Transgenic CD8αβ co-receptor rescues endogenous TCR function in TCR-transgenic virus-specific T cells

Gagan Bajwa, Inès Lanz, Mara Cardenas, Malcolm K. Brenner, Caroline Arber

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Background Genetically engineered virus-specific T cells (VSTs) are a platform for adoptive cell therapy after allogeneic hematopoietic stem cell transplantation. However, redirection to a tumor-associated antigen by the introduction of a transgenic T-cell receptor (TCR) reduces anti-viral activity, thereby impeding the possibility of preventing or treating two distinct complications - malignant relapse and viral infection - with a single cell therapy product. Availability of CD8αβ co-receptor molecules can significantly impact class I restricted T-cell activation, and thus, we interrogated whether transgenic CD8αβ improves anti-viral activity mediated by native VSTs with or without a co-expressed transgenic TCR (TCR8). Methods Our existing clinical VST manufacturing platform was adapted and validated to engineer TCR+ or TCR8+ VSTs targeting cytomegalovirus and Epstein-Barr virus. Simultaneous anti-viral and anti-tumor function of engineered VSTs was assessed in vitro and in vivo. We used pentamer staining, interferon (IFN)-γenzyme-linked immunospot (ELISpot), intracellular cytokine staining (ICS), cytotoxicity assays, co-cultures, and cytokine secretion assays for the in vitro characterization. The in vivo anti-tumor function was assessed in a leukemia xenograft mouse model. Results Both transgenic CD8αβ alone and TCR8 had significant impact on the anti-viral function of engineered VSTs, and TCR8+ VSTs had comparable anti-viral activity as non-engineered VSTs as determined by IFN-γELISpot, ICS and cytotoxicity assays. TCR8-engineered VSTs had improved anti-tumor function and greater effector cytokine production in vitro, as well as enhanced anti-tumor function against leukemia xenografts in mice. Conclusion Incorporation of transgenic CD8αβ into vectors for TCR-targetable antigens preserves anti-viral activity of TCR transgenic VSTs while simultaneously supporting tumor-directed activity mediated by a transgenic TCR. Our approach may provide clinical benefit in preventing and treating viral infections and malignant relapse post-transplant.

Original languageEnglish (US)
Article numbere001487
JournalJournal for immunotherapy of cancer
Volume8
Issue number2
DOIs
StatePublished - Nov 3 2020

Keywords

  • adoptive
  • antigen
  • cell engineering
  • immunotherapy
  • receptors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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