Genentech N/A MPDL3280A (IgG1 mAb, Fc modified) MedImmune/AZ AMP-514 MEDI4736 (fully human mAb) Merck MK-3475 N/A Pembrolizumab (humanized IgG4 mAb) EMD Serono N/A MSB0010718C Aurigene and Pierre Fabre AUNP 12 (peptide) N/A PD-1, programmed death 1 receptor; PD-L1, programmed cell death ligand 1; IgG4, immunoglobulin G4; mAb, monoclonal antibody; N/A, not available. Table 3. Selected ongoing PD-1/PD-L1 trials in melanoma, renal cell cancer (RCC), and non–small cell lung cancer (NSCLC) Sponsor Tumor Setting Phase Comparison Primary Sample Primary Clinical trials. endpoint size completion date gov identifier Bristol-Myers Squibb Melanoma 1st-line II Ipilimumab +/– nivolumab ORR 150 Jul 2014 NCT01927419 Bristol-Myers Squibb NSCLC 3rd-line squamous cell II Nivolumab vs. docetaxel OS 264 Jan 2016 NCT01642004 Bristol-Myers Squibb NSCLC 2nd-/3rd-line non- III Nivolumab vs. docetaxel OS 582 May 2015 NCT01673867 squamous cell - - - ï Merck Melanoma 1st /2nd line (ipi na ve) III Pembrolizumab vs. OS & PFS 645 Feb 2015 NCT01866319 ipilimumab Merck Melanoma 2nd-line II Pembrolizumab vs. OS & PFS 510 Mar 2015 NCT01704287 chemotherapy Bristol-Myers Squibb Melanoma 2nd-line post-ipi III Nivolumab vs. OS 405 May 2015 NCT01721746 chemotherapy Merck NSCLC 2nd-line II/III Pembrolizumab vs. OS & PFS 920 Sep 2015 NCT01905657 docetaxel Bristol-Myers Squibb Melanoma 1st-/2nd-line III Nivolumab vs. OS 410 Sept 2015 NCT01721772 chemotherapy Bristol-Myers Squibb RCC 2nd- to 4th-line III Nivolumab vs. everolimus OS 822 Feb 2016 NCT01668784 Genentech NSCLC 2nd-line II MPDL3280A vs. docetaxel OS 287 Mar 2016 NCT01903993 Bristol-Myers Squibb Melanoma 1st-line III Ipilimumab +/– nivolumab OS 915 Oct 2016 NCT01844505 Genentech NSCLC 2nd-line III MPDL3280A vs. docetaxel OS 850 Jun 2017 NCT02008227 AstraZeneca NSCLC 1st-line after concurrent III MEDI4736 vs. placebo OS & PFS 702 May 2017 NCT02125461 (stage III) chemoradiation ORR, overall response rate; OS, overall survival; PFS, progression-free survival; ipi, ipilumumab. Other footnotes as in Table 2. and subsequent T-cell dysfunction. T-lymphocyte activation is using the anti-PD-L1 antibody, BMS-936559 (NCT02028403). essentially blocked in this setting. In an experiment using B cells from Similarly, tumors use the same pathway, meant to induce HIV-infected individuals, researchers were able to show increased peripheral immune tolerance, to evade T-lymphocyte-mediated responses to HIV antigens in the presence of PD-1 blocking immune eradication. Tumors evading an active immune response [42] antibodies in vitro . This suggests that an active immune response are thought to express PD-L1 following T lymphocyte infiltration can be induced if effective blockade of the PD-1/PD-L1 pathway and expression of interferon-gamma. Expression of PD-L1 has can be implemented. A clinical trial sponsored by the US National been associated with a poor prognosis in a wide variety of human [11,43-51] Institutes of Health is currently planned to investigate that possibility tumors . Interestingly, in one analysis of glioma cases, a better Chinese Journal of Cancer 438 Chin J Cancer; 2014; Vol. 33 Issue 9 Elad Sharon et al. Immune checkpoints in cancer clinical trials prognosis was seen in patients whose tumor-adjacent brain tissue In addition, investigators reported early results using nivolumab at expressed PD-L1 and whose tumors did not express PD-L1. This a dose of 3 mg/kg every 2 weeks in patients with treatment-naïve suggests a general role for PD-L1 in protecting normal tissue from advanced NSCLC. The initial results on 20 patients revealed an immune attack, though it would be important to see these findings objective response rate of 30%. Two patients had a greater than [52] replicated elsewhere and in other tumor types . 80% target lesion reduction at 18 weeks. Of the 15 evaluable tumor In general, the results of PD-1/PD-L1 blockade have been samples, 9 were PD-L1-positive (defined as greater than 5% PD- encouraging. Higher response rates and durable responses were L1 expression using a Dako kit), and the response rate was 67% in seen with PD-1/PD-L1 blocking antibodies than with CTLA4 blockade PD-L1-positive patients; whereas no responses were observed in [55] in melanoma, RCC, and unexpectedly, NSCLC. In addition, although the 6 PD-L1-negative patients . Combinations of nivolumab with similar immune-mediated adverse events were seen with both CTLA4 conventional chemotherapy or epidermal growth factor receptor and PD-1/PD-L1 agents, the severity of adverse events has generally (EGFR) inhibitors were also reported, but results are difficult to [56,57] been lower, with the caveat that fatal pneumonitis was seen in 1% of interpret in the absence of randomized comparisons . [53] the patients on the nivolumab phase I trial described below . Pembrolizumab Pembrolizumab (MK-3475, formerly lembrolizumab) is a PD-1-targeting agents humanized IgG4 monoclonal antibody targeting PD-1. Pembro- Nivolumab lizumab has been very successful in treating melanoma and NSCLC, Nivolumab (BMS-936558) is a fully human IgG4 monoclonal similar to nivolumab. Significant differences cannot be assessed antibody targeting PD-1. A phase I/II study was reported in 2012 in the absence of a randomized trial comparing the two agents. in the New England Journal of Medicine in parallel with a plenary However, binding affinities of the agents are different. Nivolumab is a [53] session at the 2012 ASCO Annual Meeting . Patients on the trial had fully human IgG4, and pembrolizumab is humanized. In phase I trials, advanced melanoma, NSCLC, castration-resistant prostate cancer, neither agent has been found to have a maximally tolerated dose. RCC, or colorectal cancer (CRC). Patients received nivolumab at That said, more time and energy has been spent on searching for an doses of 0.1 to 10.0 mg/kg of body weight every 2 weeks for up to 12 appropriate dose for pembrolizumab. cycles until disease progression or a complete response occurred. In the first major publication involving pembrolizumab, Hamid et [58] Of the 296 patients enrolled, only 14% experienced grade 3 or 4 al . reported that patients with advanced melanoma were analyzed drug-related adverse events, but there were 3 deaths from pulmonary after being treated with three separate dosing strategies: 10 mg/ toxicity. No maximum tolerated dose (MTD) was defined. Cumulative kg of body weight every 2 or 3 weeks or 2 mg/kg every 3 weeks. response rates (all doses) were 18.4% (14/76) among patients with Ultimately, 135 patients with advanced melanoma were treated. NSCLC, 27.6% (26/94) among patients with melanoma, and 27.3% Adverse events were similar to those found in patients treated with [53] (9/33) among patients with RCC . A subsequent analysis of the nivolumab, including fatigue, rash, pruritus, and diarrhea. Response 104 patients in that trial with metastatic melanoma was performed. rates across all dose levels were 38% (95% CI, 25% to 44%). The investigators reported that the median OS in nivolumab-treated Investigators found no difference among those with and without metastatic melanoma patients was 16.8 months, and 1- and 2-year prior ipilimumab therapy. Responses were durable, and the median survival rates were 62% and 43%, respectively. Among the 33 progression-free survival (PFS) among the 135 patients was longer [58] patients (30.8%) with objective tumor regressions, the Kaplan-Meier than 7 months . estimated median response duration was 2 years. Of note, responses A subsequent prospective, randomized analysis was performed were not observed in prostate cancer and colon cancer patients on using both the 2 mg/kg and the 10 mg/kg doses, given every 3 weeks [54] the trial . to patients with ipilimumab-refractory advanced melanoma. There While preliminary results from the phase I/II trial suggested were 89 patients in the 2 mg/kg cohort and 84 patients in the 10 that PD-L1 could be an appropriate biomarker for patient selection, mg/kg cohort. The response rate was 26% at both doses. Safety [59] subsequent analyses have shown numerous PD-L1-negative profiles were similar and there were no deaths reported . Other patients had responded to treatment with nivolumab, although lower attempts to analyze patients with melanoma have been reported, rates are seen. Given the variability and limitation of the available including an analysis of 411 melanoma patients treated across PD-L1 assays, a true absence of PD-L1 expression in those patients multiple dose levels and multiple trials, which was reported at the cannot be confirmed. At this time it remains to be determined whether 2014 ASCO Annual Meeting. Median OS data was not available, but PD-L1 is a predictive marker of response for PD-1 pathway inhibitors. 