4.7 Article

In vitro OP9-DL1 co-culture and subsequent maturation in the presence of IL-21 generates tumor antigen-specific T cells with a favorable less-differentiated phenotype and enhanced functionality

Journal

ONCOIMMUNOLOGY
Volume 10, Issue 1, Pages -

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2021.1954800

Keywords

acute myeloid leukemia (AML); T cell immunotherapy; common gamma chain cytokines; hematopoietic stem cells; OP9-DL1

Funding

  1. Research Foundation - Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, FWO) [27958 2016-2021]
  2. Stichting tegen Kanker [2014-166 c/2014/230]
  3. Research Foundation - Flanders (FWO)
  4. Special Research Fund (BOF) of Ghent University

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The study demonstrates that adding IL-21 during in vitro T cell culture can generate tumor-specific T cells with a less-differentiated phenotype, potentially enhancing their anti-tumor effects.
T cell receptor (TCR)-redirected T cells target intracellular antigens such as Wilms' tumor 1 (WT1), a tumor-associated antigen overexpressed in several malignancies, including acute myeloid leukemia (AML). For both chimeric antigen receptor (CAR)- and TCR-redirected T cells, several clinical studies indicate that T cell subsets with a less-differentiated phenotype (e.g. stem cell memory T cells, T-SCM) survive longer and mediate superior anti-tumor effects in vivo as opposed to more terminally differentiated T cells. Cytokines added during in vitro and ex vivo culture of T cells play an important role in driving the phenotype of T cells for adoptive transfer. Using the OP9-DL1 co-culture system, we have shown previously that we are able to generate in vitro, starting from clinically relevant stem cell sources, T cells with a single tumor antigen (TA)-specific TCR. This method circumvents possible TCR chain mispairing and unwanted toxicities that might occur when introducing a TA-specific TCR in peripheral blood lymphocytes. We now show that we are able to optimize our in vitro culture protocol, by adding IL-21 during maturation, resulting in generation of TA-specific T cells with a less-differentiated phenotype and enhanced in vitro anti-tumor effects. We believe the favorable T-SCM-like phenotype of these in vitro generated T cells preludes superior in vivo persistence and anti-tumor efficacy. Therefore, these TA-specific T cells could be of use as a valuable new form of patient-tailored T cell immunotherapy for malignancies for which finding a suitable CAR-T target antigen is challenging, such as AML.

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