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Vincent Alcazer1, Christophe Delenda2, Laurent Poirot2
1INSERM U1052, Centre de Recherche en Cancérologie, 69008 Lyon, France; Hospices civils de Lyon, Service d'hématologie, Centre Hospitalier Lyon Sud, 69310 Pierre-Bénite, France.
Development Of Car T-Cells In Solid Tumors:
CHALLENGES AND PERSPECTIVES: While Chimeric Antigen Receptor (CAR) T-cells have shown outstanding results in some hematologic malignancies, studies in solid tumors are less encouraging with poor response rates. Several factors can account for this lack of efficiency in solid tumors: heterogeneous expression or absence of specific target antigen (and so higher risk of toxicity), immunosuppressive microenvironment, homing and tumoral trafficking issues or lack of CAR T-cell persistence. Different approaches can be considered to overcome these resistance mechanisms: bispecific CARs, use of logic gates, combination with immune checkpoint inhibitors, engineered CAR T-cells resistant to immunosuppressive molecules, addition of chemokines or enzymes, combination with oncolytic virus, intra-tumoral administration, selection of memory T cell subpopulations and development of armored CAR T-cells secreting cytokines such as IL-12, -15 or -18. Last generation optimized CAR T-cell design should thus improve therapeutic efficiency. CAR-T cells may represent in a near future a therapeutic breakthrough also in solid tumors, especially in cold tumors and/or tumors lacking MHC class I expression. Cet article fait partie du numéro supplément Les cellules CAR-T : une révolution thérapeutique ? réalisé avec le soutien institutionnel des partenaires Gilead : Kite et Celgene.
Insights
Chimeric Antigen Receptor (CAR) T-cell therapy shows promise for solid tumors, overcoming challenges like antigen heterogeneity and immunosuppression. Optimized CAR T-cell designs are key to improving treatment efficacy and expanding applications.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric Antigen Receptor (CAR) T-cells demonstrate significant efficacy in hematologic malignancies.
- Their application in solid tumors is limited by factors such as antigen heterogeneity, immunosuppressive tumor microenvironment, and poor T-cell persistence.
Purpose of the Study:
- To review the challenges and perspectives of CAR T-cell therapy in solid tumors.
- To explore strategies for enhancing CAR T-cell efficacy against solid tumors.
Main Methods:
- Review of current research on CAR T-cell therapy in solid tumors.
- Discussion of various approaches to overcome resistance mechanisms.
Main Results:
- Solid tumors present unique challenges including heterogeneous antigen expression, immunosuppressive microenvironments, and homing/trafficking issues.
- Several strategies are being investigated to improve CAR T-cell performance, including bispecific CARs, logic gates, combination therapies, and armored CAR T-cells.
Conclusions:
- Optimized CAR T-cell designs hold potential for therapeutic breakthroughs in solid tumors.
- CAR T-cell therapy may become a viable option for cold tumors and those lacking MHC class I expression.