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.

doi:10.1101/2024.01.03.573641

bioRxiv · 10.1101/2024.01.03.573641

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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Abstract

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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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.. 2024-01-03. Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity. https://doi.org/10.1101/2024.01.03.573641

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