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Early Trial Data Show Crispr Cancer Therapy Response

Crispr genome edits illustration

(NIH.gov)

13 May 2022. Initial results from a clinical trial show non-Hodgkin lymphoma patients receiving low doses of gene-edited T-cells achieve a clinical response, but with some adverse effects. Caribou Biosciences Inc. in Berkeley, California, reported the results of its experimental therapy code-named CB-010, which the company plans to present next month at a meeting of the European Hematology Association in Vienna, Austria.

Caribou Biosciences uses the gene-editing technology Crispr to create engineered immune-system cells as cancer therapies. The gene editing technology Crispr, short for clustered regularly interspaced short palindromic repeats, is derived from bacterial defense mechanisms using RNA to identify and target precise locations in DNA for editing. One of 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.

CB-010 is designed with Caribou Bio’s technology known as chRDNAs, pronounced “Chardonnays,” providing more precise DNA targeting than earlier forms of Crispr. The company says chRDNAs use more than RNA alone to find targeted genes, which makes possible more complex editing of T-cells and natural killer cells in the immune system. Caribou says for CB-010 it takes donated T-cells from healthy volunteers, then makes three types of edits in the cells’ genome, inserting chimeric antigen receptors or CARs that target genes coding for original T-cell receptors. Plus, the edits remove checkpoint proteins called PD-1 inhibiting immune responses to cancer, and target the CD19 protein, a characteristic indicator of B-cells found on the cell surface.

Four of five achieve complete response

The early-stage clinical trial is enrolling 50 patients with relapsed or stubborn, non-responsive cases of B-cell non-Hodgkin lymphoma, a cancer of lymph tissue in the immune system, a more common form of non-Hodgkin lymphoma in adults. Participants first are given chemotherapy to remove regulatory T-cells and similar immune cells that could compete with the treatments. The first trial participants are then given escalating doses of CB-010 to find the optimum dosage, and check for adverse effects. The study team is also assessing clinical responses to the treatments. Science & Enterprise reported on the start of the trial in July 2021.

By the 23 Feb. 2022 cut-off date, says Caribou Bio, five of the first six participants in the trial receiving a lower dose of engineered CAR T-cells in CB-010, completed the 28-day post-treatment evaluation period. All of these five individuals, says the company, experienced at least some clinical response to the treatments, with four participants reporting a complete response, indicating disappearance of cancer cells. Those complete responses continued for at least three months at the cut-off date, with one participant experiencing a complete response for six months following treatment.

The company says three of the six participants treated with CB-010 experienced problems from low red-, white, or platelet blood cell counts, or low levels of immunoglobulin antibodies that required medical attention. And one participant reported mild to moderate cytokine and immune effector cell release syndromes that required treatment, with that individual later among the complete clinical responses. No participants experienced graft versus host disease, immune system reactions that reject donated cells.

Caribou Bio says the safety and efficacy results so far support continuing the trial at a higher dose for patients.”CB-010 is the first allogeneic anti-CD19 CAR T-cell therapy in the clinic with a PD-1 knock-out,” says Rachel Haurwitz, Caribou’s president and CEO in a company statement, “a genome-editing strategy designed to limit premature CAR T-cell exhaustion, potentially leading to better tumor debulking and an improved therapeutic index through sustained anti-tumor activity.” Haurwitz adds that the results “represent important steps toward validating our chRDNA genome-editing platform as well as our plans for future development of CB-010 and our broader pipeline.”

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