Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity
Santollani, L.; Zhang, Y. J.; Maiorino, L.; Palmeri, J. R.; Stinson, J. A.; Duhamel, L. R.; Qureshi, K.; Suggs, J. R.; Porth, O. T.; Pinney, W.; Al Msari, R.; Wittrup, K. D.; Irvine, D. J.
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Cytokine therapies are potent immunotherapy agents but exhibit severe dose-limiting toxicities. One strategy to overcome this involves engineering cytokines for intratumoral retention following local delivery. Here, we develop a localized cytokine therapy that elicits profound anti-tumor immunity by engineered targeting to the ubiquitous leukocyte receptor CD45. We designed CD45-targeted immunocytokines (CD45-Cyt) that, upon injection, decorated the surface of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. CD45-Cyt therapy eradicated both directly treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, CD45-Cyt triggered prolonged pSTAT signaling and reprogrammed tumor-specific CD8+ T cells in the TDLN to exhibit an anti-viral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
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