Evolving synergistic combinations of targeted immunotherapies to combat cancer

• Published in: Nature reviews. Cancer Vol. 15; no. 8; pp. 457 - 472
• Main Authors: Melero, Ignacio, Berman, David M., Aznar, M. Angela, Korman, Alan J., Gracia, José Luis Pérez, Haanen, John
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2015; Nature Publishing Group
• Subjects: 631/250/251; 631/67/1059/2325; 692/700/565/1436/1437; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Biomarkers, Tumor - metabolism; Biomedicine; Cancer; Cancer immunotherapy; Cancer Research; Care and treatment; Cell death; Clinical trials; Clinical Trials as Topic; Combined Modality Therapy; CTLA-4 protein; Cytotoxicity; Drug synergism; Drug targeting; Humans; Immunotherapy; Innovations; Lymphocytes T; Melanoma; Methods; Molecular Targeted Therapy; Neoplasms - immunology; Neoplasms - therapy; Oncology; Oncology, Experimental; Patients; PD-1 protein; Pharmacology, Experimental; review-article; Tumor Microenvironment - immunology
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc3973

Key Points Clinical trials have validated immuno-oncology as a new pillar of anticancer therapy. Combinations could involve two (or more) sequential or simultaneous immunotherapies, and/or immunotherapies in combination with conventional cancer therapies. The programmed cell death protein 1 (PD1)–PD1 ligand 1 (PDL1) axis seems to be the most promising immuno-oncology target, and its blockade is likely to become the main foundation for combination strategies in the foreseeable future. The paradigm of immuno-oncology combinations is to block PD1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) simultaneously; this blockade is synergistic and shows clinical benefit in patients with melanoma but has an increased frequency of immune-mediated, albeit clinically manageable, toxic effects. Even if designing rational combinations that provide optimal benefit to patients with cancer is a challenging process, there are a number of different combination immuno-oncology therapies currently in development. Immunotherapy has undoubtedly become an effective treatment for many cancers, but how can we make the most of this approach? In this Review, Melero et al . discuss how immune-targeted therapies can be synergistically combined to provide maximal benefit to patients. Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients.