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Trial Underway for Crispr Lymphoma Therapy

Crispr-Cas9

Crispr editing with Cas9 enzyme (Broad Institute, NIH)

12 July 2021. A clinical trial enrolled its first participant testing the safety of a treatment for lymphoma, a type of cancer, using the gene-editing technique Crispr. The early-stage study is assessing the therapy candidate code-named CB-010 developed by Caribou Biosciences Inc. in Berkeley, California among patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

Non-Hodgkin lymphoma is a cancer of lymph tissue that forms part of the body’s immune system. There are different types of non-Hodgkin lymphoma reflecting different types of white blood cells. Most adults with the disorder have either diffuse large B-cell lymphoma, which is usually aggressive, or follicular lymphoma, a slower growing cancer. Participants in the trial are patients with B-cell non-Hodgkin lymphoma that relapsed or have not responded to earlier treatments.

Caribou Biosciences develops engineered immune-system cells as cancer therapies, modified with the gene editing technology Crispr, short for clustered regularly interspaced short palindromic repeats. Crispr is a genome-editing process based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. Among the company’s founders is Jennifer Doudna, professor of chemistry and biology at University of California in Berkeley, a co-recipient of the 2020 Nobel Prize in chemistry and scientific adviser to the company.

Made from healthy donor-derived T-cells

Caribou Biosciences is advancing Crispr to resolve one of its early drawbacks, a lack of editing precision. Caribou developed more precise RNA-DNA editing guides known as chRDNAs, pronounced “Chardonnays,” that provide more precise targeting than guides relying only on RNA, and enable more complex edits to T-cells and natural killer cells in the immune system. In this case, CB-010 is made from donated healthy T-cells, with three edits to insert chimeric antigen receptors, or CARs, targeting genes in T-cells that code for original T-cell receptors. CB-010 edits also remove PD-1 checkpoint proteins inhibiting immune responses to cancer, and target the CD19 protein, a characteristic indicator of B-cells found on the cell surface.

“We believe that improving cell persistence is the key to unlocking the full potential of these therapies,” says Caribou Biosciences CEO Rachel Haurwitz in a company statement, “Using our technologies, we edit the genome of healthy donor-derived T-cells to enable highly specific and efficient insertion or deletion of genes at multiple sites. This allows us to create sophisticated allogeneic cell therapies with enhanced characteristics to potentially improve their effectiveness and durability of anti-tumor activity compared to other allogeneic cell therapies.” Haurwitz adds, “With CB-010, we are evaluating the potential persistence-enhancing effects of removing the PD-1 protein from the surface of these CD19-targeted CAR T-cells.”

The clinical trial is enrolling 50 patients with B-cell non-Hodgkin lymphoma. Participants first undergo chemotherapy to deplete regulatory T-cells and other immune system competitors, before receiving CB-010, to reduce the risk of an adverse immune response. The first few participants are receiving CB-010 at three varying doses to find a safe level for the remaining participants. The study team is looking primarily for signs of adverse effects, and objective response rate indicating therapeutic effects from the treatments. There is no separate control or comparison group.

As reported by Science & Enterprise in February, drug maker AbbVie is licensing two new CAR T-cell therapies from Caribou Biosciences, but did not reveal disease targets for those therapies. CB-010 was well along in its development at the time of the license agreement, and Caribou does not indicate any involvement of AbbVie in this clinical trial.

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