A Safety and Efficacy Trial of Chidamide Combined With NKG2D CAR-NK Cell Therapy for Reducing the HIV Viral Reservoir

Background and Rationale:

Currently, highly active antiretroviral therapy (HAART) effectively suppresses HIV replication; however, it fails to eradicate the latent viral reservoir, necessitating lifelong pharmacotherapy for infected individuals. This study is predicated on the "shock and kill" strategy and combines the histone deacetylase inhibitor chidamide with allogeneic chimeric antigen receptor natural killer (CAR-NK) cells targeting NKG2D ligands, aiming to explore a novel potential approach toward a functional cure for HIV infection. Preclinical investigations have demonstrated that chidamide not only reactivates latent virus but also upregulates the expression of NKG2D ligands on the surface of infected cells, while NKG2D CAR-NK cells exhibit specific recognition and elimination of such target cells, thereby establishing a clear synergistic effect between the two modalities.

Study Objectives:

Primary Objective: To evaluate the safety and tolerability of the combined therapeutic regimen in HIV-infected individuals receiving stable antiretroviral therapy.

Secondary Objectives: To preliminarily explore the impact of this regimen on virologic and immunologic parameters, including plasma HIV RNA, cell-associated viral nucleic acids, and CD4⁺ T-cell counts.

Study Design:

This is a prospective, open-label, single-arm, phase I clinical trial comprising dose-escalation and dose-expansion stages. The study is conducted in two distinct phases:

Phase Ia (Dose Escalation): A modified "1+3+3" design will be employed to evaluate the safety of three dose levels of CAR-NK cells (DL1: 5×10⁸, DL2: 1×10⁹, DL3: 2×10⁹ cells per infusion) and to determine the recommended phase II dose (RP2D). The dose-limiting toxicity (DLT) observation period is defined as 28 days following the initial cell infusion.

Phase Ib (Dose Expansion): An expansion cohort will be enrolled at the established RP2D to further assess safety and preliminary efficacy.

Study Participants:

A total of 20 HIV-infected individuals are planned for enrollment, meeting the following eligibility criteria: age 18-65 years, receipt of antiretroviral therapy (ART) for a minimum of two years, sustained virologic suppression (plasma HIV RNA <50 copies/mL), CD4⁺ T-cell count >200 cells/μL, and compliance with additional health-related inclusion criteria.

Intervention:

All enrolled participants will receive oral chidamide (10 mg twice weekly) for approximately five weeks. During this period, participants will receive two cycles of intravenous infusion of allogeneic NKG2D CAR-NK cells (each cycle consisting of two consecutive daily infusions, separated by an interval of approximately two weeks). Throughout the treatment course, participants will continue their pre-existing antiretroviral regimen without modification.

Figure 1. Schematic Diagram of Participant Follow-Up and Study Procedures

Outcome Measures:

Safety Endpoints: Incidence and characterization of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs), with particular emphasis on cytokine release syndrome (CRS) and neurotoxicity.

Exploratory Efficacy Endpoints: Dynamic changes in plasma HIV RNA, cell-associated HIV RNA/DNA, and CD4⁺/CD8⁺ T-cell counts from baseline to post-treatment assessments.

Additional Exploratory Endpoints: In vivo expansion and persistence of CAR-NK cells (pharmacokinetics, PK), cytokine profiling, and alterations in senescence-associated biomarkers.

Significance of the Study:

This study represents the first-in-human evaluation of the safety profile of chidamide in combination with allogeneic NKG2D CAR-NK cell therapy in the context of HIV infection. Furthermore, it will provide preliminary clinical evidence regarding the potential of this combinatorial strategy to reduce the viral reservoir, thereby potentially opening new avenues for the development of functional cure strategies for HIV infection.