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December 11, 2023/Cancer/Research

Cell Therapy Offers New Hope for Refractory/Relapsed AML

Investigational chimeric antigen receptor natural killer cell therapy NKX101 associated with promising early response in patients with relapsed/refractory acute myeloid leukemia

23-CNR-4419109-CQD-Hero-650×450 Dr Sauter

A novel investigational natural killer (NK) cell therapy produced early positive results in patients with acute myeloid leukemia (AML) for whom other treatments had failed.


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The treatment, NKX101 (Nkarta), is an allogeneic cell therapy comprising NK cells derived from healthy donors and engineered to enhance killing of malignant cells. In a cohort of a phase 1 study of six patients with relapsed or refractory AML, three achieved a complete response and another achieved a complete response with incomplete hematologic recovery with NKX0101 treatment following lymphodepletion with fludarabine and cytarabine.

“We were encouraged that at least half of the patients achieved a complete response in this cohort, because the prognosis for this patient population has been quite poor,” explains study lead author Craig S Sauter, MD, Director of the Blood and Marrow Transplant Program at Cleveland Clinic Cancer Institute. “With contemporary therapies, the complete response rate is expected to be 20 to 30 percent at best.”

The Blood and Marrow Transplant Program has been working with several different engineered cellular immunotherapies for a range of hematologic malignancies, including lymphomas and multiple myelomas. “To date, there has not been a U.S. Food and Drug Administration-approved cellular therapy for AML, so this represents a potential opportunity for development of cellular therapies in this space,” says Dr. Sauter, who presented the new data at the 2023 American Society of Hematology annual meeting in San Diego.

The six patients, all seen at Cleveland Clinic, are a subgroup from a larger multicenter study of NKX101 in 36 patients with relapsed/refractory AML. All patients were heavily pre-treated with two median lines of therapy, including venetoclax. Most also had poor-risk genetic features, for which they additionally received approved targeted therapies.

However, in contrast to the 30 other participants who received traditional lymphodepletion with fludarabine/cyclophosphamide, the six in the separate cohort were given fludarabine and cytarabine (Ara-C) for lymphodepletion. The hypothesis is that this regimen might further enhance killing of malignant cells, since NKX101 is engineered to express an NKG2D ligand-chimeric antigen receptor (CAR), and Ara-C is known to upregulate NKG2D ligand expression, Sauter explains.


“The reasoning for adding cytarabine are threefold,” says Dr. Sauter. “One, it has anti-leukemia activity. Two, is its profound lymphodepleting effects. And three, unique to this particular cellular product, cytarabine is known to upregulate ligands and potentially tumor-associated antigens that would be targeted by the NKG2D artificial receptor with this product.”

The six patients first received lymphodepletion with 30mg/m2 fludarabine and 2g/m2 Ara-C each once daily for five days, followed by two days of rest. They were then treated with three or more doses of 1.5 billion viable CAR+ cells per dose of NKX101on days 0, 7 and 14.

None of the patients experienced cytokine release syndrome, immune cell-associated neurotoxicity syndrome or graft-versus-host disease. The most common higher-grade toxicities were myelosuppression and infection, but none were higher than grade 3 and there were no deaths related to the investigational treatment. “These safety data are encouraging,” Sauter notes.

Three of the six patients achieved a complete response, with no measurable residual disease. A fourth had complete response with incomplete count recovery.

Data on NKG2D ligand expression obtained via immunohistochemistry showed that responders were split between those with relatively low and higher ligand expression, suggesting that additional factors may contribute to NK cell resistance.

Expansion of the study cohort is ongoing. “We’ll provide updates as the data come in,” Sauter says.

At the same time, he notes, “we plan to continue to expand both sponsored studies as well as eventual in-house generated cellular therapeutics. The hope is to develop cellular therapies for cancers across all disease histologies, including solid organ tumors.”


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