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Updated: Jul 18, 2025
A Nonviral Approach to Generate Transient Chimeric Antigen Receptor T Cells Using mRNA for Cancer Immunotherapy
Published on: February 21, 2025
Current approaches to develop "off-the-shelf" chimeric antigen receptor (CAR)-T cells for cancer treatment: a
Cristina Aparicio1,2, Carlos Acebal1,2, Margarita González-Vallinas3,4
1Unit of Excellence Institute of Biomedicine and Molecular Genetics of Valladolid (IBGM), Universidad de Valladolid (UVa)-CSIC, Valladolid, Spain.
Abstract:
Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising advances in cancer treatment. It is based on genetically modified T cells to express a CAR, which enables the recognition of the specific tumour antigen of interest. To date, CAR-T cell therapies approved for commercialisation are designed to treat haematological malignancies, showing impressive clinical efficacy in patients with relapsed or refractory advanced-stage tumours. However, since they all use the patient´s own T cells as starting material (i.e. autologous use), they have important limitations, including manufacturing delays, high production costs, difficulties in standardising the preparation process, and production failures due to patient T cell dysfunction. Therefore, many efforts are currently being devoted to contribute to the development of safe and effective therapies for allogeneic use, which should be designed to overcome the most important risks they entail: immune rejection and graft-versus-host disease (GvHD). This systematic review brings together the wide range of different approaches that have been studied to achieve the production of allogeneic CAR-T cell therapies and discuss the advantages and disadvantages of every strategy. The methods were classified in two major categories: those involving extra genetic modifications, in addition to CAR integration, and those relying on the selection of alternative cell sources/subpopulations for allogeneic CAR-T cell production (i.e. γδ T cells, induced pluripotent stem cells (iPSCs), umbilical cord blood T cells, memory T cells subpopulations, virus-specific T cells and cytokine-induced killer cells). We have observed that, although genetic modification of T cells is the most widely used approach, new approaches combining both methods have emerged. However, more preclinical and clinical research is needed to determine the most appropriate strategy to bring this promising antitumour therapy to the clinical setting.
Insights
Allogeneic CAR-T cell therapy offers a promising alternative to autologous treatments for blood cancers. This review explores strategies to overcome challenges like immune rejection and graft-versus-host disease for broader patient access.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR)-T cell therapy is a groundbreaking cancer treatment.
- Current approved CAR-T therapies are autologous, facing limitations like manufacturing delays and high costs.
- Allogeneic CAR-T cell therapies aim to overcome these limitations for wider accessibility.
Purpose of the Study:
- To systematically review and compare various strategies for developing allogeneic CAR-T cell therapies.
- To discuss the advantages and disadvantages of each approach for clinical application.
- To identify future research directions for allogeneic CAR-T cell therapy.
Main Methods:
- Systematic review of existing literature on allogeneic CAR-T cell production.
- Classification of methods into genetic modification and alternative cell source selection.
- Analysis of strategies including gene editing, use of γδ T cells, induced pluripotent stem cells (iPSCs), and others.
Main Results:
- Multiple strategies exist for allogeneic CAR-T cell production, including genetic modifications and alternative cell sources.
- Combinations of genetic modification and alternative cell sources are emerging.
- Each strategy presents unique advantages and disadvantages regarding efficacy, safety, and scalability.
Conclusions:
- Allogeneic CAR-T cell therapy holds significant potential to improve cancer treatment accessibility.
- Further preclinical and clinical research is essential to optimize strategies and ensure safety.
- Determining the most suitable allogeneic CAR-T cell approach requires continued investigation.
