The promise, progress, and challenges of in situ immunization agents in cancer immunotherapy

In situ immunization (ISI) agents are an emerging and diverse class of locally acting cancer immunotherapeutic agents designed to promote innate immune activation in the early steps of the cancer immunity cycle to ultimately support development of a systemic tumor-specific immune response and protective immunologic memory. The aims of this review are to: (i) provide an introduction to ISI; (ii) summarize the history of ISI agents; (iii) expound upon the mechanism(s) and therapeutic objective(s) of ISI; (iv) compare the various approaches and therapeutic modalities developed and investigated to date; and (v) summarize clinical experiences in an effort to highlight the utility as well as the lessons and challenges of this promising approach. A prospective roadmap for future clinical development is provided that focuses on early and late-stage trial design considerations, the rationale and importance of investigating combination treatment, and the prospective use of ISI agents in the neoadjuvant setting.