1-year OS rate over all dose cohorts was 71%. Response rates were At the 2014 ASCO Annual Meeting, preliminary results of other encouraging as well, ranging from 26% to 57%, varying based on [60] nivolumab clinical trials were reported. In a small dose-escalation trial ipilimumab prior treatment, dose, and schedule . in Japan, 3 of 13 patients with platinum-resistant ovarian cancer had Investigators also reported preliminary results of a phase I trial objective responses to nivolumab. The initial 10 patients were treated of previously treated patients with locally advanced or metastatic at a dose of 1 mg/kg, and 2 responders were from that cohort. The NSCLC. Enrolled patients with PD-L1 detected in their tumors subsequent cohort that received 3 mg/kg had only 3 patients, but 1 by a preliminary immunohistochemical assay were randomized [3] was a responder. These results, though preliminary, were promising . to pembrolizumab at a dose of 10 mg/kg every 2 weeks or every www.cjcsysu.com Chin J Cancer; 2014; Vol. 33 Issue 9 439 Elad Sharon et al. Immune checkpoints in cancer clinical trials 3 weeks. In addition, some patients with tumors without PD-L1 Phase I results and data from multiple expansion cohorts in a expression who had received at least two prior lines of therapy were variety of histologies were presented at the 2013 ASCO Annual treated at a dose of 10 mg/kg every 2 weeks. Ultimately, 102 patients Meeting. Pharmacokinetic data supported dosing at 15 mg/kg every comprised the every-2-week cohort (including 43 whose tumors did 3 weeks or a fixed dose equivalent, as no maximally tolerated [65] not express PD-L1), and 119 patients comprised the every-3-week dose was defined. Patients were treated for up to 1 year . In an cohort. Investigators reported that 48% of patients experienced drug- expansion cohort for previously treated patients with metastatic related adverse events, with 6% experiencing grade 3/4 adverse NSCLC, 52 subjects were enrolled and treated at a dose of 15 mg/ events. As in the nivolumab trial reported above, pneumonitis was kg. Of note, 62% of those patients had heavily pretreated NSCLC [66] a concern, with 3 cases of drug-related grade 3/4 pneumonitis. The with more than 3 prior treatments. The response rate was 22% . Response Evaluation Criteria in Solid Tumors (RECIST) response Similar results were seen in a RCC cohort, in which the response [67] rate in all patients was 21%. The response rate was slightly higher rate was 13% (6/47) . In patients with metastatic melanoma treated (24%) for patients with PD-L1-positive tumors (more specifically, in the phase I portion of the trial, the response rate was 26% (9 of 35 [68] 31% on the every-2-week cohort and 22% on the every-3-week patients) . In all of the above cohorts, patients were analyzed for cohort). RECIST response rates were 8% for patients without PD-L1 PD-L1 status, and a correlation between PD-L1 status and efficacy [61] expression . was observed. Early results from patients with other tumor histologies [69] were also considered promising . Pidilizumab At the 2014 ASCO Annual Meeting, investigators presented Pidilizumab is a humanized IgG1 antibody targeting PD-1. The preliminary data from a clinical trial involving patients with metastatic agent was initially evaluated in a phase I trial targeting hematologic bladder cancer. Patients were divided into PD-L1-positive and PD- malignancies. Presently, there are a number of clinical trials L1 negative cohorts, based on an analysis of the PD-L1 expression [62] underway in both hematologic and solid tumors . of immune-infiltrating cells within tumor specimens. In the PD- The results of two pidilizumab clinical trials were recently L1-positive cohort, 20 patients were enrolled, and of those, 10 published in peer-reviewed journals. In a single-center, single-arm, responded to therapy (9 partial responses and 1 complete response). phase II trial, 32 patients with relapsed follicular lymphoma received Response rates for patients with PD-L1-negative tumors have yet to [5] pidilizumab at a dose of 3 mg/kg every 4 weeks for 4 infusions with be published . up to 8 additional infusions administered. In addition, rituximab was given at a dose of 375 mg/m of body surface area every week for MEDI4736 4 weeks. Investigators reported that 19 of 29 evaluable patients MEDI4736 is a human IgG1 monoclonal antibody recognizing achieved an objective response, with complete responses in 15 human PD-L1. It is similar to MPDL3280A, as the molecule also has [63] patients (51.7%) . mutations in the Fc receptor, which therefore eliminates complement- [70] An additional phase II trial involved patients with diffuse large mediated cytotoxicity and ADCC . Results from early clinical B-cell lymphoma (DLBCL) following autologous hematologic stem cell trials are still pending. A phase I dose of 10 mg/kg every 2 weeks transplantation (AHSCT). Sixty-six patients were treated with 3 doses is currently being evaluated in several histologies in an expansion [71] of pidilizumab in the first 1 to 3 months after AHSCT. The PFS rate phase . Of note, at the 2014 ASCO Annual Meeting, investigators was 72% at 6 months after AHSCT (90% CI, 60% to 82%), meeting reported the preliminary results of 13 NSCLC patients treated with [72] the primary endpoint. Thirty-five patients had measurable disease MEDI4736, with 3 partial responses already observed . Several [7] following AHSCT, and the response rate in those patients was 51% . large combination trials in lung cancers are ongoing. Investigators also presented results on the use of pidilizumab in metastatic melanoma at the 2014 ASCO Annual Meeting. In this MSB0010718C trial, 103 patients were randomized in a 1:1 ratio to receive either MSB0010718C is a fully human IgG1 monoclonal antibody 1.5 mg/kg or 6 mg/kg every 2 weeks for 27 doses. Response rates targeting PD-L1. As opposed to the PD-L1-targcting agents from were lower than those observed in patients treated with other PD- Genentech and MedImmune/AstraZeneca, MSB0010718C has 1-targeting agents, but the OS rate at 12 months was 64.5% (90% a native Fc receptor, allowing for ADCC. Results from a phase CI, 55.6% to 72.0%). No significant differences were seen between I trial with the agent were reported at the 2014 ASCO Annual [64] [66] different strata or dose groups . Meeting . Twenty-seven patients with relapsed cancers were treated. No maximally tolerated dose was determined, and the investigators demonstrated that MSB0010718C could be safely PD-L1-targeting agents administered in doses up to 20 mg/kg every 2 weeks. Further clinical MPDL3280A trials are planned in a variety of tumors. MPDL3280A is an engineered human IgG1 