Language
English
Publication Date
10-31-2023
Journal
International Journal of Molecular Sciences
DOI
10.3390/ijms242115806
PMID
37958791
PMCID
PMC10649234
PubMedCentral® Posted Date
10-31-2023
PubMedCentral® Full Text Version
Post-print
Abstract
The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors (CARs), and C7R-modified GD2.CAR T-cells are currently undergoing clinical trials. To determine if the C7R could also enhance the activity of T-cells recognizing tumors via their native T-cell receptors (TCRs), we evaluated its effects in Epstein–Barr virus (EBV)-specific T-cells (EBVSTs) that have produced clinical benefits in patients with EBV-associated malignancies. EBVSTs were generated by stimulation of peripheral blood T-cells with overlapping peptide libraries spanning the EBV lymphoma antigens, LMP1, LMP2, and EBNA 1, followed by retroviral vector transduction to express the C7R. The C7R increased STAT5 signaling in EBVSTs and enhanced their expansion over 30 days of culture in the presence or absence of exogenous cytokines. C7R-EBVSTs maintained EBV antigen specificity but were dependent on TCR stimulation for continued expansion. C7R-EBVSTs produced more rapid lymphoma control in a murine xenograft model than unmodified EBVSTs and persisted for longer. The findings have led to a clinical trial, evaluating C7R-EBVSTs for the treatment of refractory or relapsed EBV-positive lymphoma (NCT04664179).
Keywords
Humans, Animals, Mice, Herpesvirus 4, Human, Epstein-Barr Virus Infections, Interleukin-7, T-Lymphocytes, Lymphoma, Receptors, Antigen, T-Cell, Cytokines, Tumor Microenvironment
Published Open-Access
yes
Recommended Citation
Sharma, Sandhya; Sauer, Tim; Omer, Bilal A; et al., "Constitutive Interleukin-7 Cytokine Signaling Enhances the Persistence of Epstein-Barr Virus-Specific T-Cells" (2023). Faculty, Staff and Students Publications. 6343.
https://digitalcommons.library.tmc.edu/baylor_docs/6343