Inc. antineoplastic effects by preventing cancer cells and the tumor microenvironment to deliver inhibitory signals to T lymphocytes.1-6The first-in-class of such agents, ipilimumab, which is now commercialized by Bristol-Myers Squibb (New York, NY, US) under the trade name of Yervoy, has been approved by the US FDA for use in individuals with unresectable or metastatic melanoma on 2011, March 25th.7-11Similar to pembrolizumab, ipilimumab prevents the delivery of inhibitory signals to AT7519 immune effector cells, although it specifically targets another immunosuppressive receptor, namely cytotoxic T lymphocyte-associated protein 4 (CTLA4).12-16In a large, randomized, double-blind, double-dummy, Phase III clinical AT7519 trial enrolling 676 melanoma patients (NCT00094653), the administration of ipilimumab as a standalone immunotherapeutic intervention was associated with a 4-month improvement in overall survival (OS) over the administration of a peptide vaccine targeting the melanoma-associated antigen premelanosome protein (PMEL, best known as gp100).7Accordingly, ipilimumab-treated patients exhibited an overall response rate of AT7519 10.9%, while that of individuals receiving the gp100-targeting vaccine was 1.5% only. Common side effects associated with the use of ipilimumab included fatigue, diarrhea, skin rash, endocrine deficiencies, and colitis. Moreover, severe to fatal autoimmune reactions were observed in 12.9% of patients treated with ipilimumab. These side effects often, but not always, could be managed with treatment discontinuation coupled to the administration of corticosteroids.7 Pembrolizumab was granted accelerated approval upon the disclosure of safety and efficacy results from a clinical trial enrolling 173 participants with advanced melanoma whose disease progressed after prior treatment.17Remarkably, 24% of the patients who received pembrolizumab at the recommended dose of 2 mg/kg experienced tumor regression, a response that lasted at least 1.48.5 months. A similar response rate was observed among patients treated with 10 mg/kg pembrolizumab (sourcehttp://www.fda.gov/NewsEvents/Newsroom/PressAnnou-ncements/ucm412802.htm).17The safety of pembrolizumab had previously been established in a clinical study enrolling 411 individuals with advanced melanoma (NCT01295827).18In this cohort, the most common side effects associated with the use of pembrolizumab were fatigue, Cd86 cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia and diarrhea. In addition, pembrolizumab caused severe immunological side effects involving healthy organs such as the lungs, colon, hormone-producing glands and liver, in a limited fraction of the study participants.18 Another monoclonal AT7519 antibody targeting PD-1 (nivolumab, commercialized by Bristol-Myers Squibb under the trade name of Opvido) has been licensed for use in humans by Japanese regulatory agencies only a month ago.19The safety and favorable therapeutic profile of nivolumab have been demonstrated in several, randomized clinical trials (most of which involving melanoma patients).20-24Last July, Bristol-Myers Squibb announced that it would seek FDA approval on nivolumab by September 30th, 2014 (sourcehttp://www.zacks.com/stock/news/139801/BristolMyers-to-Seek-US-Approval-for-ImmunoOncology-Drug). Now, according to a recent Bloomberg report, Bristol-Myers Squibb has filed a lawsuit against Merck & Co. Inc., accusing the latter of patent infringement around the development of pembrolizumab (http://www.bloomberg.com/news/2014-09-08/uber-technologies-bristol-myers-intellectual-property.html). The therapeutic profile of several antibodies specific for the major PD-1 ligand, i.e., CD274 (best known as PD-L1 or B7-H1),25,26is also being intensively investigated in both pre-clinical and clinical settings.2,27,28These agents include, but are not limited to, MEDI4736 (developed by Astra Zeneca, London, UK), MPDL3280A (developed by Roche, Basel, Switzerland), and MSB0010718C (developed by EMD Serono, Inc., a subsidiary of Merck and Co. Inc. based in Rockland, MA, US).29-35Conversely, molecules that would specifically inhibit the other main endogenous activator of PD-1, i.e., PDCD1 ligand 2 (PDCD1LG2, best known as PD-L2), have failed to reach clinical development yet.2,28 As it stands, immune checkpoint blockers including ipilimumab, pembrolizumab and nivolumab represent a new, efficient alternative to the standard management of advanced melanoma.9,36-42Other immunotherapeutics employed as standalone interventions also provide clinical benefits to melanoma patients, at least in part reflecting the peculiar immunological features of melanoma cells.43-45At odds with several other immunotherapeutic agents, however, checkpoint blockers used as monotherapy are efficient against a wide panel of neoplasms other than melanoma, including (but not limited to)34,46,47hematological malignancies,48non-small cell lung carcinoma,32,49-55renal cell carcinoma,56-60sarcoma,61head and neck carcinoma,62,63ovarian carcinoma,64bladder carcinoma,65and perhaps thymoma66and colorectal cancer.67In addition, blocking immune checkpoints may consistently ameliorate the efficacy of other (immuno)therapeutic regimens, including not only immunostimulatory cytokines68-71and adoptive cell transfer,72-77but also dendritic cell-, peptide- and DNA-based anticancer vaccines,78-86Toll-like receptor agonists,87-89irradiation,90-96conventional and targeted chemotherapeutics (in particular when these also exert immunostimulatory effects),97-108oncolytic viruses,109-112tumor-targeting monoclonal antibodies,28,33,113,114and immunomodulatory drugs (e.g., lenalidomide).115-117 Combinatorial regimens that simultaneously inhibit CTLA4 and PD-1 mediate superior clinical activity as compared to the blockage of either these immunosuppressive receptors, especially in immunosensitive tumors such as melanoma23and renal cell carcinoma.118Along comparable lines, combining immune checkpoint blockers with immunostimulatory monoclonal antibodies like lirilumab, which interferes with the activity of inhibitory killer-cell immunoglobulin-like receptors on natural killer cells,119,120or MEDI6469, which promotes the activity of tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40),42may.