Priorities for local immunotherapy research and drug development

Local immunotherapy comprises broad classes of therapeutics that aim to trigger a robust "in situ" immune response that can ultimately generate systemic antitumor immunity. These agents are appealing as resistance to standard immune checkpoint inhibitors has been linked to a lack of baseline immune activity or immune suppressive elements in the tumor microenvironment. By administering agents directly to the tumor microenvironment, local immune therapies can both stimulate immune response and attempt to "reprogram" or subvert the effects of immune suppressive cell populations. Proof of concept for the benefit of local immune therapy has been demonstrated by several Food and Drug Administration-approved therapies.A "Summit on Intralesional Immunotherapy" was held in September 2024, which comprised lectures and discussion from an international panel of experts on local immune therapy. In this consensus paper, we will discuss unique considerations for local immunotherapy development across the continuum from pre-clinical and early-stage investigation through registration intent clinical trials.Early phase trials offer an opportunity to gain understanding of the biologic activity of candidate therapies and determine optimal dosing schedules. For local immunotherapies, it is most informative to measure the direct effect of the therapy in the tumor microenvironment at both injected and non-injected tumor sites. Carefully planned pharmacodynamic endpoints using on-treatment biopsies and novel imaging strategies to track immune cell activity will maximize the insights from early phase trials. For promising local therapies, selecting the proper patient population and treatment setting are critical. In order to intervene before the tumor microenvironment has reached a fixed immune suppressive state, local immunotherapies may best be suited as part of neoadjuvant or frontline metastatic therapy regimens. We also highlight several specific classes of local immunotherapy under investigation including oncolytic viruses, radiation, messenger RNA, Toll-like receptor agonists, stimulator of interferon gene agonists, CD40 agonists and cytokines.Novel local therapies currently being investigated are poised to expand the field and show promising activity in generating systemic antitumor immunity. Thoughtful trial design in both early stage as well as registration intent settings will accelerate the advancement of this field.