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

OncoImmunology

Stijn de Munter¹  Georges Leclercq¹  Glenn Goetgeluk¹  Laurenz de Cock¹  Tom Taghon¹  Bart Vandekerckhove¹  Sarah Bonte²  Joline Ingels²  Lore Billiet²  Tessa Kerre²  Melissa Pille²  Karin Weening²  Hanne Jansen² 

[1] Cancer Research Institute Ghent (CRIG);Ghent University;

关键词: acute myeloid leukemia (aml);    t cell immunotherapy;    common gamma chain cytokines;    hematopoietic stem cells;    op9-dl1;   

DOI  :  10.1080/2162402X.2021.1954800

来源: DOAJ

【 摘 要 】

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, TSCM) 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 TSCM-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.

【 授权许可】

Unknown