Clinical testing of cell-based NKX019 in lupus nephritis to begin

Dose-escalation study will assess safety, activity of NK therapy in 12 patients

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by Steve Bryson PhD |

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The U.S. Food and Drug Administration (FDA) has approved Nkarta’s request to launch a clinical trial in the U.S. to test its experimental therapy NKX019 in people with lupus nephritis, a lupus complication marked by kidney inflammation and damage.

The multi-center, dose-escalation study will assess the safety and clinical activity of the off-the-shelf natural killer (NK) cell therapy in up to 12 patients with hard-to-treat lupus nephritis. The first participant is expected to be enrolled in the first half of 2024.

“We believe that NKX019, as an NK cell-based approach, has the potential to distinguish itself in the growing field of cell therapy for autoimmune diseases through improved access and tolerability,” David R. Shook, MD, Nkarta’s chief medical officer, said in a company press release. “Patients with severe autoimmune diseases such as lupus nephritis need safe and novel therapies.”

In lupus, abnormal immune B-cells produce self-reactive antibodies that target various tissues, including the skin, joints, brain, heart, lungs, and kidneys. Lupus nephritis is among the disease’s most severe manifestations, with up to 30% of patients progressing to kidney failure.

“Patients with lupus nephritis have limited treatment options,” said Roberto Caricchio, MD, professor of medicine and chief of the division of rheumatology in the department of medicine at the University of Massachusetts Chan Medical School. “The potential of cell therapy to reset the immune system and provide long-term, drug-free remissions for patients with severe autoimmune disease may represent the biggest medical breakthrough in the last 50 years of [this field].”

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Benefit of NK cells in lupus nephritis

The first generation of cell therapies to use immune cells focused on T-cells, a type of immune cell with cancer-fighting abilities. In most CAR T-cell therapies, a patient’s own T-cells are collected and modified to have a chimeric antigen receptor, or CAR, that’s designed to target a specific molecule.

The engineered T-cells are then infused back into the patient after a chemotherapy regimen to eliminate disease-causing immune cells before treatment. Called lymphodepletion, the process is associated with significant side effects.

Using NK cells, a type of immune cell less likely to trigger unwanted immune reactions, for CAR-based therapy may be a safer approach. Unlike T-cells, NK cells can be collected from one person and used in many patients without the risk of being recognized as foreign by the host immune system and triggering immune responses against it.

NKX019 is a CAR NK cell therapy that targets B-cells. It involves collecting immune NK cells from healthy donor blood and modifying them with a CAR designed to target CD19, a protein on the surface of B-cells.

To sustain therapeutic activity, the CAR NK cells have been altered to have a modified version of an immune signal protein (cytokine) called interleukin-15 on their surface. NKX019 is then frozen to be used on demand or off the shelf.

“Off-the-shelf availability reduces patient burden and eliminates the need for costly infrastructure and treatment delays required for [self-collected] cell therapies,” Shook said. “Our proprietary engineering may also improve safety through a reduced need for lymphodepletion. NKX019 is active immediately and is self-sustaining, without the need for large cytokine surges from preparative chemotherapy.”

In the upcoming trial, people with treatment-resistant lupus nephritis will undergo lymphodepletion with an agent with an established safety profile in lupus, followed by three doses of NKX019 (either 1 or 1.5 billion cells) separated by one week each.

“We will continue to work closely with leading investigators to bring the promise of cell therapy to patients in need to explore this potentially transformative therapeutic approach,” Shook said.

NKX019 is also being tested as a treatment for non-Hodgkin lymphoma, a type of B-cell cancer.