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

• Published in: European journal of cancer (1990) 2017-03, Vol.74, p.55-72
• Main Authors: Dempke, Wolfram C.M, Fenchel, Klaus, Uciechowski, Peter, Dale, Stephen P
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - therapeutic use; Antigens, CD - drug effects; Antineoplastic Agents - therapeutic use; B-Lymphocytes - immunology; B7 Antigens - antagonists & inhibitors; B7 Antigens - immunology; Brake presses; Cancer; Cancer immunotherapy; Caspase; Caspase-8; CD137 antigen; CD223 antigen; CD40 antigen; CD40 Antigens - agonists; Cell activation; Cell death; Chemotherapy; Clinical development; Clinical trials; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Cytokines - immunology; Drug delivery; Drug development; Drug resistance; Drugs; Exhaustion; Gene amplification; Glucocorticoid-Induced TNFR-Related Protein - drug effects; Hematology, Oncology and Palliative Medicine; Hepatitis A Virus Cellular Receptor 2 - antagonists & inhibitors; Humans; Immune response; Immune system; Immunity, Cellular - physiology; Immuno-oncology; Immunotherapy; Immunotherapy - methods; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Inducible T-Cell Co-Stimulator Protein - agonists; Killer Cells, Natural - immunology; Lymphocyte Activation - immunology; Lymphocytes T; Major histocompatibility complex; Major Histocompatibility Complex - immunology; Medical research; Molecular biology; Molecules; Monoclonal antibodies; Mutation; Neoplasms - immunology; Neoplasms - therapy; Novel antibodies; Oncology; OX40 Ligand - agonists; Patients; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Receptors, KIR - antagonists & inhibitors; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Cytotoxic - immunology; Toxicity; Tumor Necrosis Factor Receptor Superfamily, Member 9 - agonists
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2017.01.001

Abstract 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 cl