Anti-PD1-IL18 immunoconjugate promotes effector T cell-mediated antitumor immunity.

Authors

Nicole Oelgarth, Kea Martin, Fabian Junker, Clara Serger, Caoimhe Herr, Mélanie Buchi, Lilian Gremlich, Irene Fusi, Jonas Fürst, Petra Herzig, Philipp Moosmann, Viola Heinzelmann-Schwarz, Kirsten D Mertz, Robert Rosenberg, Karin Schaeuble, Jean-Philippe Carralot, Thuy T Luu, Bertolt Kreft, Vijaya Pattabiraman, Alfred Zippelius

Published in

Journal for immunotherapy of cancer. Volume 14. Issue 7. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Immune checkpoint inhibitors have revolutionized cancer therapy, yet a substantial proportion of patients exhibit primary or acquired resistance. Immunocytokines offer a strategy to enhance antitumor immunity by delivering cytokine signals selectively to the tumor microenvironment. Here, we describe the immunoconjugate anti-programmed cell death protein 1 (PD-1)-interleukin (IL)-18 (aPD1-IL18_mut), designed to couple PD-1-blockade with localized IL-18-mediated immune activation.
aPD1-IL18_mut was generated by chemically conjugating the anti-human PD-1 antibody Lipustobart to an IL-18 variant engineered to evade IL-18 binding protein. Its mechanism of action was characterized using human PD-1 transgenic mouse models. To assess the translational relevance of these in vivo findings, complementary in vitro assays were conducted on human tumor samples, alongside analyses of publicly available single-cell RNA sequencing datasets.
In vitro, PD-1 engagement enhanced functional IL-18 activity, preserving interferon (IFN)-γ secretion even under IL-18BP pressure. In MC38 tumors, aPD1-IL18_mut induced robust CD8⁺ T cell-driven tumor control, accompanied by intratumoral accumulation of activated CD8⁺ T cells and a pronounced type 1-associated cytokine response. In anti-PD-1-resistant YUMM1.7 tumors, therapeutic efficacy instead relied predominantly on Th1-like CD4⁺ effector T cells, and aPD1-IL18_mut stimulation was associated with enhanced activation, proliferation, IFN-γ, and granzyme B expression in PD-1⁺IL-18Rɑ⁺ CD4⁺ T cells. In human cancer digest cultures, aPD1-IL18_mut elicited a dominant IL-18/IFN-γ-driven cytokine signature and enhanced tumor cell killing. Importantly, analyses of the immune infiltrate across multiple human solid tumor types identified analogous PD-1⁺IL-18Rɑ⁺ CD4⁺ Th1-like and CD8⁺ effector-like T-cell subsets with effector-associated and tumor-reactive transcriptional and protein signatures.
aPD1-IL18_mut activates T-cell populations with tumor-reactive features and promotes IFN-γ-driven inflammation across distinct tumor immune contexts. Its ability to activate CD8⁺ and CD4⁺ Th1-like effector cells, together with the presence of analogous subsets in multiple human cancers, provides mechanistic and translational support for PD-1-targeted IL-18 therapy.

PMID:
42448430
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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