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Murine Pre-B cell ALL induces T cell dysfunction not fully reversed by introduction of a chimeric antigen receptor

Haiying Qin, Kazusa Ishii, Sang Nguyen, Paul P. Su, Chad R. Burk, Bong-Hyun Kim, Brynn B. Duncan, Samikasha Tarun, Nirali N. Shah, M. Eric Kohler and Terry J. Fry

Key points

  • Pre-B cell ALL induces T cell dysfunction in vivo mediated, in part, by a non-T cell receptor linked mechanism.

  • Prior exposure of T cells to pre-B cell ALL in vivo impairs subsequent functionality of chimeric antigen receptor expressing T cells.

Abstract

Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CART) has demonstrated dramatic success in relapsed/refractory pre-B cell ALL but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T cell function but this has not been well studied in ALL and in the context of CAR expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors including PD1, Tim3 and LAG3 and were dysfunctional following adoptive transfer in a model of TCR-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B ALL induced inhibitory receptor expression, at least in part, via a T cell receptor (TCR) independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.

  • Submitted December 4, 2017.
  • Accepted August 25, 2018.