Cancer Immunotherapy: Factors Important for the Evaluation of Safety in Nonclinical Studies.

The development of novel therapies that can harnass the immune system to eradicate cancer is an area of intensive research. Several new biopharmaceuticals that target the immune system rather than the tumor itself have recently been approved and fundamentally transformed treatment of many cancer diseases. This success has intensified the search for new targets and modalities that could be developed as even more effective therapeutic agents either as monotherapy or in combination. While great benefits of novel immunotherapies in oncology are evident, the safety of these therapies has to also be addressed as their desired pharmacology, immune activation, can lead to "exaggerated" effects and toxicity. This review is focused on the unique challenges of the nonclinical safety assessment of monoclonal antibodies that target immune checkpoint inhibitors and costimulatory molecules. This class of molecules represents several approved drugs and many more drug candidates in clinical development, for which significant experience has been gained. Their development illustrates challenges regarding the predictivity of the animal models for assessing safety and setting starting doses for first-in-human trials as well as the translatability of nonclinical in vitro and in vivo data to the human findings. Based on learnings from the experience to date, factors to consider and novel approaches to explore are discussed to help address the unique safety issues of immuno-oncology drug development.