One of the pioneers behind CAR-T cell therapy has reached a new milestone: successfully using engineered T cells created through CRISPR/Cas9 gene editing to treat cancers.
A team led by University of Pennsylvania physician-scientist Dr. Carl June published a paper in the journal Science on the use of a CRISPR/Cas9-edited T-cell receptor (TCR) cell therapy, the university announced Friday. The data, on the first three patients enrolled in a Phase I clinical trial, showed it is possible to successfully edit cells such that they persist and have a sustained ability to attack and kill tumors.
“Our data from the first three patients enrolled in this clinical trial demonstrate two important things that, to our knowledge, no one has every shown before,” June said in a statement. June is the director of UPenn’s Parker Institute for Cancer Immunotherapy and its Center for Cellular Immunotherapies, at the Abramson Cancer Center.
June led the team that originally developed the autologous CAR-T therapy that would later become the first CAR-T to win Food and Drug Administration approval, Novartis’ Kymriah (tisagenlecleucel). The therapy is approved for pediatric acute lymphoblastic leukemia and diffuse large B-cell lymphoma.
According to the paper, the TCR cells were engineered to attack NY-ESO-1, a protein present in certain cancers like multiple myeloma and some sarcomas. Of the three patients, all of whom were refractory to prior therapies, two had multiple myeloma and one had a sarcoma.
The results showed that none of the participants experienced cytokine release syndrome (CRS), a serious and potentially fatal immune system reaction associated with some cell therapies, particularly CAR-Ts. The best clinical responses were stable disease in two patients. The sarcoma patient had a mixed response, with a 50% decrease in a large abdominal mass that was sustained for four months, though other lesions progressed. All of the patients had progressed as of December 2019. One of the myeloma patients died from progressive disease, and the other two were receiving other therapies.
TCRs differ from CAR-Ts in that they can target proteins on the inside of cancer cells, whereas CAR-Ts target proteins expressed on cancer cells’ surfaces. The authors wrote that they opted to use TCR instead of a chimeric antigen receptor, or CAR, because TCRs tend to produce less CRS. Additionally, TCRs tend to be HLA-restricted, meaning that they can only be used in patients who fit a particular genetic profile, and that is the case with the ones from the UPenn study.
Other companies have sought to apply gene editing, including CRISPR/Cas9 and other methods, to cell therapy, particular to create allogeneic therapies that can use donor cells rather than autologous therapies that use patients’ own cells. Beam Therapeutics, which last week announced it had raised $180 million in its initial public offering, is using single-letter base editing to develop CAR-Ts, for example. Meanwhile, natural killer cell-based CAR-NK therapies may obviate the need to use gene editing altogether, given that NK cells are not specific to individual patients’ genomes.
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