monoclonal antibody that targets PD-L1. Of note, MPDL3280A was engineered to eliminate Combinations of Immunotherapeutic antibody-dependent cell-mediated cytotoxicity (ADCC) effector Agents function. As a result, MPDL3280A, unlike some other anti-PD-L1 antibodies, does not deplete cells expressing PD-L1. In spite of the promising single agent indications mentioned Chinese Journal of Cancer 440 Chin J Cancer; 2014; Vol. 33 Issue 9 Elad Sharon et al. Immune checkpoints in cancer clinical trials above, a majority of patients will not respond to immune checkpoint or more. Grade 3 or 4 adverse events related to therapy occurred in inhibition in the histologies tested thus far. The need for newer 53% of patients in the concurrent treatment cohort. In the sequenced combination strategies has become obvious. cohort, 18% of patients had grade 3 or 4 adverse events and a [74] Early in the development of anti-CTLA4 antibodies, there was response rate of 20% was reported . an effort to combine these therapies with high-dose interferon in The combination of ipilimumab and nivolumab has subsequently order to take advantage of the immunomodulatory effects already been evaluated in a variety of malignancies. In RCC, two variations noted in advanced melanoma. In one such trial, tremelimumab was of the combination were tested. In the arm with nivolumab at a dose administered at a dose of 15 mg/kg every 12 weeks while high-dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg, 21 patients were interferon was administered concurrently in standard doses, involving treated, and there were 6 objective responses and 7 patients with 6 2 20×10 U/m of body surface area for 5 days a week, followed by stable disease. In the arm with nivolumab at a dose of 1 mg/kg and 6 2 maintenance interferon at a dose of 10 × 10 U/m of body surface ipilimumab at a dose of 3 mg/kg, 23 patients were treated, and there [75] area subcutaneously 3 times a week for 8 weeks. Thirty-six patients were 9 objective responses and 9 patients with stable disease . were ultimately enrolled. Of the 33 evaluable patients, there were 3 The same regimen was evaluated in NSCLC, with disappointing complete responses and 7 partial responses. The median OS was results. Fewer responses were reported, in part due to early [36] 15.9 months . A similar trial with ipilimumab and high-dose interferon treatment discontinuation caused by adverse events. Further safety is currently enrolling patients (NCT01708941). evaluations are now underway at lower doses (1 mg/kg of ipilimumab [76] A randomized phase II trial of ipilumumab investigated the and 1 mg/kg of nivolumab) . This stresses the need for investigators potential synergy of adding granulocyte macrophage colony- to carefully tailor regimens to specific patient populations. It is clear [73] stimulating factor (GM-CSF, or sargramostim) with ipilumumab . that the number and severity of co-morbidities, average age of In this trial, patients with metastatic melanoma were randomized to patients, and number and intensity of prior treatments may alter the either ipilumumab alone at a dose of 10 mg/kg every 3 weeks for 4 suitability of a given immunotherapy. cycles followed by maintenance of ipilimumab every 12 weeks or to A number of other combinations among immunotherapeutic the same dose and schedule of ipilumumab in addition to GM-CSF at agents are currently underway or planned. Time will tell if the 250 μg subcutaneously on days 1-14 of 21-day cycles for 4 cycles. remarkable successes of the combinations noted above will be Toxicity and response rates did not differ significantly between the replicated when other immunotherapeutic agents are used in two arms. However, the median OS in the combination arm was 17.5 combination. months versus 12.7 months in the ipilimumab alone arm, which was shown to translate to a 36% reduction in mortality risk (P = 0.014). Conclusions Of note, there were 2 grade 5 adverse events in the combination arm and 7 grade 5 events in the ipilumumab alone arm, suggesting Immunotherapy for cancer was declared to be the breakthrough the possibility that GM-CSF improved the tolerability of ipilimumab of the year in 2013 as a result of the significant advances seen and [77] therapy. described above . While much has been accomplished, more still One area of remarkable success involved the use of nivolumab needs to be done. A wide variety of important clinical and scientific and ipilimumab in patients with metastatic melanoma. In the first questions must be addressed efficiently to significantly benefit trial combining these two immune checkpoint inhibitors, 53 patients patients and to improve understanding of the interactions of tumor received concurrent therapy with nivolumab and ipilimumab, and biology and human immunology. If translational scientists and clinical 33 received sequenced treatment. Among all patients enrolled who investigators work together to solve these problems, what is now received concurrent treatment, the response rate was 40%. In the thought to be the breakthrough of the year can soon be thought of as concurrent arm using 3 mg of ipilimumab and 1 mg of nivolumab the medical breakthrough of the century. every 3 weeks, 53% of patients had an objective response, and all of those responding in that arm showed a tumor reduction of 80% Received: 2014-07-31; accepted: 2014-08-22. 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Immune checkpoint inhibitors in clinical trials

Chinese Journal of Cancer , Volume 33 (9) – Sep 1, 2014

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Pubmed Central
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Chinese Journal of Cancer
ISSN
1000-467X
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1944-446X
DOI
10.5732/cjc.014.10122
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Abstract

Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called “immune checkpoints.” These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibody- based therapies targeting cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development. Key words Immune checkpoints, PD-1, PD-L1, CTLA4, immunotherapy, immune modulators [2] Immune checkpoints refer to regulatory pathways in the pathogens as evidenced by T-cell exhaustion in these conditions . immunome that inhibit a portion of an active immune response Cancer, however, arises from within the host. While some immune [1] against a specific target or set of targets . Immune checkpoints checkpoints are engaged to avoid immune-mediated eradication, are therefore seen as a normal part of the immune system’s others are merely a part of the normal immune response to stimuli. regulatory cascade and necessary to modulate and maintain immune We are only beginning to understand these pathways. homeostasis. These regulatory pathways are redundant, multi- As a therapeutic class, drugs that inhibit these co-inhibitory faceted, and complex (Figure 1). Their presence and evolutionary signaling pathways, also known as immune checkpoint inhibitors, development are thought to reflect the fact that a normal immune have emerged as a mainstay in melanoma therapy, with potential response can also be potentially deadly to a host if not properly roles in the treatment of renal cell carcinoma (RCC), non–small cell regulated, as evidenced by autoimmune disease. lung cancer (NSCLC), urothelial cancer, head and neck cancer, [3-11] As immunotherapy has gained a foothold in the anticancer ovarian cancer, and various lymphomas . In fact, ClinicalTrials. a r m a m e n t a r i u m , t h e r e i s a c o m m o n l y h e l d b e l i e f a m o n g gov now lists dozens of trials with immune checkpoint inhibitors in a oncologists that cancers thwart these