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.
Kyowa Kirin Pharmaceutical Development, Galashiels, United Kingdom; University of Munich, University Hospital of Grosshadern, Department of Haematology and Oncology, Germany. Electronic address: wolfram.dempke@kyowakirin.com.
Wolfram C M
WCM
Dempke
Medical School Hamburg (MSH), Hamburg, Germany.
Klaus
K
Fenchel
RWTH Aachen University, Medical Faculty, Institute of Immunology, Germany.
Peter
P
Uciechowski
Kyowa Kirin Pharmaceutical Development, Galashiels, United Kingdom.
Stephen P
SP
Dale
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D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D060887:B7 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C556692:ICOS protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D060889:Inducible T-Cell Co-Stimulator Protein; D053278:OX40 Ligand; D061026:Programmed Cell Death 1 Receptor; D054340:Receptors, KIR; C491405:TNFRSF18 protein, human; C505714:TNFRSF9 protein, human; C089251:TNFSF4 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C000588758:VSIR protein, human; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
Clinical development; Immuno-oncology; Molecular biology; Novel antibodies