With Natural Killer Cell Immunotherapy, Alloreactive Cell Dose May Be Predictive of Response

Research has shown that adoptive immunotherapy using natural killer cells may be beneficial in leukemia treatment. The follow-up to a recent study found that the dose of alloreactive natural killer cells matters for treatment response.

The treatment landscape for cancer has evolved significantly in recent years, with immunotherapy proving its value in multiple diseases. One emerging immunotherapy option in several cancer types, including acute myeloid leukemia (AML), is adoptive immunotherapy using natural killer (NK) cells. A recent study published in Frontiers in Immunology found that in the long-term, overall survival (OS) is related to the dose of alloreactive NK cells specifically.

NK cells are a type of lymphocyte that play a crucial role in identifying and mitigating the growth of malignant cell populations. Specifically, NK cells develop cytotoxic properties when receptors called killer cell immunoglobulin-like receptors (KIRs) are stimulated upon detecting abnormal cells.

Initial research has found NK cell therapies beneficial in leukemia when haploidentical KIR-ligand-mismatched NK cells in leukemia control were derived from haploidentical T-cell-depleted allogeneic stem cell transplantation, study authors Sarah Parisi, et al note. But further research has found that AML patients could also be treated safely and effectively with adoptive immunotherapy using haploidentical NK.

Based on these findings, Parisi et al analyzed outcomes of adoptive immunotherapy with donor-derived, highly purified, KIR-ligand-mismatched, haploidentical NK cells in a cohort of relapsed or refractory, adult, high-risk, AML patients in a phase 1 study.

They found that adoptive immunotherapy with NK was well-tolerated and did not result in any instances of graft-versus-host disease, a potential adverse event with this type of treatment. The investigators also were able to track donor-versus-recipient alloreactive NK cells in vivo after infusion and found that adoptively transferred NK cells were alloreactive against the recipient’s leukemic cells.

In another study of adoptively transferred NK cells in 17 elderly AML patients who were unfit for allogeneic stem cell transplantation, the treatment was tolerable and 9 were alive and disease-free 22.5 months post-treatment. In this cohort, both response to treatment and duration of response were significantly linked with the percentage of donor-derived alloreactive NK cell clones in the transferred cells. The functional dose they identified as predictive of response was 2 × 105/kg alloreactive NK cells.

The current study is a longer-term analysis of those findings, with a median follow-up of 55.5 months. Median patient age at enrollment was 64 years old, and all patients received a lympho-depleting chemotherapy regimen with fludarabine (25 mg/m2) followed by cyclophosphamide 4 g/m2) and then NK cell infusion followed by interleukin 2 (IL-2) injection. IL-2 was given 3 times weekly for 2 weeks.

At 55 months of follow-up, 16 patients were evaluable and 8 were alive and disease-free. Eight patients relapsed at a median of 9 months from complete response (CR), and 3 of the relapsed patients remained in CR after NK cell adoptive immunotherapy at 15, 24, and 51 months, respectively. The patient who relapsed after 51 months received a second NK infusion and achieved CR again. Two patients who were positive for MRD at the time of infusion achieved MRD clearance after one NK infusion.

In all, 11 of 16 patients in the cohort (69%) were considered responders, defined as maintaining CR for at least 6 months after infusion. When long-term disease-free survival (DFS) and OS in responders was compared with DFS and OS in non-responders, responders had significantly better outcomes. In a control cohort treated with the same chemotherapy but not with NK immunotherapy, 14 of 15 patients (93%) relapsed within 11 months.

“Indeed, long-term analysis confirmed our previous data, supporting the view that patients who had received more than 2 × 105/kg alloreactive NK cells may have significantly improved OS and DFS,” the authors wrote. “With the limitation of the low number of patients, these data show the long-term correlation between response to NK cell immunotherapy and the frequency of infused alloreactive NK cells.”

The study was limited by a small cohort, and further research is ongoing to confirm the safety and efficacy of NK infusion and the impact of infusing a minimum amount of alloreactive NK cells.


Parisi S, Ruggeri L, Dan E, et al. Long-term outcome after adoptive immunotherapy with natural killer cells: Alloreactive NK cell dose still matters. Front Immunol. Published online January 31, 2022. doi:10.3389/fimmu.2021.804988

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