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Cancer Patients in Early Trial Receive Personalized, CRISPR-Edited T-Cell Therapy

NEW YORK — More than a dozen cancer patients with solid tumors have received a personalized treatment in which CRISPR was used to edit their T cells to better attack their tumor.

In a Phase I cell dose-escalation clinical trial, researchers from the University of California, Los Angeles, and trial sponsor PACT Pharma isolated T cells from 16 patients — the majority of whom had colorectal cancer — and used CRISPR to swap their endogenous T-cell receptor genes for versions more specific to their cancer, with the goal of getting those immune cells to better target their tumor.

The approach combines the ability of CRISPR to insert or remove certain genes with that of immunotherapy to boost the immune system's own functions against cancer cells. In a feasibility study reported in Nature on Thursday, the researchers reported that the altered T cells do traffic to patients' tumors. "This is a leap forward in developing a personalized treatment for cancer, where the isolation of immune receptors that specifically recognize mutations in the patient's own cancer are used to treat the cancer," co-corresponding author Antoni Ribas, a professor of medicine and surgery at UCLA, said in a statement.

The research team first collected tumor biopsy samples and peripheral blood mononuclear cells from patients to isolate and clone TCRs that recognized specific neoantigens from patients' own tumors. In all, they identified 175 unique, cancer-specific TCRs across the 16 patients and selected up to three TCRs per patient for their treatment. Using CRISPR, the researchers then knocked out the endogenous TCRs from T cells they isolated from patients and knocked in the tumor-specific ones.

All 16 patients received these patient- and cancer-specific neoTCR T cells. They had a range of solid tumors, including colorectal cancer, breast cancer, ovarian cancer, lung cancer, and melanoma, and had received a median five lines of prior therapy. Following a course of conditioning chemotherapy, the patients were infused with up to three gene-edited TCR cell products — a total of 37 immune receptors were infused into the 16 patients.

All patients in the study experienced pancytopenia — a decrease in red and white blood cells, as well as platelets — which the researchers attributed to the lymphodepletion conditioning regimen they underwent prior to the infusion. There were two additional toxicity reports that could be attributed to the neoTCR-transgenic T cell therapy: One patient experienced a grade 1 cytokine release and another grade 3 encephalitis. Both patients recovered, indicating that the treatment may be relatively well tolerated.

When the researchers analyzed patient tumor biopsies following treatment, they found that the gene-edited immune cells represented at least 2 percent and up to 20 percent of the immune cells present, indicating that the infused edited cells reached the tumors.

Overall, 11 patients had disease progression and five patients had stable disease 28 days after treatment. Target lesions in two of those patients decreased in size.

"We are thrilled to share the findings from this first-in-human clinical trial which met its primary endpoints, demonstrating both the tolerability and feasibility of TCR discovery and manufacturing of a multi-TCR product using complete non-viral gene editing and safety of the infusion of a three TCR product," Stefanie Mandl, CSO of PACT Pharma, said in a statement.

Astero Klampatsa from the Institute of Cancer Research in London, who was not involved in the study, added in a statement that the "study suggests there is future potential for T-cell therapy in solid cancers, and its safety profile is certainly encouraging."

Klampatsa noted, though, that the treatment has limitations, including time, labor, and expense. "It would be interesting to see whether this therapy will be applied in a bigger trial, where efficacy, but also the experimental protocols, can be further tested," she added.