Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity

  • bioRxiv. 2024 Jan 3:2024.01.03.573641. doi: 10.1101/2024.01.03.573641.
Luciano Santollani  1  2 ,  Yiming J Zhang  2  3 ,  Laura Maiorino  2  4 ,  Joseph R Palmeri  1  2 ,  Jordan A Stinson  2  3 ,  Lauren R Duhamel  2  3 ,  Kashif Qureshi  2 ,  Jack R Suggs  1  2 ,  Owen T Porth  2  3 ,  William Pinney 3rd  2  3 ,  Riyam Al Msari  2  3 ,  K Dane Wittrup  1  2  3 ,  Darrell J Irvine  2  3  5  4  6
Affiliations
  • 1. Department of Chemical Engineering, Massachusetts Institute of Technology; Cambridge, MA, USA.
  • 2. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; MA, USA.
  • 3. Department of Biological Engineering, Massachusetts Institute of Technology; Cambridge, MA, USA.
  • 4. Howard Hughes Medical Institute; Chevy Chase, MD, USA.
  • 5. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; Cambridge, MA, USA.
  • 6. Department of Materials Science and Engineering; Massachusetts Institute of Technology, Cambridge, MA, USA.
PMID: 38260254 DOI: 10.1101/2024.01.03.573641
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 (αCD45-Cyt) that, upon injection, decorated the surface of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. αCD45-Cyt therapy eradicated both directly treated Tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, αCD45-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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