Journal article
Production of an interleukin-10 blocking antibody by genetically engineered macrophages increases cancer cell death in human gastrointestinal tumor slice cultures
Cancer gene therapy, Vol.30(9), pp.1227-1233
09/01/2023
DOI: 10.1038/s41417-023-00632-z
PMID: 37296315
Abstract
Although it can promote effector T-cell function, the summative effect of interleukin-10 (IL-10) in the tumor microenvironment (TME) appears to be suppressive; therefore, blocking this critical regulatory cytokine has therapeutic potential to enhance antitumor immune function. As macrophages efficiently localize to the TME, we hypothesized that they could be used as a delivery vehicle for drugs designed to block this pathway. To test our hypothesis, we created and evaluated genetically engineered macrophages (GEMs) that produce an IL-10-blocking antibody (alpha IL-10). Healthy donor human peripheral blood mononuclear cells were differentiated and transduced with a novel lentivirus (LV) encoding BT-063, a humanized alpha IL-10 antibody. The efficacy of alpha IL-10 GEMs was assessed in human gastrointestinal tumor slice culture models developed from resected specimens of pancreatic ductal adenocarcinoma primary tumors and colorectal cancer liver metastases. LV transduction led to sustained production of BT-063 by alpha IL-10 GEMs for at least 21 days. Transduction did not alter GEM phenotype as evaluated by flow cytometry, but alpha IL-10 GEMs produced measurable quantities of BT-063 in the TME that was associated with an similar to 5-fold higher rate of tumor cell apoptosis than control.
Details
- Title: Subtitle
- Production of an interleukin-10 blocking antibody by genetically engineered macrophages increases cancer cell death in human gastrointestinal tumor slice cultures
- Creators
- Kevin P. Labadie - University of WashingtonShannon A. Kreuser - Seattle Children's HospitalKatherine J. Brempelis - Seattle Children's HospitalSara K. Daniel - University of WashingtonXiuyun Jiang - University of WashingtonKevin M. Sullivan - University of WashingtonAlan F. Utria - University of WashingtonHeidi L. Kenerson - University of WashingtonTeresa S. Kim - University of WashingtonCourtney A. Crane - Seattle Children's HospitalVenu G. Pillarisetty - Brotman Baty Institute
- Resource Type
- Journal article
- Publication Details
- Cancer gene therapy, Vol.30(9), pp.1227-1233
- DOI
- 10.1038/s41417-023-00632-z
- PMID
- 37296315
- NLM abbreviation
- Cancer Gene Ther
- ISSN
- 0929-1903
- eISSN
- 1476-5500
- Publisher
- Springer Nature
- Number of pages
- 7
- Grant note
- Brotman Baty Institute for Precision Medicine Washington Research Foundation R25NS079200 / National Institute of Neurological Disorders and Stroke, the National Institutes of Health CA150370P2 / US Army Medical Research Acquisition Activity (USAMRAA) Seattle Translational Tumor Research Merck Investigator Studies Program Stand Up to Cancer P30 CA015704 / UW/Fred Hutchinson Cancer Center Support Grant (CCSG) U54CA193461-03; R01CA195718-02 / National Cancer Institute, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 09/01/2023
- Academic Unit
- Surgery
- Record Identifier
- 9985015818602771
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