regulatory mechanisms to broad range of indications. As the targets of therapy are components evade immune detection and continue their growth and spread. of the immune system, there is currently no theoretical reason However, the whole picture is more complex. In many chronic to exclude any potential histologies or tumor types from clinical infections, immune checkpoints are exploited by parasitic and viral evaluation. However, from a drug development perspective, this can be a challenge, as the resources are constantly constrained. It will Authors′ Affiliations: Cancer Therapy Evaluation Program, Division of be important to optimize the development of strategies to efficiently Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, explore the therapeutic potentials. MD 20892, USA; Medical Oncology Service, Center for Cancer While a variety of agents could be deemed to interact with Research, National Cancer Institute, Bethesda, MD 20892, USA. immune checkpoint inhibitors, the focus of this review are limited Corresponding Author: Elad Sharon, 9609 Medical Center Drive, 5W502, Bethesda, MD 20892, USA. Tel: +1-240-276-6565; Fax: +1- to the most advanced agents in clinical trials, those targeting the 240-276-7894; Email: sharone@mail.nih.gov. cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 doi: 10.5732/cjc.014.10122 www.cjcsysu.com Chinese Anti-Cancer Association 434 CACA Elad Sharon et al. Immune checkpoints in cancer clinical trials [14] (PD-1), and programmed cell death ligand 1 (PD-L1) pathway. The lymphocyte-activation gene 3 (LAG3) , T-cell membrane protein 3 [15] [16] early trials involving CTLA4- and PD-1/PD-L1-targeting agents have (TIM3) , signal transducer and activator of transcription 3 (STAT3) , shown how the addition of just one blocking antibody can reveal glucocorticoid-induced tumor necrosis factor receptor (TNFR) family- [17] a hidden immune response, with potentially massive therapeutic related protein (GITR) , and agents against the human inhibitory benefit for patients. Immune modulators targeting other mechanisms killer IgG-like receptor (anti-KIR) targeting natural killer (NK) cells [12,13] [18-20] ( Ta b l e 1 ) , s u c h a s i n d o l e a m i n e 2 , 3 - d i o x i g e n a s e ( I D O ) , have also entered the clinical trials arena . Figure 1. Regulatory pathways in immuno-oncology. The immune system has multiple levels of co-stimulatory (shown in green) and co-inhibitory (shown in red) pathways, helping to maintain immune homeostasis in the midst of responding - - to antigenic stimulation. Antibodies blocking cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD 1), and programmed cell death ligand 1 (PD-L1) have shown remarkable clinical activity and further development is underway. Agonist antibodies, which directly interact with co-stimulatory pathways such as 41BB and CD40, are also in clinical development. Other means of affecting the immune responses are being explored, including direct actionon regulatory T (Treg) cells and natural killer (NK) cells. MHC, major histocompatibility complex; TCR, T-cell receptor. Table 1. Other immunotherapeutic agents in development Target Name Indication(s) Company Phase Clinical Trials.gov identifier (selected trials) B7.1 Galiximab Lymphoma Biogen Idec Phase II NCT00516217 B7H3 MGA271 Solid tumors Macrogenics Phase I NCT01391143 LAG3 IMP321 Solid tumors Immuntep Phase I/II NCT00349934 BMS-986016 Solid tumors Bristol-Myers Squibb Phase I NCT01968109 CD137 BMS-663513 Solid tumors Bristol-Myers Squibb Phase I/II NCT00309023 PF-05082566 Lymphoma Pfizer Phase I NCT01307267 KIR IPH2101 Myeloma, AML Innate Pharma (BMS) Phase II NCT01248455 NCT01256073 CCR4 KW-0761 ATL, CTCL Kyowa Kirin Phase I/II NCT00920790 CD27 CDX-1127 Solid tumors & Heme CellDex Therapeutics Phase I NCT01460134 Ox40 MEDI-6469 Solid tumors MedImmune/AZ Phase I NCT02205333 CD40 CP-870,893 Pancreatic Genentech Phase I NCT01456585 Heme, hematologic tumors; ATL, acute T-cell leukemia; CTCL, cutaneous T-cell lymphoma; AML, acute myeloid leukemia. www.cjcsysu.com Chin J Cancer; 2014; Vol. 33 Issue 9 435 Elad Sharon et al. Immune checkpoints in cancer clinical trials (FDA) and the European Medicines Agency for the treatment CTLA4 Inhibition and Human Cancers of metastatic melanoma following research showing improved [29] survival . Ipilimumab is a fully humanized immunoglobulin (Ig) G1 CTLA4 background kappa monoclonal antibody that antagonizes CTLA4 and prevents [30] CTLA4 is one of several co-inhibitory molecules that aid in ligand binding . modifying the T-cell response to antigen activation. The primary role A phase III combination study of ipilimumab at 3 mg/kg with a of CTLA4 is to modify T-lymphocyte response to stimuli. CTLA4 glycoprotein 100 (gp100) peptide vaccine was conducted with 676 regulates the clonal burst size during priming and secondary patients with stage III or IV unresectable melanoma, randomized in expansion, which is thought to be proportional to the activation a 3:1:1 ratio. The results showed the median overall survival (OS) in strength of the complex formed by the T-cell receptor major the ipilimumab plus gp100 group was 10.0 months [95% confidence histocompatibility complex (TCR-MHC complex), both in terms of interval (CI), 8.5 to 11.5 months], as compared with 6.4 months binding affinity and co-stimulation by accessory signals. CTLA4, (95% CI, 5.5 to 8.7 months) in the gp100 alone group [hazard ratio also known as cluster of differentiation (CD) 152, is an inhibitory (HR) for death, 0.68; P < 0.001]. The median OS in the ipilimumab molecule found on T cells, and its counterpart is CD28. CD28 is a co- alone group was 10.1 months (95% CI, 8.0 to 13.8 months; HR for stimulatory signal, but it is important to note that CTLA4 has higher death with ipilimumab alone as compared with gp100 alone, 0.66; avidity for its ligands than CD28, which suggests a dominance of P = 0.003). Grade 3 or 4 immune-related adverse events occurred inhibitory signals in immune activation. The ligands for both CD28 in 10% to 15% of patients treated with ipilimumab and in 3% of and CTLA4 are known as B7 proteins, which are found on antigen- patients treated with gp100 alone. The investigators concluded that presenting cells (APCs). There are two types of B7 proteins: B7-1 (also ipilimumab, with or without a gp100 peptide vaccine, as compared [21,22] known as CD80) and B7-2 (also known as CD86) . with gp100 alone, improved OS in patients with previously treated In normal circumstances, T lymphocytes are thought to express metastatic melanoma. Adverse events can be severe, long-lasting, or CTLA4 on their surface immediately upon response to antigenic both, but most are reversible with appropriate treatment, particularly [29] stimulation of TCR. Because a blocking antibody would attenuate corticosteroids . the inhibitory signal, an anti-CTLA4 antibody would appear to have a Another supportive study in metastatic melanoma involved 502 clear role in enhancing antitumor immunity, as the interaction of B7 patients in a 1:1 randomized trial of ipilimumab at a dose of 10 mg/kg with CD28 would thereby be enhanced. Indeed, in preclinical models, plus dacarbazine at a dose of 850 mg/m of body surface area versus [23] this is exactly what was seen . However, B7 is rarely present in the dacarbazine and placebo. The OS was longer in the group receiving tumor microenvironment, leading to a second hypothesis for how anti- ipilimumab-dacarbazine therapy than in the dacarbazine-placebo [22] CTLA4 antibodies may enhance immune-mediated tumor rejection . arm (11.2 months vs. 9.1 months). Survival rates were also higher CTLA4 is differentially expressed among separate T-lymphocyte for the ipilimumab-dacarbazine