Safety and Efficacy of Allogeneic Natural Killer Cell Immunotherapy on Human Immunodeficiency Virus Type 1 Immunological Non-Responders: A Brief Report
Introduction
Despite the success of antiretroviral therapy (ART) in suppressing viral replication in human immunodeficiency virus type 1 (HIV-1) patients, a significant proportion of individuals fail to restore their CD4+ T-cell counts to levels comparable to healthy controls. This group, known as immunological non-responders (INRs), is typically defined as patients with peripheral CD4 counts below 200 cells/mL after two years of ART initiation, despite having an undetectable plasma viral load. The mechanisms underlying this inadequate immune reconstitution remain unclear, but factors such as low nadir CD4 count, older age, reduced thymic output, aberrant immune activation, and residual virus replication are thought to play a role. The failure to restore immune function is associated with increased morbidity and mortality in HIV-1 patients, and effective treatments for this condition are currently lacking.
Natural killer (NK) cells are critical components of the innate immune system, capable of rapidly recognizing and killing virally infected cells. Allogeneic NK cell immunotherapy has emerged as a promising strategy in the treatment of various cancers, but its potential role in improving CD4 recovery in HIV-1 INRs has not been extensively studied. This study aimed to investigate the safety and efficacy of allogeneic NK cell immunotherapy in HIV-1 INRs receiving ART.
Methods
The study was a prospective, randomized, controlled, open-label clinical trial conducted at Nankai University Second People’s Hospital between February and April 2018. A total of 20 HIV-1 INRs meeting specific inclusion criteria were enrolled and randomly allocated in a 1:1 ratio to either the combined treatment group (NK + ART, n = 10) or the control group (ART alone, n = 10). The inclusion criteria included age between 18 and 65 years, stable ART for at least two years, CD4 count below 200 cells/mL after two years of ART initiation, and plasma HIV RNA levels below 20 copies/mL. Exclusion criteria included a history of prior malignancies, active opportunistic infections within four months prior to recruitment, active substance abuse, pregnancy or breastfeeding, allergic constitution, critical illness, or any psychiatric or medical condition that might influence the study.
Allogeneic NK cells were prepared under good manufacturing practice (GMP) conditions from healthy donors who were selected based on killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatch with the recipients. The NK cells were expanded and activated in vitro using a human NK cell culture synergistic kit, interleukin (IL)-2, and IL-21, and purified using a magnetic cell separator. Each patient in the NK + ART group received three courses of NK cell immunotherapy, with each course consisting of three consecutive daily infusions of 10^8 cells. The interval between courses was one month.
Key immune parameters, including CD4 count, CD8 count, and CD4/CD8 ratio, were measured at baseline and at months 1, 3, 6, 9, 12, and 24. Laboratory tests, including complete blood counts and biochemistry panels, were also performed. Adverse events (AEs) were recorded and evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Statistical analysis was performed using repeated measurement analysis of variance (ANOVA) and generalized estimating equations (GEE) models to evaluate the overall effect of the NK + ART group compared to the ART group.
Results
The study included 20 participants, with 10 in the NK + ART group and 10 in the ART group. The two groups were comparable in terms of sex, age, CD4+ T-cell count, nadir CD4 count, CD8+ T-cell count, CD4/CD8 ratio, plasma HIV RNA levels, and duration of ART.
From baseline to 24 months, the mean CD4 count increased from 139 to 243 cells/mL in the NK + ART group and from 144 to 176 cells/mL in the ART group, with a significant difference of 67 cells/mL (95% CI, 10 to 124; P = 0.024). The mean CD8 count increased from 637 to 839 cells/mL in the NK + ART group but decreased from 771 to 541 cells/mL in the ART group, with a non-significant difference of 298 cells/mL (95% CI, -61 to 657; P = 0.098). There was no significant difference in the CD4/CD8 ratio between the two groups at 24 months (0.34 vs. 0.38; difference, -0.04; 95% CI, -0.19 to 0.11; P = 0.569).
Using the GEE model, it was estimated that the NK + ART group significantly improved CD4 levels (b = 54.59, P = 0.006) and CD8 levels (b = 322.47, P = 0.010) on average across the six measurements compared to the ART group.
Safety assessments revealed no significant differences in blood cell counts or biochemical markers related to liver and kidney function between the two groups at any of the seven time points. Two participants in the NK + ART group developed a transient mild fever after the first course of treatment, which was considered a mild adverse event. No severe adverse events, relapses of HIV-1 viremia, or deaths were reported during the study.
Discussion
This study represents one of the first attempts to evaluate the safety and efficacy of allogeneic NK cell immunotherapy in HIV-1 INRs. The results indicate that this treatment is safe and well-tolerated, with only mild adverse events reported. Moreover, the NK + ART group showed significant improvement in CD4 recovery compared to the ART group, suggesting that allogeneic NK cell immunotherapy may be a promising strategy for enhancing immune reconstitution in HIV-1 INRs.
The findings are consistent with previous studies demonstrating the anti-tumor efficacy of allogeneic NK cells, which are known to exhibit potent cytolytic activity against non-self targets without prior activation. The use of KIR/HLA-Cw mismatched donors in this study likely contributed to the safety and efficacy of the treatment, as such mismatches are associated with reduced risk of graft-versus-host disease and enhanced NK cell activity.
However, the study also revealed that NK cell immunotherapy did not significantly improve the CD4/CD8 ratio, which remains a challenge in HIV-1 management. This may be due to the initiation of ART during the chronic phase of HIV infection, as previous studies have shown that patients who start ART during this phase often fail to normalize their CD4/CD8 ratio even after long-term viral suppression.
Limitations and Future Directions
This study has several limitations, including the small sample size, which limits the generalizability of the findings. Additionally, the study did not analyze other immunological markers, such as immune activation or exhaustion, which could provide further insights into the mechanisms underlying the observed effects. The time of HIV-1 infection was also not considered during participant selection, which may have influenced the results.
Future studies should aim to validate these findings in larger cohorts and explore the potential mechanisms by which allogeneic NK cells enhance CD4 recovery. Long-term follow-up observations are also necessary to assess the durability of the treatment effects and its impact on clinical outcomes.
Conclusion
In conclusion, this study provides preliminary evidence that allogeneic NK cell immunotherapy is safe and may significantly improve CD4 recovery in HIV-1 INRs. While the treatment did not affect the CD4/CD8 ratio, it represents a promising approach for enhancing immune reconstitution in this challenging patient population. Further research is needed to confirm these findings and explore the underlying mechanisms of action.
doi.org/10.1097/CM9.0000000000001189
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