eprintid: 36449
rev_number: 23
eprint_status: archive
userid: 8945
dir: disk0/00/03/64/49
datestamp: 2025-09-04 06:48:32
lastmod: 2025-09-04 06:49:07
status_changed: 2025-09-04 06:48:32
type: doctoralThesis
metadata_visibility: show
creators_name: Yao, Hao
title: Reshape of CAR-T cells by overexpression of TCF-1
subjects: ddc-570
subjects: ddc-610
divisions: i-911600
adv_faculty: af-05
abstract: Despite the remarkable success of CAR-T cell therapy in leukemia and lymphoma patients, lack of CAR-T cell persistence remains a significant clinical problem. In particular, CAR-T cells often exhibit a deficiency in TCF-1 expression, rendering cells susceptible to TCF-1-associated pathways and consequently to short survival in the host. Therefore, it is intriguing to modulate TCF-1 expression in CAR-T cells to address the challenge of CAR-T cell persistence and further improve therapeutic outcomes.
In this study, third generation CAR vectors were used, and a double transduction system was established. The effect of TCF-1 overexpression in CAR-T cells was comprehensively explored regarding various aspects. Given the phenotype and functionality of CAR-T cells after transduction, two different CAR models (CD19.CAR vector and CD33.CAR vector) were settled in the study to generalize the effect of overexpression of TCF-1. We found that (1) the overexpression of TCF-1 can enrich the naïve and stem cell-like CAR-T cells exhibiting a better killing efficacy; (2) the cytokine profile of CAR-T cells were switched from proinflammatory or killing related to inactive through overexpression of TCF-1; (3) the apoptotic status of CAR- T cells could be modulated by TCF-1 overexpression, thus resulting in a better long- term functionality in terms of repetitive tumor killing and reduced multiple inhibitory receptors.
In summary, overexpression of TCF-1 in CAR-T cells could reduce apoptosis, occurrence of CRS and improve their persistence, resulting in enhanced antitumor efficacy of CAR-T cells. Thus, overexpression of TCF-1 might improve CAR-T cell persistence in vivo and enhance the effect of CAR-T cell therapy in patients with relapsed/refractory hematologic malignancies.
date: 2025
id_scheme: DOI
id_number: 10.11588/heidok.00036449
own_urn: urn:nbn:de:bsz:16-heidok-364494
date_accepted: 2025-07-23
advisor: HASH(0x5638d5df6f50)
language: eng
bibsort: YAOHAORESHAPEOFC20250430
full_text_status: public
place_of_pub: Heidelberg
citation:   Yao, Hao  (2025) Reshape of CAR-T cells by overexpression of TCF-1.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/36449/1/Yao_Hao_1992_12_28_Reshape%20of%20CAR_T%20cells%20by%20overexpression%20of%20TCF_1.pdf