TY  - JOUR
AU  - Poelchen, Juliane
AU  - Pardo, Sandra
AU  - Novak, Daniel
AU  - Sun, Qian
AU  - Steinfass, Tamara
AU  - Vierthaler, Marlene
AU  - Cicek Sener, Özge
AU  - Granados Blanco, Karol
AU  - Wang, Yiman
AU  - Nicolay, Jan Peter
AU  - Guermonprez, Pierre
AU  - Harbottle, Richard
AU  - Umansky, Viktor
AU  - Utikal, Jochen
TI  - Generation and functional analysis of melanoma antigen-specific CD8+ T cells derived from S/MAR vector-transfected human induced pluripotent stem cells.
JO  - International journal of cancer
VL  - 157
IS  - 9
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2025-01214
SP  - 1876-1887
PY  - 2025
N1  - #EA:A370#LA:A370# / 2025 Nov 1;157(9):1876-1887
AB  - Melanoma accounts for the majority of all skin cancer-related deaths with rising incidence rates. Adoptive cell therapies (ACT) with tumor antigen-specific CD8+ T cells derived from human-induced pluripotent stem cells (hiPSCs) might offer a promising treatment strategy for advanced malignant melanoma patients. In this study, we investigated two strategies for the generation of CD8+ T cells from hiPSCs expressing a T cell receptor (TCR) specific for the melanoma-associated antigen recognized by T cells (MART-1) or a chimeric antigen receptor (CAR) specific for the melanoma-associated chondroitin sulfate proteoglycan (MCSP), respectively. While the long-term co-culture of bioengineered OP9 stromal cells with CD34+ hematopoietic stem/progenitor cells (HSPCs) facilitated the generation of CD4 + CD8+ double-positive (DP) T cells, we encountered difficulties in obtaining high percentages of CD8+ single-positive (SP) T cells using this method. However, the replacement of the OP9 cells with a T cell differentiation kit enabled the generation of CD8+ SP T cells after 47 days. Despite a low expression of the T cell marker CD3 on the surface of the generated CD8+ SP T cells, we detected intracellular IFN-γ and surface CD107a expression upon stimulation. Moreover, the generated CD8+ SP T cells exhibited cytotoxic effects when co-cultured with melanoma cell lines. The use of scaffold/matrix attachment region (S/MAR) DNA vectors ensured persistent expression of the TCR or the CAR during differentiation of T cells. Hence, these findings demonstrate the potential as well as the challenges associated with using S/MAR DNA vector-transfected hiPSCs for the generation of melanoma antigen-specific CD8+ T cells.
KW  - T cells (Other)
KW  - adoptive cell therapy (Other)
KW  - hiPSCs. S/MAR vector (Other)
KW  - melanoma (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40504044
DO  - DOI:10.1002/ijc.35524
UR  - https://inrepo02.dkfz.de/record/302016
ER  -