From the Journals

CRISPR-engineered T cells may be safe for cancer, but do they work?



There were no major adverse reactions to CRISPR-engineered T cells in three patients with advanced cancer enrolled in a first-in-human trial, according to a report in Science.

Dr. Joseph Fraietta, University of Pennsylvania

The results of no harm support this “promising” area of cancer immunotherapy, according to study investigator Edward A. Stadtmauer, MD, of the University of Pennsylvania in Philadelphia and colleagues.

However, there was no evidence of benefit in this trial. One patient transfused with CRISPR-engineered T cells has since died, and the other two have moved on to other treatments.

“The big question that remains unanswered by this study is whether gene-edited, engineered T cells are effective against advanced cancer,” Jennifer Hamilton, PhD, and Jennifer Doudna, PhD, both of the University of California, Berkeley, wrote in an accompanying editorial.

The study enrolled six patients with refractory cancer, and three of them received CRISPR-engineered T cells. Two patients had multiple myeloma, and one had metastatic sarcoma.

Dr. Stadtmauer and colleagues drew blood from the patients, isolated the T cells, and used CRISPR-Cas9 to modify the cells. The T cells were transfected with Cas9 protein complexed with single guide RNAs against TRAC and TRBC (genes encoding the T-cell receptor chains TCR-alpha and TCR-beta) as well as PDCD1 (a gene encoding programmed cell death protein 1). The T cells were then transduced with a lentiviral vector to express a transgenic NY-ESO-1 cancer-specific T-cell receptor.

The investigators expanded the cell lines and infused them back into the patients after administering lymphodepleting chemotherapy. The sarcoma patient initially had a 50% decrease in a large abdominal mass, but all three patients ultimately progressed.

The editorialists noted that gene disruption efficiencies in this study were “modest,” ranging from 15% to 45%, but the investigators used a protocol from 2016, when the study was given the go-ahead by the National Institutes of Health and the Food and Drug Administration. With current protocols, gene disruption efficiencies can exceed 90%, which means patients might do better in subsequent trials.

There was no more than mild toxicity in this trial, and most adverse events were attributed to the lymphodepleting chemotherapy.

There was concern about potential rejection of infused cells because of preexisting immune responses to Cas9, but it doesn’t seem “to be a barrier to the application of this promising technology,” the investigators said.

They noted that “the stable engraftment of our engineered T cells is remarkably different from previously reported trials ... where the half-life of the cells in blood was [about] 1 week. Biopsy specimens of bone marrow in the myeloma patients and tumor in the sarcoma patient demonstrated trafficking of the engineered T cells to the tumor in all three patients” beyond that point. The decay half-life of the transduced cells was 20.3 days, 121.8 days, and 293.5 days in these patients.

The editorialists said the details in the report are a model for other researchers to follow, but “as more gene-based therapies are demonstrated to be safe and effective, the barrier to clinical translation will become cell manufacturing and administration.”

This work was funded by the National Institutes of Health and others. Dr. Stadtmauer didn’t report any disclosures, but other investigators disclosed patent applications and commercialization efforts. Dr. Doudna disclosed that she is a cofounder or adviser for several companies developing gene-editing therapeutics.

SOURCE: Stadtmauer EA et al. Science. 2020 Feb 6. doi: 10.1126/science.aba7365.

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