HIV immune evasin Nef enhances allogeneic CAR T cell potency Journal Article
| Authors: | Perica, K.; Kotchetkov, I. S.; Mansilla-Soto, J.; Ehrich, F.; Herrera, K.; Shi, Y.; Dobrin, A.; Gönen, M.; Sadelain, M. |
| Article Title: | HIV immune evasin Nef enhances allogeneic CAR T cell potency |
| Abstract: | Autologous chimeric antigen receptor (CAR) T cells are a genetically engineered therapy that is highly effective against B cell malignancies and multiple myeloma1. However, the length and cost of personalized manufacturing limits access and leaves patients vulnerable to disease progression. Allogeneic cell therapies have the potential to increase patient access and improve treatment outcomes but are limited by immune rejection2,3. To devise a strategy to protect allogeneic CAR T cells from host immune cells, we turned to lymphotropic viruses that have evolved integrated mechanisms for immune escape of virus-infected lymphocytes4. We find that viral evasins that partially reduce human leukocyte antigen class I expression can shelter CAR T cells from mismatched CD8+ T cells without triggering ‘missing-self’ rejection by natural killer cells. However, this protection alone is insufficient to sustain effective allogeneic CAR T cell therapy. HIV-1 Nef uniquely also acts through the serine/threonine kinase Pak2 to abate activation-induced cell death and promote survival of CAR T cells in vivo. Thus, virus-like immune escape can harness several mechanisms that act in concert to enhance the therapeutic efficacy of allogeneic CAR T cells. © The Author(s), under exclusive licence to Springer Nature Limited 2025. |
| Keywords: | signal transduction; survival; controlled study; human cell; nonhuman; flow cytometry; polymerase chain reaction; t lymphocyte; animal cell; mouse; cell viability; immune system; gene expression; animal experiment; animal model; cytotoxicity; in vitro study; enzyme linked immunosorbent assay; immune response; antigen; genetic transfection; western blotting; cell isolation; human immunodeficiency virus; cell activation; disease exacerbation; cd19 antigen; rna extraction; cell component; human; female; article; luciferase assay; crispr-cas9 system; nih 3t3 cell line; nalm-6 cell line |
| Journal Title: | Nature |
| Volume: | 640 |
| Issue: | 8059 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-30 |
| Start Page: | 793 |
| End Page: | 801 |
| Language: | English |
| DOI: | 10.1038/s41586-025-08657-0 |
| PUBMED: | 39884316 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Michel Sadelain -- Source: Scopus |
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