Cell surface-targeted immunocytokines program systemic anti-tumor immunity

Systemically-administered cytokines are potent immunotherapy agents but exhibit severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention following local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest abscopal effects at distal untreated tumors. Here we report a localized cytokine therapy that safely elicits potent systemic anti-tumor immunity by engineered targeting of the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines (αCD45-Cyt) exhibit significantly diminished internalization rates relative to their wild-type counterparts; this prolonged surface retention sustains downstream pSTAT induction and enables both cis and trans signaling between lymphocytes. Intratumoral αCD45-Cyt administration led to decoration of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. Therapeutically, a single dose of αCD45-IL12 followed by a single dose of αCD45-IL15 eradicated both treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, prolonged exposure to αCD45-Cyt in the tumor and TDLN reprogrammed CD8+ T cells in the TDLN to exhibit an anti-viral transcriptional signature and expanded tumor-specific effector T cells in both the tumor and TDLN. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.