The Efficacy and Safety of CD-19 Directed CAR-NK Therapy in Adults with B-Cell Malignancies: A Meta-Analysis
Authors: Carfagnini Christina , Singh Rishabh , Bechara Simon-Bahos , Kandula Manasa 
Published: December 2024

Introduction:
Anti-CD-19 chimeric antigen receptor (CAR) T-cell therapies have demonstrated good response rates in B-cell malignancies; however, their use is resource-intensive and associated with severe adverse effects. CAR-Natural Killer (NK) cell therapy has been linked to a favorable side effect profile, but published data on the safety and efficacy of novel CD-19-directed CAR-NK therapy in B-cell malignancies is scarce. This meta-analysis summarizes the response to treatment and adverse effect profile for CD-19-directed CAR-NK therapy in adults with B-cell malignancies.
Methods:
PubMed and Embase were searched for studies investigating response rates of CAR-NK therapies in patients with B-cell malignancies published between 2019 and 2024. Searches resulted in 46 articles after duplicates were removed. Studies that enrolled patients 18 years of age or older and reported data on complete response (CR) within 30 days of treatment were included. Studies were excluded if the number of patients who achieved a CR was not reported. Meta-analysis was performed using the “metafor” package version 3.4-0 in R version 4.1.2.
Results:
Four prospective studies (N = 81) were analyzed. Sample sizes of studies ranged from 5 to 37 patients. The median age of patients reported ranged from 59 to 64 years old. 78% of enrolled patients had Non-Hodgkin's lymphoma, and 32% had a diagnosis of lymphoid leukemia. The median number of prior therapies was 4 in all trials. The minimum dose of CAR-NK therapy was in a dose-escalation and expansion trial that provided a single infusion with 10^7 cells per kilogram of body weight. The maximum dose provided was a flat dose of 1.5x10^9 NK-cells on days 0, 7, and 14 of a 28-day cycle. Pooled results found objective response (OR) in 52% of patients (95% CI 39% - 64%), which was not statistically significant (p = 0.464). Similarly, 37% (95% CI 22% - 55%; p = 0.183) of patients achieved a CR within 30 days of treatment. There was mild statistical heterogeneity for OR (I^2 = 41.8%) across included studies and moderate heterogeneity for CR (I^2 = 0.0%) according to Cochrane's Q test. No patient developed graft-versus-host disease (GvHD) or neurotoxicity, and only 7% (95% CI 3% - 17%) of patients developed cytokine release syndrome (CRS).
Conclusion:
Limited data exists on the use of CAR-NK cell therapy. The lack of statistical significance in CR or OR one month after CD-19-directed CAR-NK treatment can be attributed to the small sample size. It is crucial to re-evaluate the efficacy of CAR-NK therapy as new data becomes available. All studies consistently assessed CR at one-month post-treatment. More studies are needed to evaluate long-term follow-up and assess the durability of responses. The favorable adverse effect profile, indicated by the low incidence of CRS and the absence of GvHD and neurotoxicity, is promising compared to CAR-T studies. However, the efficacy of CAR-NK cells will need to be directly compared to CAR-T cells.