arm at 1 year (47.3% vs. 36.3%), subsets. Indeed, higher levels of surface expression of CTLA4 are 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%), with seen in regulatory T cells (Treg cells) as compared with effector an HR for death at 0.72 (P < 0.001). Grade 3 or 4 adverse events T cells (Teff cells). Researchers have established that higher Teff/ were recorded in 56.3% of patients in the experimental arm and only [31] Treg ratios in both CD4-positive and CD8-positive tumor-infiltrating 27.5% in the control arm . These findings further support the use of lymphocytes are associated with enhanced tumor eradication when ipilimumab in metastatic melanoma. [24,25] CTLA4 blockade is employed in tumor models . The preliminary results of the first adjuvant trial were reported Other mechanisms of action involving Treg cells have been at the 2014 Annual Meeting of the American Society of Clinical hypothesized. For example, Treg cells are known to reduce B7 Oncology (ASCO). The European Organization for Research and [26] expression on both human and animal APCs . While B7 is thought Treatment of Cancer (EORTC) conducted a trial with 951 patients to directly signal CTLA4, leading to its co-inhibitory effect, the reverse, with stage III melanoma following complete resection (EORTC 18071, or CTLA4 signaling to APCs via B7, also occurs. CTLA4 reverse NCT00636168). Patients were randomized to receive ipilimumab at signaling via B7 can lead to increased expression of IDO. IDO leads a dose of 10 mg/kg versus placebo every 3 weeks for 4 doses. The to a reduced level of local tryptophan stores in the microenvironment, median relapse-free survival was 26.1 months for the ipilimumab arm [27] which inhibits T-lymphocyte activation and proliferation . Lastly, and 17.1 months for the placebo arm, with an HR of 0.75 (95% CI, recently discovered alternatively spliced mRNA molecules encode 0.64 to 0.90; P = 0.001). The adverse event profile was thought to soluble CTLA4 molecules lacking transmembrane domains. These be generally consistent with that seen in advanced melanoma, but a [32] soluble inhibitors could also mediate immune suppression, either by higher incidence of endocrinopathies were reported . down-regulating B7 expression as noted above or by blocking the While the results were largely seen as positive, there are still [28] potential interaction of B7 and the co-stimulatory molecule CD28 . unresolved issues that may limit the ability of regulatory agencies to approve ipilimumab in the adjuvant setting. In particular, patients with stage III melanoma have the option of high-dose interferon, Ipilimumab [33] which is the standard of care in the United States . In addition, as The first anti-CTLA4 agent in clinical development, ipilimumab, noted above, the dose chosen in EORTC 18071 trial was 10 mg/kg was approved by the United States Food and Drug Administration of ipilimumab, higher than the dose used in the metastatic setting. Chinese Journal of Cancer 436 Chin J Cancer; 2014; Vol. 33 Issue 9 Elad Sharon et al. Immune checkpoints in cancer clinical trials [37] Another large adjuvant trial, E1609 (NCT01274338), addresses the 0.0011) . Regardless, the study failed to demonstrate a statistically questions of the optimal dose of ipilumumab and its comparative significant survival advantage of treatment with the investigational effectiveness to high-dose interferon. In this trial, conducted by the drug over standard-of-care chemotherapy. Eastern Cooperative Oncology Group (ECOG) under the sponsorship While the results were disappointing, there was a possibility that of the United States National Cancer Institute (NCI), 1,500 patients the dosing schedule of tremelimumab (once every 3 months) was with stage III or IV melanoma that has been fully resected are insufficient to achieve results similar to that of ipilimumab. As a result, randomized to three arms: high-dose interferon, ipilimumab at 3 mg/ ongoing efforts with tremelimumab as a monotherapy have used more [30] kg, and ipilimumab at 10 mg/kg . The trial is close to completing frequent dosing. The preferred dose and schedule for tremelimumab accrual and the outcome data are eagerly awaited. for ongoing trials has generally been 10 mg/kg intravenously, every Other indications with ipilimumab are still under clinical 4 weeks for 6 months. A phase II, single-arm study of tremelimumab d e v e l o p m e n t . O n C l i n i c a l Tr i a l s . G o v, a s e a r c h w i t h t h e t e r m as a second-line treatment was conducted with 29 patients with “ipilimumab” returns 191 trials, over 100 of which remain open. Much malignant mesothelioma. Results showed a partial response in 4 of the attention in ipilimumab clinical development has moved to patients (13.8%) and stable disease in 11 patients (37.9%), with OS [38] combination therapy, particularly with the anti-PD-1 agent nivolumab. of 11.5 months . As a result, a phase III, double-blinded, randomized [39] The development of ipilumumab brought up interesting ques- trial is currently underway using tremelimumab in mesothelioma . tions about the best endpoints of efficacy assessment for this class Tremelimumab is also being tested in various combinations in a of agents. In the phase III melanoma trials with ipilimumab described variety of other tumor types. above, improvements in OS seen in the metastatic setting were not accompanied by significant radiographic responses to therapy. This - - PD 1/PD L1 Inhibition and Human has complicated efficient drug development, as response rate is Cancers less likely to serve as a readout of efficacy, at least when ipilimumab is used as a monotherapy. Monotherapy is still being explored in PD-1/PD-L1 background various settings, however. In one example, in a single institution case series, 5 patients with recurrent glioblastoma multiforme (GBM) Compared to the limited development with CTLA4, there is who were treated with ipilimumab were followed. Patients had time an immense level of interest and investment by pharmaceutical to progression ranging from 1 to 6 months, and 1 patient remains companies in the PD-1/PD-L1 pathway (Table 2). Seven major recurrence-free 19 months after therapy, suggesting penetration of companies have entered the fray, with multiple phase III registration [34] this drug across the blood-brain barrier . trials already underway in a variety of malignancies, most notably Currently, there are no biomarkers to predict which patients or melanoma, RCC, and NSCLC (Table 3). This enthusiasm is justified, tumor types are more likely to respond to anti-CTLA4 therapies. as clinical trial results thus far confirm that targeting the PD-1/PD- Some analysis suggested that a high mutational load may be L1 pathway represents the most exciting opportunity for advancing associated with a clinical benefit from ipilimumab. In particular, cancer immunotherapy to date. one group of researchers has focused on identifying a “neoantigen Whereas CTLA4 is involved in central tolerance and control, the signature” that correlates with benefit. Findings are preliminary, PD-1 receptor is critical in peripheral tolerance. PD-1 is expressed on but this suggests that tumor genetics might explain the divergent T lymphocytes during thymic development. Similar to CTLA4, PD-1 [35] outcomes among patients treated with ipilimumab . becomes expressed on CD4- and CD8-positive T lymphocytes during antigenic stimulation, serving as a co-inhibitory signal. In addition, Tremelimumab PD-1 is expressed on numerous other immune cells, including natural killer T cells, B cells, monocytes, and certain dendritic cell [40,41] Tremelimumab (formerly CP-675,206) is a human IgG2 subsets . PD-1 has two main ligands, namely