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Stimulating the innate and adaptive immunity against cancer necessitates the tricking of a system evolved to fight microbial pathogens and directing its activity towards transformed self-tissue. Efficacious interventions to start and sustain the response will probably require a number of agents to tamper simultaneously or sequentially with several immune mechanisms. Although master switches controlling various functions may exist, the goal of a curative immune response will probably demand the combined actions of several therapeutic components. Synergy occurs when drugs interact in ways that enhance or magnify one or more effects or side effects. In cancer immunotherapy, two agents that have minor or no therapeutic effects as single agents can be powerful when combined. Mouse experimentation provides multiple examples of synergistic combinations. Elements to be combined include chiefly: tumor vaccines, adoptive T-cell therapies, cytokines, costimulatory molecules, molecular deactivation of immunosuppressive or tolerogenic pathways and immunostimulatory monoclonal antibodies. These novel therapies, even as single agents, are extremely complex products to be developed owing to the associated biomolecules, cell therapies or gene therapies. At present, drug-development programs are run individually for each immunotherapeutic agent and combinations are considered only at a later stage in clinical development, even in the absence of formal compulsory regulations to prevent clinical trials with combinations. As a result, instead of the search for maximal efficacy, ease of combination with standard treatments, intellectual property management, regulations and business-based decisions often guide the way. Even though the maximal effort must be made in order to prevent adverse effects in patients, it seems reasonable that combination pilot trials should be performed at an early stage, following safe completion of Phase I trials. These trials should be performed based on evidence for synergy in animal models and be simplified in terms of regulatory requirements. Such 'short-cut' combination immunotherapy trials can bring much needed efficacy earlier to the bedside.

Original publication




Journal article



Publication Date





845 - 853


Centro de Investigación Médica Aplicada y Clinica Universitaria. Universidad de Navarra, Avenida de Pio XII 55, 31008 Pamplona, Spain.


Animals, Humans, Mice, Antineoplastic Combined Chemotherapy Protocols, Cancer Vaccines, Antibodies, Monoclonal, Drugs, Investigational, Immunotherapy, Adoptive Transfer, Combined Modality Therapy, Drug Synergism, Clinical Trials as Topic, Drug Discovery