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Updated: Sep 2, 2025
In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
Target isoforms are an overlooked challenge and opportunity in chimeric antigen receptor cell therapy
Mike Bogetofte Barnkob1, Kristoffer Vitting-Seerup2, Lars Rønn Olsen2
1Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Department of Clinical Immunology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
Abstract:
The development of novel chimeric antigen receptor (CAR) cell therapies is rapidly growing, with 299 new agents being reported and 109 new clinical trials initiated so far this year. One critical lesson from approved CD19-specific CAR therapies is that target isoform switching has been shown to cause tumour relapse, but little is known about the isoforms of CAR targets in solid cancers. Here we assess the protein isoform landscape and identify both the challenges and opportunities protein isoform switching present as CAR therapy is applied to solid cancers.
Insights
Chimeric antigen receptor (CAR) therapies face challenges in solid tumors due to target protein isoform switching, which can lead to cancer relapse. Understanding these isoforms is crucial for developing effective CAR cell therapies for solid cancers.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) cell therapy development is rapidly advancing, with numerous new agents and clinical trials.
- CD19-specific CAR therapies have shown that target isoform switching can cause tumor relapse.
- Limited knowledge exists regarding CAR target isoforms in solid cancers.
Purpose of the Study:
- To assess the protein isoform landscape of CAR targets in solid cancers.
- To identify challenges and opportunities presented by protein isoform switching in solid tumor CAR therapy.
- To inform the development of more effective CAR cell therapies for solid tumors.
Main Methods:
- Bioinformatic analysis of protein isoform data.
- Comparative assessment of isoform expression in solid tumors versus hematological malignancies.
- Literature review on known CAR targets and their isoforms.
Main Results:
- Identification of diverse protein isoforms for key CAR targets in solid tumors.
- Characterization of specific isoforms that may evade CAR recognition.
- Highlighting potential alternative targets or modified CAR designs to overcome isoform switching.
Conclusions:
- Protein isoform switching represents a significant hurdle for CAR therapy in solid cancers.
- Understanding the specific isoform landscape is essential for designing robust and durable CAR treatments.
- Further research into isoform-specific targeting strategies is warranted for solid tumor immunotherapy.
