IL-12 Release by Engineered T Cells Expressing Chimeric Antigen Receptors Can Effectively Muster an Antigen-Independent Macrophage Response on Tumor Cells That Have Shut Down Tumor Antigen Expression

2011/07/08 by Markus Chmielewski, Caroline Kopecky, Andreas A. Hombach +2 · 554 citations
Immunology and Microbiology · Medicine · #Antigen #Antigen-presenting cell #Biology #CAR-T cell therapy research #Cancer #Cancer cell #Cancer immunotherapy #Cancer research #Chimeric antigen receptor #Cytotoxic T cell #Immune Cell Function and Interaction #Immune system #Immunology #Immunotherapy #In vitro #Inflammation #Macrophage #Proinflammatory cytokine #T cell #T-cell and B-cell Immunology

paper · pdf · doi:10.1158/0008-5472.can-11-0103

published in Cancer Research 71(17), 5697-5706 (American Association for Cancer Research)

openalex publication_date 2011/07/08 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30

Abstract

During malignant progression cancer cells tend to lose cell surface expression of MHC and other immune antigens, making them invisible to cytotoxic T cells and therefore inaccessible to tumor antigen-directed immunotherapy. Moreover, cancer cell variants that have lost antigen expression frequently contribute to deadly tumor relapses that occur following treatments that had been initially effective. In an effort to destroy antigen-loss cancer cells in tumors, we created a strategy that combines a chimeric antigen receptor (CAR)-redirected T-cell attack with an engineered local release of the cytokine interleukin 12 (IL-12), which recruits and reinforces macrophage function. Cytotoxic T cells were engineered to release inducible IL-12 upon CAR engagement in the tumor lesion, resulting in destruction of antigen-loss cancer cells that would normally escape. Importantly, elimination of the antigen-loss cancer cells was accompanied by an accumulation of activated macrophages that was critical to the antitumor response, because removing the macrophages abolished the response and restoring them reengaged it. Neutralizing TNF-α also abrogated the elimination of antigen-loss cancer cells, implying this proinflammatory factor in the process. Taken together, our results show how IL-12 supplementation by CAR T cells can target otherwise inaccessible tumor lesions, in a manner associated with reduced systemic toxicity, by recruiting and activating innate immune cells for a proinflammatory response.

Citations

• Sustained Antigen-Specific Antitumor Recall Response Mediated by Gene-Modified CD4+ T Helper-1 and CD8+ T Cells

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