AACR 2025 | Natural killers elicit remission in acute myeloid leukemia
In an ongoing Phase I trial, a first-in-class off-the-shelf CAR NK cell therapy has achieved complete remission in patients with relapsed or refractory acute myeloid leukemia.
According to results of an ongoing Phase I trial presented at the AACR Annual Meeting (25–30 April; Chicago, IL, USA) by Stephen Strickland, director of leukemia research at the Sarah Cannon Research Institute (TN, USA), a novel off-the-shelf chimeric antigen receptor natural killer (CAR NK) cell therapy has triggered complete remission in patients with relapsed or refractory acute myeloid leukemia (AML).
Adoptive cell therapies are a promising treatment option for blood cancers. Currently, the most widely used of these is CAR T-cell therapy, which involves extracting a sample of patients’ T-cells and modifying them ex vivo into CAR T-cells that can recognise and kill cancerous cells before reinfusing them back into the patient in expanded quantities.
While CAR T-cell therapy has seen positive results in some cancer types, it has been less successful in AML, due to its high heterogeneity, which helps cancer cells evade detection by CAR T-cells. The process of extracting and modifying T-cells for personalised therapies also requires time, which, in rapidly progressing cases, some patients may not be able to afford. Additionally, AML patients often have high proportions of dysfunctional T-cells, which could hinder or prevent their effectiveness when transformed into therapeutic CAR T-cells.
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To combat these issues, Strickland and his research group developed a first-in-class adoptive cell therapy based on natural killer (NK) cells, a different type of immune cell. Due to differences in their nature, utilizing NK cells rather than T-cells allowed for the production of an ‘off-the-shelf’ cell therapy, meaning the therapeutic CAR NK cells can be developed from healthy donor cells and stored until needed. This enabled the creation of a therapy that is readily available to patients, without risking the incorporation of dysfunctional cells.
The researchers utilised logic-gating technology in the design of their CAR NK cell therapy to tackle AML cell heterogeneity whilst minimizing off-target effects. The logic-gated CAR NK cells can identify two different targets on AML cells, CD33 and FLT3, broadening their reach in a highly heterogeneous population. Additionally, the CAR NK cells contain an inhibitory receptor, which is expressed on healthy cells, to prevent them from being mistakenly targeted if they express CD33 or FLT3. This enables CAR NK cells to kill cancer cells without depleting healthy cell populations.
In the Phase I study, nine patients with relapsed or refractory AML received the CAR NK therapy following a course of lymphodepleting chemotherapy. All participants saw a reduction in disease, with four experiencing complete remission and a fifth achieving a morphologic leukaemia-free state. Although patients did experience some side effects, these were largely not attributed to the CAR NK therapy, with some thought to be the result of the chemotherapy. No life-threatening adverse events were reported.
“The deep and durable responses observed in patients for whom we have follow-up data are impressive,” Strickland enthused. “We are hopeful this can be a new type of treatment for AML patients where the unmet medical need is extremely high.”
Clinical studies are continuing into Phase II to further evaluate the CAR NK treatment’s safety and efficacy. The team hopes that this will lead to new logic-gated treatments being developed for other cancer types.