Production of an interleukin-10 blocking antibody by genetically engineered macrophages increases cancer cell death in human gastrointestinal tumor slice cultures.

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 (αIL-10). Healthy donor human peripheral blood mononuclear cells were differentiated and transduced with a novel lentivirus (LV) encoding BT-063, a humanized αIL-10 antibody. The efficacy of αIL-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 αIL-10 GEMs for at least 21 days. Transduction did not alter GEM phenotype as evaluated by flow cytometry, but αIL-10 GEMs produced measurable quantities of BT-063 in the TME that was associated with an ~5-fold higher rate of tumor cell apoptosis than control.

• Authors: Kevin P Labadie, Shannon A Kreuser, Katherine J Brempelis, Sara K Daniel, Xiuyun Jiang, Kevin M Sullivan, Alan F Utria, Heidi L Kenerson, Teresa S Kim, Courtney A Crane, Venu G Pillarisetty
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 30 Issue 9 Pg. 1227-1233 (09 2023) ISSN: 1476-5500 [Electronic] England
• PMID: 37296315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Interleukin-10

Topics

• Humans
• Apoptosis (genetics)
• Gastrointestinal Neoplasms (genetics, therapy)
• Interleukin-10 (antagonists & inhibitors, immunology)
• Leukocytes, Mononuclear
• Macrophages (pathology)
• Pancreatic Neoplasms (therapy, drug therapy)
• Tumor Microenvironment (genetics)