The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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3. Non-viral precision T cell receptor replacement for personalized cell therapy
Foy, S., P., Jacoby, K., Bota D., A. et al. Nature. 615: 687–696. (2023).
doi: 10.1038/s41586-022-05531-1.
Summary of the findings
In theory, every patient with cancer carriers their own cure. T cells in the body can specifically recognize and kill individual cancer cells through engagement of the T cell receptor (TCR). This first in-human phase I clinical trial demonstrated the clinical feasibility of truly patient-specific adoptive TCR T cell therapies for the treatment of patients with solid cancers. In order to do this, three novel core technologies had to be developed: 1) capture of tumour-specific T cells from the blood of each patient, followed by TCR isolation and validation for the selection of up to three unique patient tumour-specific TCRs 2) a non-viral precision genome engineering technology for TCR gene replacement of the original TCR with the tumour-specific TCR using CRISPR technology, and 3) a clinical grade manufacturing process for the generation of a multi-TCR T cell product of a defined composition. Sixteen patients were safely treated with their own personalized cell therapy in a dose-escalation trial; 5 had stable disease and 11 had disease progression. Post-treatment analysis demonstrated that T cells both persisted and trafficked to the tumour. Together, these technologies and Phase I clinical trial demonstrate the feasibility of patient-specific adoptive TCR-T cell therapies.
A personalized TCR T cell therapy starts and ends with the patient’s own cells. A tumour biopsy and blood sample are used to predict cancer specific mutations and generate a personalized peptide-HLA library to then capture an individual cancer-specific T cell from a patient’s own blood. T cells are then non-virally precision genome engineered to the replace the endogenous TCR with the cancer-specific TCR and Up-to-three unique neoTCR-products are manufactured and infused back into the patient. Image created with Biorender.
Future impact
This phase I clinical trial demonstrates for the first time, that a truly personalized TCR T cell therapy for the treatment of patients with solid cancer is feasible and safe. It provides the groundwork and a path forward that could open a new era in cancer therapy. With further development and optimization of the described novel technologies for HLA-inclusive T cell capture followed by TCR isolation and validation plus non-viral precision engineering for the manufacture of a personalized autologous cell product, personalized adoptive cell therapy could become a more widespread option for patients with cancer.
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The Cancer Researcher is an online magazine for the cancer research community from the European Association for Cancer Research.
The EACR, a registered charity, is a global community for those working and studying in cancer research. Our mission is “The advancement of cancer research for the public benefit: from basic research to prevention, treatment and care.”
Summary of the findings
Summary of the findings