PD-L1 (also known monoclonal antibody specific for CTLA4. In a large, single-arm phase as B7-H1) and PD-L2 (also known as B7-DC). While PD-L2 has a II trial, 241 response-evaluable patients with advanced refractory or much higher affinity for PD-1, it is expressed chiefly on activated relapsed melanoma were treated at a dose of 15 mg/kg intravenously dendritic cells, macrophages, certain B-cell subsets, and other every 3 months. Objective responses were observed in 6.6% of those immune cells. PD-L1 is more widely expressed on hematologic and [36] [1] patients, which led to a phase III trial in a similar patient population . non-hematologic tissues . In the phase III trial in advanced melanoma, 655 patients were As a co-inhibitory signal, PD-1 engagement results in reduced [41] enrolled and randomly assigned to treatment with tremelimumab or cytokine production, cytolytic activity, and lymphocyte proliferation . chemotherapy. Median OS by intent to treat was 12.6 months (95% PD-1 is up-regulated in T lymphocytes following viral infections and CI, 10.8 to 14.3 months) for tremelimumab and 10.7 months (95% down-regulated following viral clearance. In chronic viral infections, CI, 9.36 to 11.96 months) for chemotherapy (HR, 0.88; P = 0.127). however, CD8-positive T lymphocytes express PD-1 constitutively, Of note, while objective response rates were similar in the two arms likely through gene demethylation, contributing to what has been (10.7% in the tremelimumab arm and 9.8% in the chemotherapy termed a T-cell exhaustion phenotype. In human immunodeficiency arm), duration of response was significantly longer among patients virus (HIV) infection, for example, high levels of PD-1 expression treated with tremelimumab (35.8 months vs. 13.7 months, P = allow for persistent interaction between PD-L1 expressed by APCs www.cjcsysu.com Chin J Cancer; 2014; Vol. 33 Issue 9 437 Elad Sharon et al. Immune checkpoints in cancer clinical trials Table 2. Agents targeting PD-1/PD-L1 in clinical development Company Agent targeting PD-1 Agent targeting PD-L1 Bristol-Myers Squibb BMS-936558/MDX-1106 BMS-936559/MDX-1105 (fully human IgG4 mAb) Nivolumab (fully human IgG4 mAb) CureTech CT-011 N/A Pidilizumab (humanized IgG1 mAb) Genentech N/A MPDL3280A (IgG1 mAb, Fc modified) MedImmune/AZ AMP-514 MEDI4736 (fully human mAb) Merck MK-3475 N/A Pembrolizumab (humanized IgG4 mAb) EMD Serono N/A MSB0010718C Aurigene and Pierre Fabre AUNP 12 (peptide) N/A PD-1, programmed death 1 receptor; PD-L1, programmed cell death ligand 1; IgG4, immunoglobulin G4; mAb, monoclonal antibody; N/A, not available. Table 3. Selected ongoing PD-1/PD-L1 trials in melanoma, renal cell cancer (RCC), and non–small cell lung cancer (NSCLC) Sponsor Tumor Setting Phase Comparison Primary Sample Primary Clinical trials. endpoint size completion date gov identifier Bristol-Myers Squibb Melanoma 1st-line II Ipilimumab +/– nivolumab ORR 150 Jul 2014 NCT01927419 Bristol-Myers Squibb NSCLC 3rd-line squamous cell II Nivolumab vs. docetaxel OS 264 Jan 2016 NCT01642004 Bristol-Myers Squibb NSCLC 2nd-/3rd-line non- III Nivolumab vs. docetaxel OS 582 May 2015 NCT01673867 squamous cell - - - ï Merck Melanoma 1st /2nd line (ipi na ve) III Pembrolizumab vs. OS & PFS 645 Feb 2015 NCT01866319 ipilimumab Merck Melanoma 2nd-line II Pembrolizumab vs. OS & PFS 510 Mar 2015 NCT01704287 chemotherapy Bristol-Myers Squibb Melanoma 2nd-line post-ipi III Nivolumab vs. OS 405 May 2015 NCT01721746 chemotherapy Merck NSCLC 2nd-line II/III Pembrolizumab vs. OS & PFS 920 Sep 2015 NCT01905657 docetaxel Bristol-Myers Squibb Melanoma 1st-/2nd-line III Nivolumab vs. OS 410 Sept 2015 NCT01721772 chemotherapy Bristol-Myers Squibb RCC 2nd- to 4th-line III Nivolumab vs. everolimus OS 822 Feb 2016 NCT01668784 Genentech NSCLC 2nd-line II MPDL3280A vs. docetaxel OS 287 Mar 2016 NCT01903993 Bristol-Myers Squibb Melanoma 1st-line III Ipilimumab +/– nivolumab OS 915 Oct 2016 NCT01844505 Genentech NSCLC 2nd-line III MPDL3280A vs. docetaxel OS 850 Jun 2017 NCT02008227 AstraZeneca NSCLC 1st-line after concurrent III MEDI4736 vs. placebo OS & PFS 702 May 2017 NCT02125461 (stage III) chemoradiation ORR, overall response rate; OS, overall survival; PFS, progression-free survival; ipi, ipilumumab. Other footnotes as in Table 2. and subsequent T-cell dysfunction. T-lymphocyte activation is using the anti-PD-L1 antibody, BMS-936559 (NCT02028403). essentially blocked in this setting. In an experiment using B cells from Similarly, tumors use the same pathway, meant to induce HIV-infected individuals, researchers were able to show increased peripheral immune tolerance, to evade T-lymphocyte-mediated responses to HIV antigens in the presence of PD-1 blocking immune eradication. Tumors evading an active immune response [42] antibodies in vitro . This suggests that an active immune response are thought to express PD-L1 following T lymphocyte infiltration can be induced if effective blockade of the PD-1/PD-L1 pathway and expression of interferon-gamma. Expression of PD-L1 has can be implemented. A clinical trial sponsored by the US National been associated with a poor prognosis in a wide variety of human [11,43-51] Institutes of Health is currently planned to investigate that possibility tumors . Interestingly, in one analysis of glioma cases, a better Chinese Journal of Cancer 438 Chin J Cancer; 2014; Vol. 33 Issue 9 Elad Sharon et al. Immune checkpoints in cancer clinical trials prognosis was seen in patients whose tumor-adjacent brain tissue In addition, investigators reported early results using nivolumab at expressed PD-L1 and whose tumors did not express PD-L1. This a dose of 3 mg/kg every 2 weeks in patients with treatment-naïve suggests a general role for PD-L1 in protecting normal tissue from advanced NSCLC. The initial results on 20 patients revealed an immune attack, though it would be important to see these findings objective response rate of 30%. Two patients had a greater than [52] replicated elsewhere and in other tumor types . 80% target lesion reduction at 18 weeks. Of the 15 evaluable tumor In general, the results of PD-1/PD-L1 blockade have been samples, 9 were PD-L1-positive (defined as greater than 5% PD- encouraging. Higher response rates and durable responses were L1 expression using a Dako kit), and the response rate was 67% in seen with PD-1/PD-L1 blocking antibodies than with CTLA4 blockade PD-L1-positive patients; whereas no responses were observed in [55] in melanoma, RCC, and unexpectedly, NSCLC. In addition, although the 6 PD-L1-negative patients . Combinations of nivolumab with similar immune-mediated adverse events were seen with both CTLA4 conventional chemotherapy or epidermal growth factor receptor and PD-1/PD-L1 agents, the severity of adverse events has generally (EGFR) inhibitors were also reported, but results are difficult to [56,57] been lower, with the caveat that fatal pneumonitis was seen in 1% of interpret in the absence of randomized comparisons . [53] the patients on the nivolumab phase I trial described below . Pembrolizumab Pembrolizumab (MK-3475, formerly lembrolizumab) is a PD-1-targeting agents humanized IgG4 monoclonal antibody targeting PD-1. Pembro- Nivolumab lizumab has been very successful in treating melanoma and NSCLC, Nivolumab (BMS-936558) is a fully human IgG4 monoclonal similar to nivolumab. Significant differences cannot be assessed antibody targeting PD-1. A phase I/II study was reported in 2012 in the absence of a randomized trial comparing the two agents. in the New England Journal of Medicine in parallel with a plenary However, binding affinities of the agents are different. Nivolumab is a [53] session at the 2012 ASCO Annual Meeting . Patients on the trial had fully human