Personalized Immuno-Oncology.

Cancer immunotherapy, which aims to control the immune system to eradicate cancer cells and prevent their spread, needs to be personalized because anticancer immune responses can be inhibited in several ways that vary from patient to patient. Cancer immunotherapy includes pharmaceuticals such as immune checkpoint inhibitors and monoclonal antibodies (MAbs) as well as cell therapy, immunogene therapy, and vaccines. Combination of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) drugs with other immunotherapy drugs, for example, antibody-drug conjugates, as well as combination of PD-1/PD-L1 drugs with other therapies, for example, chemotherapy and radiation therapy, are being explored. Biomarkers are important for predicting the response to immunotherapy. Molecular diagnostics and sequencing are important technologies for guiding treatment in immuno-oncology. Genomic profiling of tumor mutational burden may enhance the predictive utility of PD-L1 expression and facilitate personalized combination immunotherapy. Optimization of personalized immuno-oncology requires integration of several technologies and selection of those best suited for an individual patient. Advances in immuno-oncology are also attributed to technologies for targeted delivery of anticancer therapeutics such as antigen-capturing nanoparticles for precision targeting and selective delivery. A breakthrough in cell therapy of cancer is a chimeric antigen receptors-T cell, which combines the antigen-binding site of a MAb with the signal activating machinery of a T cell, freeing antigen recognition from major histocompatibility complex restriction. Gene-editing tools such as clustered regularly interspaced short palindromic repeats have a promising application for removing alloreactivity and decreasing immunogenicity of third-party T cells. In conclusion, personalized immuno-oncology is one of the most promising approaches to management of cancer.

Jain KK 《-》

Second- and third-generation drugs for immuno-oncology treatment-The more the better?

Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to 'step on the gas' while 'cutting the brakes', although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field.

Dempke WCM ，Fenchel K ，Uciechowski P ，Dale SP ... -  《-》

Immunotherapy for hepatocellular carcinoma.

Despite significant research efforts, only a few treatment approaches have been developed for hepatocellular carcinoma (HCC). In recent years, immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies) have exhibited potential therapeutic effects for advanced HCC. With the development of gene-editing technologies, gene-sequencing technologies, big data strategies, and artificial intelligence algorithms, engineered immune cell infusion and personalized cancer vaccine therapy have emerged as important directions for anti-HCC treatment. Combining different immunotherapies or combining immunotherapies with conventional therapeutic approaches may provide synergistic effects and facilitate the development of personalized medicine. In this study, we provide an overview of the liver immunoanatomy, the potential immune mechanisms of HCC, and current (pre)clinical developments in this field.

Zongyi Y ，Xiaowu L 《-》

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immuno-oncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.

Cheng AL ，Hsu C ，Chan SL ，Choo SP ，Kudo M ... -  《-》

Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge". Napoli, December 1st-4th 2015.

Ascierto PA ，Agarwala S ，Botti G ，Cesano A ，Ciliberto G ，Davies MA ，Demaria S ，Dummer R ，Eggermont AM ，Ferrone S ，Fu YX ，Gajewski TF ，Garbe C ，Huber V ，Khleif S ，Krauthammer M ，Lo RS ，Masucci G ，Palmieri G ，Postow M ，Puzanov I ，Silk A ，Spranger S ，Stroncek DF ，Tarhini A ，Taube JM ，Testori A ，Wang E ，Wargo JA ，Yee C ，Zarour H ，Zitvogel L ，Fox BA ，Mozzillo N ，Marincola FM ，Thurin M ... -  《Journal of Translational Medicine》