Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

Abstract

Significance Patients with compromised T-cell function are at risk for opportunistic fungal infections. We have developed a novel approach to restore immunity by using a fungal pattern-recognition receptor Dectin-1 to redirect T-cell specificity to carbohydrate antigen in the fungal cell wall. We did so by genetically modifying T cells using the nonviral Sleeping Beauty gene-transfer system to enforce expression of a chimeric antigen receptor (CAR) that recapitulates the specificity of Dectin-1 (D-CAR). The D-CAR + T cells can be electroporated and propagated on artificial activating and propagating cells in a manner suitable for human application, enabling this immunology to be translated into immunotherapy. This approach has implications for genetically modifying T cells to express CARs with specificity for carbohydrate and thus broadening their application in the investigational treatment of pathogens and malignancies.

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…Adoptive transfer of anti- Aspergillus T cells has been shown to improve survival following hematopoietic transplantation [170]. In addition, re-engineered T cells expressing a chimeric antigen receptor that recapitulates the specificity of dectin-1 were effective against A. fumigatus in an experimental model [171]. Furthermore, innate cell therapy has steadily gathered pace as a promising alternative approach.…”

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

“…Although most CAR targets have been limited to natural cell-surface antigens in the form of proteins, it is possible to target post-translational modifications of proteins 26,27 and glycosphingolipids with CARs. 28 T cells can also be genetically modified with natural or engineered T cell receptors (TCRs), which recognize peptides presented in the context of major histocompatibility complex (MHC).…”

Supportive (Maintenance) Therapy in Hematopoietic Stem Cell Transplantation: Main Principles and New Perspectives

“…Еще более новым подходом является приме-нение Т-клеток с искусственно сконструированным химерным антигенным рецептором (сhimeric antigen receptor, ХАР) с противогрибковым эффектом [31][32][33][34]. Некоторые исследователи создают мультиспецифиче-ские ХАР: к рецептору CD19 и к антигену Dectin-1 для контроля аспергиллеза [34].…”