IgG4, and pembrolizumab is humanized. In phase I trials, advanced melanoma, NSCLC, castration-resistant prostate cancer, neither agent has been found to have a maximally tolerated dose. RCC, or colorectal cancer (CRC). Patients received nivolumab at That said, more time and energy has been spent on searching for an doses of 0.1 to 10.0 mg/kg of body weight every 2 weeks for up to 12 appropriate dose for pembrolizumab. cycles until disease progression or a complete response occurred. In the first major publication involving pembrolizumab, Hamid et [58] Of the 296 patients enrolled, only 14% experienced grade 3 or 4 al . reported that patients with advanced melanoma were analyzed drug-related adverse events, but there were 3 deaths from pulmonary after being treated with three separate dosing strategies: 10 mg/ toxicity. No maximum tolerated dose (MTD) was defined. Cumulative kg of body weight every 2 or 3 weeks or 2 mg/kg every 3 weeks. response rates (all doses) were 18.4% (14/76) among patients with Ultimately, 135 patients with advanced melanoma were treated. NSCLC, 27.6% (26/94) among patients with melanoma, and 27.3% Adverse events were similar to those found in patients treated with [53] (9/33) among patients with RCC . A subsequent analysis of the nivolumab, including fatigue, rash, pruritus, and diarrhea. Response 104 patients in that trial with metastatic melanoma was performed. rates across all dose levels were 38% (95% CI, 25% to 44%). The investigators reported that the median OS in nivolumab-treated Investigators found no difference among those with and without metastatic melanoma patients was 16.8 months, and 1- and 2-year prior ipilimumab therapy. Responses were durable, and the median survival rates were 62% and 43%, respectively. Among the 33 progression-free survival (PFS) among the 135 patients was longer [58] patients (30.8%) with objective tumor regressions, the Kaplan-Meier than 7 months . estimated median response duration was 2 years. Of note, responses A subsequent prospective, randomized analysis was performed were not observed in prostate cancer and colon cancer patients on using both the 2 mg/kg and the 10 mg/kg doses, given every 3 weeks [54] the trial . to patients with ipilimumab-refractory advanced melanoma. There While preliminary results from the phase I/II trial suggested were 89 patients in the 2 mg/kg cohort and 84 patients in the 10 that PD-L1 could be an appropriate biomarker for patient selection, mg/kg cohort. The response rate was 26% at both doses. Safety [59] subsequent analyses have shown numerous PD-L1-negative profiles were similar and there were no deaths reported . Other patients had responded to treatment with nivolumab, although lower attempts to analyze patients with melanoma have been reported, rates are seen. Given the variability and limitation of the available including an analysis of 411 melanoma patients treated across PD-L1 assays, a true absence of PD-L1 expression in those patients multiple dose levels and multiple trials, which was reported at the cannot be confirmed. At this time it remains to be determined whether 2014 ASCO Annual Meeting. Median OS data was not available, but PD-L1 is a predictive marker of response for PD-1 pathway inhibitors. 1-year OS rate over all dose cohorts was 71%. Response rates were At the 2014 ASCO Annual Meeting, preliminary results of other encouraging as well, ranging from 26% to 57%, varying based on [60] nivolumab clinical trials were reported. In a small dose-escalation trial ipilimumab prior treatment, dose, and schedule . in Japan, 3 of 13 patients with platinum-resistant ovarian cancer had Investigators also reported preliminary results of a phase I trial objective responses to nivolumab. The initial 10 patients were treated of previously treated patients with locally advanced or metastatic at a dose of 1 mg/kg, and 2 responders were from that cohort. The NSCLC. Enrolled patients with PD-L1 detected in their tumors subsequent cohort that received 3 mg/kg had only 3 patients, but 1 by a preliminary immunohistochemical assay were randomized [3] was a responder. These results, though preliminary, were promising . to pembrolizumab at a dose of 10 mg/kg every 2 weeks or every www.cjcsysu.com Chin J Cancer; 2014; Vol. 33 Issue 9 439 Elad Sharon et al. Immune checkpoints in cancer clinical trials 3 weeks. In addition, some patients with tumors without PD-L1 Phase I results and data from multiple expansion cohorts in a expression who had received at least two prior lines of therapy were variety of histologies were presented at the 2013 ASCO Annual treated at a dose of 10 mg/kg every 2 weeks. Ultimately, 102 patients Meeting. Pharmacokinetic data supported dosing at 15 mg/kg every comprised the every-2-week cohort (including 43 whose tumors did 3 weeks or a fixed dose equivalent, as no maximally tolerated [65] not express PD-L1), and 119 patients comprised the every-3-week dose was defined. Patients were treated for up to 1 year . In an cohort. Investigators reported that 48% of patients experienced drug- expansion cohort for previously treated patients with metastatic related adverse events, with 6% experiencing grade 3/4 adverse NSCLC, 52 subjects were enrolled and treated at a dose of 15 mg/ events. As in the nivolumab trial reported above, pneumonitis was kg. Of note, 62% of those patients had heavily pretreated NSCLC [66] a concern, with 3 cases of drug-related grade 3/4 pneumonitis. The with more than 3 prior treatments. The response rate was 22% . Response Evaluation Criteria in Solid Tumors (RECIST) response Similar results were seen in a RCC cohort, in which the response [67] rate in all patients was 21%. The response rate was slightly higher rate was 13% (6/47) . In patients with metastatic melanoma treated (24%) for patients with PD-L1-positive tumors (more specifically, in the phase I portion of the trial, the response rate was 26% (9 of 35 [68] 31% on the every-2-week cohort and 22% on the every-3-week patients) . In all of the above cohorts, patients were analyzed for cohort). RECIST response rates were 8% for patients without PD-L1 PD-L1 status, and a correlation between PD-L1 status and efficacy [61] expression . was observed. Early results from patients with other tumor histologies [69] were also considered promising . Pidilizumab At the 2014 ASCO Annual Meeting, investigators presented Pidilizumab is a humanized IgG1 antibody targeting PD-1. The preliminary data from a clinical trial involving patients with metastatic agent was initially evaluated in a phase I trial targeting hematologic bladder cancer. Patients were divided into PD-L1-positive and PD- malignancies. Presently, there are a number of clinical trials L1 negative cohorts, based on an analysis of the PD-L1 expression [62] underway in both hematologic and solid tumors . of immune-infiltrating cells within tumor specimens. In the PD- The results of two pidilizumab clinical trials were recently L1-positive cohort, 20 patients were enrolled, and of those, 10 published in peer-reviewed journals. In a single-center, single-arm, responded to therapy (9 partial responses and 1 complete response). phase II trial, 32 patients with relapsed follicular lymphoma received Response rates for patients with PD-L1-negative tumors have yet to [5] pidilizumab at a dose of 3 mg/kg every 4 weeks for 4 infusions with be published . up to 8 additional infusions administered. In addition, rituximab was given at a dose of 375 mg/m of body surface area every week for MEDI4736 4 weeks. Investigators reported that 19 of 29 evaluable patients MEDI4736 is a human IgG1 monoclonal antibody recognizing achieved an objective response, with complete responses in 15 human PD-L1. It