eprintid: 35845
rev_number: 14
eprint_status: archive
userid: 8664
dir: disk0/00/03/58/45
datestamp: 2024-12-20 10:46:24
lastmod: 2025-01-07 10:24:36
status_changed: 2024-12-20 10:46:24
type: doctoralThesis
metadata_visibility: show
creators_name: Chih, Yu-Chan
title: Development of MHC-dependent immunotherapy for gliomas
subjects: ddc-500
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
cterms_swd: Glioma
cterms_swd: Immunotherapy
abstract: Glioblastoma (GB) is the most common and aggressive brain tumor with limited effective treatments available. Despite significant advances in cancer immunotherapy, GB patients have not benefited substantially due to disease characteristics, including protection from the blood-brain barrier, an immunosuppressive tumor microenvironment, and a relatively low mutation burden. TCR-transgenic T (TCR-T) cell therapy, which has shown promising clinical results in treating solid tumors, presents a potential circumvention as it allows safe and ubiquitous targeting of GB-derived peptidome. Here, a GB-associated antigen (GAA), PTPRZ1, was well-characterized in brain tumors, exclusively expressed in cancer cells and abundantly presented on MHC class I (MHCI). Using patient material from the GAPVAC-101 vaccine therapy trial, a PTPRZ1-reactive TCR was retrieved and demonstrated to be potent in controlling GB in vitro and in vivo in an antigen-specific and HLA-restricted manner without evidence of off-target reactivity. Intriguingly, GB stem cells and distinct subsets of GB cells were preferentially targeted due to their association with PTPRZ1 expression. These results prompted a first-in-human TCR-T cell therapy phase I clinical trial against GB, INVENT4GB. To further expand the horizon of TCR-T cell therapy for GB, additional GAAs were shortlisted with their immunogenic epitopes predicted. For TCR discovery, their immunogenic peptides were employed to immunize the HLA-humanized mouse A2.DR1, resulting in corresponding immunogenicity. Antigen-reactive CD4+ T cells were isolated and expanded in vitro, and a reactive TCR was cloned and authenticated. Concurrently, antigen-reactive CD8+ T cells were isolated and expanded in vitro using an optimized expansion protocol, yet the truly reactive TCRs await validation. Furthermore, tumoral MHC class II (MHCII) expression has previously been linked to immunotherapy efficacy though its role remained poorly understood in GB. Through immunostaining and transcriptomic analysis, glioma MHCII expression was confirmed. Cell lines recapitulating MHCII-proficient and MHCII-deficient gliomas were established. In alignment with human data, MHCII+ gliomas in mice recruited more immune cells and promoted T cell exhaustion, but the association with poor prognosis observed in human patients could not be modeled. Further research is required to elucidate glioma MHCII role with validated immunotherapy models.
date: 2024
id_scheme: DOI
id_number: 10.11588/heidok.00035845
ppn_swb: 1913633756
own_urn: urn:nbn:de:bsz:16-heidok-358455
date_accepted: 2024-12-12
advisor: HASH(0x55b82b610378)
language: eng
bibsort: CHIHYUCHANDEVELOPMEN20241218
full_text_status: public
place_of_pub: Heidelberg
citation:   Chih, Yu-Chan  (2024) Development of MHC-dependent immunotherapy for gliomas.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/35845/1/YCC_PhD_dissertation_final.pdf