Recherche
A new preclinical model to improve TCR-based cancer immunotherapy
Researchers from the Department of Oncology UNIL-CHUV and collaborators have developed a preclinical model that enables testing human T-cell receptor (TCR) therapies in mice with a fully competent immune system.
Published in Journal for ImmunoTherapy of Cancer (JITC), this innovation* promises to accelerate the development of combination therapies that harness the immune system to fight solid tumors.
Adoptive T-cell therapies (ACT), particularly T cells engineered to express tumor-specific T-cell receptors (TCRs), hold great promise in cancer treatment. Recent successes, such as the FDA approval of the first TCR-based gene therapy for solid tumors, highlight their clinical potential. However, evaluating these therapies preclinically in immune-compromised mouse models fails to replicate the full complexity of the human immune system.
To address this gap, the group of Dr. Melita Irving and post-doctoral scientist Dr. Aikaterini Semilietof, jointly supported with Prof. Vincent Zoete, and Prof. Olivier Michielin, at the Department of Oncology UNIL-CHUV, the Swiss Institute of Bioinformatics (SIB), and the University Hospitals of Geneva (HUG), have developed an innovative chimeric syngeneic tumor model. Their work combines human TCR-engineered mouse T cells with immune-competent transgenic mice expressing human HLA-A2, engrafted with tumors that have been engineered to present a target peptide in complex with HLA-A2.
In this proof-of-concept study, the team evaluated the performance of T cells expressing TCRs of varying affinities against NY-ESO-1 that they had previously developed by structure-based computational design. Results showed that the affinity-optimized TCR not only improved tumor control but also reprogrammed the immune microenvironment, enhancing the presence and activity of other immune cells within the tumors.
This novel model overcomes significant limitations of previous preclinical systems by incorporating the endogenous immune response, which can either support or hinder ACT efficacy. “We faced many engineering challenges in this project and are delighted to now be able to share our know-how with other labs also dedicated to advancing more effective T-cell therapies to the clinic.” says Dr. Irving, corresponding author of this study. Such tools will enable researchers to design better combination therapies that optimize T-cell function and exploit the patient’s own immune system for sustained tumor control.
This study was made possible with support from the Ludwig Institute for Cancer Research, the Swiss Cancer League, the ISREC Foundation, and the Swiss National Science Foundation.
* Preclinical model for evaluating human TCRs against chimeric syngeneic tumors
About:
Melita Irving is Privat-Docent at the Faculty of Biology and Medicine and the head of the T cell engineering group – Department of Oncology UNIL-CHUV and part of the Ludwig Institute for Cancer Research, Lausanne Branch.
Vincent Zoete is Associate Professor at the Faculty of Biology and Medicine and the head of the Computer-aided molecular engineering group – Department of Oncology UNIL-CHUV and part of the Ludwig Institute for Cancer Research, Lausanne Branch.
Aikaterini Semilietof was a post-doctoral scientist working in the lab of Dr. Irving and also supported by Profs. Vincent Zoete and Olivier Michielin. She is currently a post-doctoral scientist at UCSF.
