Language
English
Publication Date
4-1-2025
Journal
The Journal for ImmunoTherapy of Cancer
DOI
10.1136/jitc-2024-010685
PMID
40169286
PMCID
PMC11962782
PubMedCentral® Posted Date
4-1-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Curative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses.
Methods: In this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (NCT05538624) to identify Tpex recruitment capabilities at tolerable cytokine doses.
Results: We show IL-12 cytokine factories can effectively treat a broad spectrum of cancer types. Single-cell RNA sequencing data suggests that the antitumor efficacy seen in our studies was due to retinal pigmented epithelial cells-mIL12 treatment inducing differentiation of Tpex cells within the tumor microenvironment. When administered in combination with checkpoint therapy, IL-12 cytokine factory treatment generated systemic abscopal immunity, preventing subcutaneous tumor outgrowth in 8/9 mice with colorectal cancer and lung metastasis in mice with melanoma. Furthermore, this platform was well tolerated in a non-human primate without signs of toxicity.
Conclusions: Our new immunotherapy approach provides a robust strategy for inducing Tpex recruitment and systemic immunity against a range of solid peritoneal malignancies, many incurable with current immunotherapy strategies. Notably, these features were achieved using IL-12, and by leveraging our technology, we avoided the toxicities that have prevented the translation of IL-12 to the clinic. Our findings provide a strong rationale for the clinical development of IL-12 cytokine factories.
Keywords
Animals, Humans, Mice, Immunotherapy, Interleukin-12, Neoplasm Metastasis, Neoplasms, Cell Line, Tumor, Cytokine, Abscopal, Colorectal Cancer, Gastric Cancer, Immune modulatory
Published Open-Access
yes
Recommended Citation
Nash, Amanda; DeBonis, Jonathon; Murungi, Danna; et al., "Il-12-Producing Cytokine Factories Induce Precursor Exhausted T Cells and Elimination of Primary and Metastatic Tumors" (2025). Faculty and Staff Publications. 4877.
https://digitalcommons.library.tmc.edu/baylor_docs/4877
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons