ASH: CRISPR-edited CAR-T cells show enhanced activation against leukemia in mice

Novartis’ CAR-T cancer therapy Kymriah, which was originally developed at the University of Pennsylvania, can induce long-term remissions in some forms of leukemia and lymphoma, but many patients either relapse or don’t respond at all. Now, Penn researchers are proposing a new method for boosting the response rate to these personalized treatments.

The researchers used gene editing system CRISPR-Cas9 to eliminate the gene CD5 from CAR-T cells. CD5 makes a protein that can inhibit the activation of the cancer-killing cells. The edited CAR-Ts improved tumor shrinkage and survival in mouse models of leukemia, the team reported at the virtual annual meeting of the American Society of Hematology (ASH).

The Penn team engineered the CAR-T cells to seek out CD5 on malignant cells and kill them. But CD5 is also expressed on normal T cells, so to avoid killing those cells—and to stimulate CAR-T action that might otherwise be stifled by the presence of the protein—they removed CD5 from the CAR-Ts.

In a mouse model of T-cell leukemia, the approach cured more than 50% of the animals, the researchers reported. It worked even better in models of CD19+ B-cell leukemia.

In that case, the researchers knocked out CD5 in CTL019 CAR-T cells with CRISPR. They observed long-term complete remissions in the majority of the mice, they said.

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How might anti-CD5 CAR-T cells improve on the current generation of cell therapy in blood cancer? The Penn researchers studied genomic records from 8,000 patient biopsies to answer that question. They found a correlation between levels of CD5 and outcomes.

“Basically, in most cancer types, the less CD5 expressed in T cells, the better the outcome,” said study presenter Marco Ruella, M.D., an assistant professor of medicine at Penn's Perelman School of Medicine and scientific director of the lymphoma program, in a statement. “The level of CD5 in your T cells matters.”

This is one of many efforts underway to improve upon T-cell therapies in cancer. Several teams are focusing on the phenomenon known as T-cell “exhaustion,” in which the cells lose their potency over time. Last year, for example, a Penn team discovered that a protein called TOX alters the evolution of exhaustion in T cells. They suggested that therapies targeting the protein could be used to reverse that process.

Several combination strategies are being tested to combat T-cell exhaustion, but their anti-CD5 approach could offer an opportunity to intervene earlier—at the point of CAR-T activation, noted CAR-T pioneer and co-author of the current study, Carl June, M.D., professor and director of the Abramson Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy.

“Looking at the long term, this could represent a more universal strategy to enhance the anti-tumor effects of CAR T cells,” June said in the statement.

The Penn team is planning further studies of the anti-CD5 CAR-T cells with the aim of potentially starting a phase 1 clinical trial next year, they said.