CD28 and 41BB costimulation enhances the effector function of CD19-specific engager T cells

Mireya Paulina Velasquez, Arpad Szoor, Abishek Vaidya, Aarohi Thakkar, Phuong Nguyen, Meng Fen Wu, Hao Liu, Stephen Gottschalk

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

T cells expressing CD19-specific chimeric antigen receptors (CARs) with endodomains that encode a signaling domain derived from CD3ζ and CD28 or 41BB have potent antitumor activity in early-phase clinical studies for B-cell malignancies. Besides CD19-specific CARs, other approaches are actively being pursued to redirect T cells to CD19, including recombinant bispecific T-cell engager (BiTE) proteins or T cells genetically modified to express BiTEs [engager (ENG) T cells]. As BiTEs provide no costimulation, we investigated here if provision of costimulation through CD28 and 41BB enhances the effector function of CD19-ENG T cells. CD19-ENG T cells expressing CD80 and 41BBL on their cell surface (CD19-ENG.41BBL/CD80 T cells) were generated by retroviral transduction. CD19-ENG.41BBL/CD80 T cells retained their antigen specificity and had superior effector function compared with both unmodified T cells and CD19-ENG T cells expressing either CD80, 41BBL, or no costimulatory molecule, as judged by cytokine (IFNγ and IL2) production, T-cell proliferation, and their ability to sequentially kill target cells. In vivo, CD19-ENG.41BBL/CD80 T cells had superior antileukemia activity in the BV173 xenograft model, resulting in a survival advantage in comparison to CD19-ENG T cells. Thus, provision of costimulation is critical for the effector function of ENG T cells.

Original languageEnglish (US)
Pages (from-to)860-870
Number of pages11
JournalCancer Immunology Research
Volume5
Issue number10
DOIs
StatePublished - Oct 2017
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Velasquez, M. P., Szoor, A., Vaidya, A., Thakkar, A., Nguyen, P., Wu, M. F., Liu, H., & Gottschalk, S. (2017). CD28 and 41BB costimulation enhances the effector function of CD19-specific engager T cells. Cancer Immunology Research, 5(10), 860-870. https://doi.org/10.1158/2326-6066.CIR-17-0171