Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity

• Published in: Nature immunology Vol. 25; no. 10; pp. 1820 - 1829
• Main Authors: Santollani, Luciano, Maiorino, Laura, Zhang, Yiming J., Palmeri, Joseph R., Stinson, Jordan A., Duhamel, Lauren R., Qureshi, Kashif, Suggs, Jack R., Porth, Owen T., Pinney, William, Msari, Riyam Al, Walsh, Agnes A., Wittrup, K. Dane, Irvine, Darrell J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2024; Nature Publishing Group
• Subjects: 631/250/2520; 631/250/580; 631/67/1059/2325; Animal models; Animals; Antitumor activity; Biomedical and Life Sciences; Biomedicine; CD45 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Line, Tumor; Cell surface; Cytokines; Cytokines - metabolism; Female; Humans; Immunity; Immunology; Immunotherapy; Immunotherapy - methods; Infectious Diseases; Interleukin 15; Interleukin-15 - metabolism; Internalization; Lesions; Leukocyte Common Antigens - metabolism; Lymph nodes; Lymphatic drainage; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Neoplasms - immunology; Neoplasms - therapy; Retention; Toxicity; Transcription activation; Tumors
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-024-01925-7

Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8 + T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy. Cytokine therapies have been used to treat cancer but are susceptible to adverse effects owing to the activation of systemic inflammatory pathways. Here the authors avoid this toxicity by developing CD45-targeted IL-12 and IL-15 immunocytokines that are effective in treating tumors in mice when dosed intratumorally.