Santollani et al. focused on improving the safety and efficacy of cytokine therapy by locally delivering engineered cytokines that would be retained on cells of the tumor, without systemic exposure. CD45 was abundantly expressed on immune cells and not internalized, so they designed anti-CD45-conjugated IL-12 and IL-15 immunocytokines (injected sequentially as αCD45-Cyt) and showed in multiple syngeneic mouse models that intratumoral αCD45-Cyt therapy eradicated injected tumors and untreated distal tumors. Mechanistically, αCD45-Cyt resulted in prolonged STAT5 signaling, producing potent tumor-reactive CD8+ T cells in the TME and TDLN, with a viral signature.
Contributed by Katherine Turner
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.