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Scientists report positive safety and durability results from the first U.S. test of CRISPR gene editing in human patients with advanced cancer. The trial (ClinicalTrials.gov identifier: NCT03399448) results are published in the journal Science.1





T cell therapies and cancer









The genetically engineered TCRs can mispair, whereby the alpha and beta chains of the genetically engineered TCRs bind with those of the endogenous (the body's own) TCRs.



This reduces the expression of the genetically engineered TCR and can also generate TCRs that are "self-reactive". Furthermore, T cell exhaustion can occur which stops optimal control of tumors.









How can CRISPR improve T cell therapy?





In mice, the transfer of T cells

that were targeted against a specific cancer antigen known as New York esophageal squamous cell carcinoma 1 (or NY-ESO-1), in addition to a monoclonal antibody that targeted PD-1, enhanced antitumor efficacy

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CRISPR for cancer – what the world’s been waiting for?

However, the safety of applying CRISPR-Cas9 gene editing in human cells for therapeutic purposes is still in the early stages of research.



Stadtmauer and colleagues designed a first-in-human Phase I human clinical trial to test both the safety and feasibility of CRISPR-Cas9 genome editing for synthetic biology cancer immunotherapy.



The trial included three participants, two females and one male. When asked about the choice of sample, Regina Young, Director of Research Operations at the Center for Cellular Immunotherapies and one of the study authors told Technology Networks: "Two myeloma patients and one sarcoma patient were treated. The CRISPR-edited T cell product used in this trial targets tumors expressing NY-ESO-1 and requires the presence of an antigen, HLA A2. Patients were screened for study eligibility."



Stadtmauer adds: "This was just a small sample of patients to determine safety and feasibility of this novel approach. The average age of a patients with myeloma is 69 years. Sarcoma is younger. A larger sample is required to assess the clinical effectiveness of an approach like this."



In the trial, T cells were removed from the patients' blood and edited using CRISPR to delete a select set of genes. Young says: "Three genes were removed using CRISPR-Cas9 editing: the endogenous TCR chains, TCRα (TRAC) and TCRβ (TRBC), to limit TCR mispairing and improve the expression of the cancer-specific TCR transgene, and PD-1 (PDCD1), to limit T cell exhaustion."



The T cells were then engineered by lentiviral transduction to express HLA A2-restricted TCR-specific for the SLMMWITQC peptide in NY-ESO-1. The resulting T cell was named “NYCE” (NY-ESO-1 transduced CRISPR 3X edited cells).





"NYCE" results from the pilot study





"We have shown proof of principal"



He concludes, "The gene editing field is rapidly advancing. Our trial used cutting edge techniques at the time they were developed. We have shown proof of principle. We are very confident that with even more technology advances the manufacturing and effectiveness of the genetically modified T cells will become easier and applicable for a greater population of patients in need."



Edward A. Stadtmauer, MD, Perelman Center for Advanced Medicine, and Regina Young, Director of Research Operations at the Center for Cellular Immunotherapies, were speaking with Molly Campbell, Science Writer, Technology Networks..



References:

1. Stadtmauer et al. (2020). CRISPR-engineered T cells in patients with refractory cancer. Science. https://science.sciencemag.org/lookup/doi/10.1126/science.aba7365.

2. Liu et al. (2017). CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res. DOI: 10.1038/cr.2016.142.

3. Moon et al. (2016). Blockade of programmed death 1 augments the ability of human T cells engineered to target NY-ESO-1 to control tumor growth after adoptive transfer. Clin. Cancer Res. 22, 436–447 doi:10.1158/1078-0432.