is similar to MPDL3280A, as the molecule also has [63] patients (51.7%) . mutations in the Fc receptor, which therefore eliminates complement- [70] An additional phase II trial involved patients with diffuse large mediated cytotoxicity and ADCC . Results from early clinical B-cell lymphoma (DLBCL) following autologous hematologic stem cell trials are still pending. A phase I dose of 10 mg/kg every 2 weeks transplantation (AHSCT). Sixty-six patients were treated with 3 doses is currently being evaluated in several histologies in an expansion [71] of pidilizumab in the first 1 to 3 months after AHSCT. The PFS rate phase . Of note, at the 2014 ASCO Annual Meeting, investigators was 72% at 6 months after AHSCT (90% CI, 60% to 82%), meeting reported the preliminary results of 13 NSCLC patients treated with [72] the primary endpoint. Thirty-five patients had measurable disease MEDI4736, with 3 partial responses already observed . Several [7] following AHSCT, and the response rate in those patients was 51% . large combination trials in lung cancers are ongoing. Investigators also presented results on the use of pidilizumab in metastatic melanoma at the 2014 ASCO Annual Meeting. In this MSB0010718C trial, 103 patients were randomized in a 1:1 ratio to receive either MSB0010718C is a fully human IgG1 monoclonal antibody 1.5 mg/kg or 6 mg/kg every 2 weeks for 27 doses. Response rates targeting PD-L1. As opposed to the PD-L1-targcting agents from were lower than those observed in patients treated with other PD- Genentech and MedImmune/AstraZeneca, MSB0010718C has 1-targeting agents, but the OS rate at 12 months was 64.5% (90% a native Fc receptor, allowing for ADCC. Results from a phase CI, 55.6% to 72.0%). No significant differences were seen between I trial with the agent were reported at the 2014 ASCO Annual [64] [66] different strata or dose groups . Meeting . Twenty-seven patients with relapsed cancers were treated. No maximally tolerated dose was determined, and the investigators demonstrated that MSB0010718C could be safely PD-L1-targeting agents administered in doses up to 20 mg/kg every 2 weeks. Further clinical MPDL3280A trials are planned in a variety of tumors. MPDL3280A is an engineered human IgG1 monoclonal antibody that targets PD-L1. Of note, MPDL3280A was engineered to eliminate Combinations of Immunotherapeutic antibody-dependent cell-mediated cytotoxicity (ADCC) effector Agents function. As a result, MPDL3280A, unlike some other anti-PD-L1 antibodies, does not deplete cells expressing PD-L1. In spite of the promising single agent indications mentioned Chinese Journal of Cancer 440 Chin J Cancer; 2014; Vol. 33 Issue 9 Elad Sharon et al. Immune checkpoints in cancer clinical trials above, a majority of patients will not respond to immune checkpoint or more. Grade 3 or 4 adverse events related to therapy occurred in inhibition in the histologies tested thus far. The need for newer 53% of patients in the concurrent treatment cohort. In the sequenced combination strategies has become obvious. cohort, 18% of patients had grade 3 or 4 adverse events and a [74] Early in the development of anti-CTLA4 antibodies, there was response rate of 20% was reported . an effort to combine these therapies with high-dose interferon in The combination of ipilimumab and nivolumab has subsequently order to take advantage of the immunomodulatory effects already been evaluated in a variety of malignancies. In RCC, two variations noted in advanced melanoma. In one such trial, tremelimumab was of the combination were tested. In the arm with nivolumab at a dose administered at a dose of 15 mg/kg every 12 weeks while high-dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg, 21 patients were interferon was administered concurrently in standard doses, involving treated, and there were 6 objective responses and 7 patients with 6 2 20×10 U/m of body surface area for 5 days a week, followed by stable disease. In the arm with nivolumab at a dose of 1 mg/kg and 6 2 maintenance interferon at a dose of 10 × 10 U/m of body surface ipilimumab at a dose of 3 mg/kg, 23 patients were treated, and there [75] area subcutaneously 3 times a week for 8 weeks. Thirty-six patients were 9 objective responses and 9 patients with stable disease . were ultimately enrolled. Of the 33 evaluable patients, there were 3 The same regimen was evaluated in NSCLC, with disappointing complete responses and 7 partial responses. The median OS was results. Fewer responses were reported, in part due to early [36] 15.9 months . A similar trial with ipilimumab and high-dose interferon treatment discontinuation caused by adverse events. Further safety is currently enrolling patients (NCT01708941). evaluations are now underway at lower doses (1 mg/kg of ipilimumab [76] A randomized phase II trial of ipilumumab investigated the and 1 mg/kg of nivolumab) . This stresses the need for investigators potential synergy of adding granulocyte macrophage colony- to carefully tailor regimens to specific patient populations. It is clear [73] stimulating factor (GM-CSF, or sargramostim) with ipilumumab . that the number and severity of co-morbidities, average age of In this trial, patients with metastatic melanoma were randomized to patients, and number and intensity of prior treatments may alter the either ipilumumab alone at a dose of 10 mg/kg every 3 weeks for 4 suitability of a given immunotherapy. cycles followed by maintenance of ipilimumab every 12 weeks or to A number of other combinations among immunotherapeutic the same dose and schedule of ipilumumab in addition to GM-CSF at agents are currently underway or planned. Time will tell if the 250 μg subcutaneously on days 1-14 of 21-day cycles for 4 cycles. remarkable successes of the combinations noted above will be Toxicity and response rates did not differ significantly between the replicated when other immunotherapeutic agents are used in two arms. However, the median OS in the combination arm was 17.5 combination. months versus 12.7 months in the ipilimumab alone arm, which was shown to translate to a 36% reduction in mortality risk (P = 0.014). Conclusions Of note, there were 2 grade 5 adverse events in the combination arm and 7 grade 5 events in the ipilumumab alone arm, suggesting Immunotherapy for cancer was declared to be the breakthrough the possibility that GM-CSF improved the tolerability of ipilimumab of the year in 2013 as a result of the significant advances seen and [77] therapy. described above . While much has been accomplished, more still One area of remarkable success involved the use of nivolumab needs to be done. A wide variety of important clinical and scientific and ipilimumab in patients with metastatic melanoma. In the first questions must be addressed efficiently to significantly benefit trial combining these two immune checkpoint inhibitors, 53 patients patients and to improve understanding of the interactions of tumor received concurrent therapy with nivolumab and ipilimumab, and biology and human immunology. If translational scientists and clinical 33 received sequenced treatment. Among all patients enrolled who investigators work together to solve these problems, what is now received concurrent treatment, the response rate was 40%. In the thought to be the breakthrough of the year can soon be thought of as concurrent arm using 3 mg of ipilimumab and 1 mg of nivolumab the medical breakthrough of the century. every 3 weeks, 53% of patients had an objective response, and all of those responding in that arm showed a tumor reduction of 80% Received: 2014-07-31; accepted: 2014-08-22. 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Published: Sep 1, 2014

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