Immune checkpoint blockade therapies have demonstrated promising therapeutic effects; however, clinical outcomes are variable, with only a subgroup of cancer patients achieving durable complete responses. New therapeutic strategies, including local administration of immunomodulatory antibodies, have been considered as better routes for improving the overall efficacy of antibody-based therapy. In this issue of Clinical Cancer Research, Dai and colleagues (1] report that locally delivering combinations of immunomodulatory antibodies completely eradicates larger tumors in three murine tumor models. In the same issue, Mangsbo and colleagues (2) report that local injection of CD40 agonistic antibody to activate dendritic cells (DC) significantly suppresses tumor growth. Both preclinical observations suggest that a local route to deliver immunomodulatory antibodies with different mechanisms of action could be a better way to initiate, enhance, and maintain a strong local antitumor T-cell response. Both reports also demonstrate that intratumoral injection of immunomodulatory antibodies not only elicits rejection of local tumors but also results in systemic protective immunity against distant tumors or a rechallenge with the same tumors. The search for an optimal route of delivery of cancer immu-notherapy agents has been a research focus since Coley's first clinical attempt of injecting mixed bacterial toxin into primary tumor tissues. At that time, intratumoral injection was considered by Coley to be crucial to a patient's survival (3). Since then, local delivery of immunotherapy agents, such as vaccines and adjuvants, has been the main route of immunotherapy administration for decades. However, in the 1980s, the use of IL2 in patients with melanoma and renal tumors changed the landscape of cancer therapy. As researchers realized that a strong systemic antitumor immune response could eventually not only reject local tumors but also prevent tumor metastasis, intravenous injection of immunomodulatory agents remained a major route of cancer immunotherapy until now. However, some limitations of systemic delivery have been identified. For example, it is unknown to what extent systemically delivered therapeutic agents eventually accumulate at the tumor sites.
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