Melanoma reactive TCR-modified T cells generated without activation retain a less differentiated phenotype and mediate a superior in vivo response

Sci Rep. 2021 Jun 25;11(1):13327. doi: 10.1038/s41598-021-92808-6.

Abstract

Adoptive T cell therapy with T cell receptor (TCR)-modified T cells has shown promise in treating metastatic melanoma and other malignancies. However, studies are needed to improve the efficacy and durability of responses of TCR-modified T cells. Standard protocols for generating TCR-modified T cells involve activating T cells through CD3 stimulation to allow for the efficient transfer of tumor-reactive receptors with viral vectors. T cell activation results in terminal differentiation and shortening of telomeres, which are likely suboptimal for therapy. In these studies, we demonstrate efficient T cell transduction with the melanoma-reactive TIL1383I TCR through culturing with interleukin 7 (IL-7) in the absence of CD3 activation. The TIL1383I TCR-modified T cells generated following IL-7 culture were enriched with naïve (TN) and memory stem cell populations (TSCM) while maintaining longer telomere lengths. Furthermore, we demonstrated melanoma-reactivity of TIL1383I TCR-modified cells generated following IL-7 culture using in vitro assays and a superior response in an in vivo melanoma model. These results suggest that utilizing IL-7 to generate TCR-modified T cells in the absence of activation is a feasible strategy to improve adoptive T cell therapies for melanoma and other malignancies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • Cell Line
  • Cell- and Tissue-Based Therapy / methods
  • Female
  • HEK293 Cells
  • Humans
  • Immunologic Memory / immunology
  • Interleukin-7 / immunology
  • Lymphocyte Activation / immunology*
  • Male
  • Melanoma / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phenotype
  • Receptors, Antigen, T-Cell / immunology*
  • T-Lymphocytes / immunology*
  • Transduction, Genetic / methods

Substances

  • Interleukin-7
  • Receptors, Antigen, T-Cell