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Last week, PACT Pharma shared results from the first clinical trial using CRISPR to direct patients’ immune cells to treat solid tumours. The findings, which were published in an unedited manuscript in Nature, provide early proof-of-concept that patient immune cells can be reprogrammed to attack their own cancer. The results were als 
Pierre-Luc Jellimann 's curator insight,
December 1, 2022 3:01 AM
Nouvelle article montrant l'efficaicté de CRISPR dans le traitement des tumeurs solides (first clinical trial using CRISPR to direct patients’ immune cells to treat solid tumours)
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BigField GEG Tech's insight:
In this study, the scientists highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition.
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BigField GEG Tech's insight:
Present adoptive immunotherapy strategies to recognize tumor antigens are based on the genetic engineering of T-cells. In this study, the authors use megaTAL and CRISPR/Cas9 to disrupt T-cell receptor expression. They optimized the conditions for the delivery and assessed off target cleavage to give translatable manufacturing process to produce safe cellular substrates for next generation immunotherapies.
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BigField GEG Tech's insight:
In this work, the authors assembled 12 transcription activator-like effector nucleases (TALENs) and five guide RNAs (gRNAs) for CRISPR system to knock out endogenous TCR expression. Using nuclease-expressing plasmid DNA, they achieved up to 19.9% and 12.2% knockout of TCR expression in primary T cells with CRISPR/Cas9 and TALENs, respectively. In contrast, delivery of TALEN mRNA by electroporation resulted in high viability and TCR knockout efficiencies of up to 78.8% for the TCR α chain and 81.2% for the β chain on day 6 after electroporation.
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BigField GEG Tech's insight:
Here, the auhtors reviewed the recent gene editing tools, such as TALEN and CRIPSR, which provide a platform to delete endogenous TCR and HLA genes, which removes allo-reactivity and decreases immunogenicity of third party T cells. This represents an important step towards generic off-the-shelf T cell products that may be used in the future for the treatment of large numbers of patients.
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In most cases, the number of naturally occurring cancer-targeting T cells will be far too low to trigger an immune response capable of eradicating a patient's tumor(s). PACT Pharma is a privately held biopharmaceutical company developing personalized, neo-antigen-specific T-cell receptor (TCR)-T therapies to treat a range of solid tumors. Patient T cells are isolated and CRISPR-modified by electroporation with Cas9 protein, guide RNAs to knock out endogenous TCR genes (TCRα ( TRAC) and TCRβ ( TRBC)) and an HR template plasmid encoding the transgenic neoTCR. The results of a phase 1 clinical trial that were published in Nature. The researchers report that CRISPR-modified T cells were preferentially directed to the tumor and could be recovered from post-infusion biopsies in all patients for whom biopsies were available. They also note that CRISPR-edited T cells frequently accounted for the top 2-20% of immune cells in the tumor, and a reduction in tumor size was observed in some lesions in a single lung cancer patient.