A Safety and Efficacy Trial of Chidamide Combined With NKG2D CAR-NK Cell Therapy for Reducing the HIV Viral Reservoir
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 20
- 试验地点
- 1
研究概览
简要总结
This study aims to investigate the safety and preliminary efficacy of an innovative therapeutic strategy combining chidamide with NKG2D-directed chimeric antigen receptor natural killer (CAR-NK) cells in individuals living with HIV. The approach is predicated on the "shock and kill" paradigm: chidamide is employed to reactivate latent HIV reservoirs and upregulate surface target ligands (NKG2D ligands) on infected cells; subsequently, allogeneic NKG2D CAR-NK cells are infused to specifically recognize and eliminate these "marked" cells.
This is a phase I, open-label, single-arm clinical trial comprising two distinct stages: a dose-escalation phase (phase Ia, utilizing a "1+3+3" design) and a dose-expansion phase (phase Ib). A total of 20 HIV-infected individuals who are stable on antiretroviral therapy (ART) and have suppressed plasma viremia are planned for enrollment. Participants will receive oral chidamide over approximately five weeks, followed by two cycles of intravenous CAR-NK cell infusion.
The primary endpoint is the safety and tolerability of the regimen, with particular attention to immune-related adverse events including cytokine release syndrome (CRS). Secondary endpoints encompass exploratory assessments of potential virologic and immunologic effects, such as alterations in plasma HIV RNA, cell-associated viral nucleic acids, and CD4+ T-cell counts. This study is intended to provide initial human safety data and preliminary evidence regarding the potential of this combination strategy to contribute toward a functional cure for HIV infection.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A participant will be deemed eligible for enrollment only if all of the following criteria are met:
- •Diagnosis of HIV infection, with a current history of highly active antiretroviral therapy (HAART) for a minimum duration of two years.
- •Age between 18 and 65 years, inclusive.
- •Plasma HIV RNA level < 50 copies/mL (virologic suppression).
- •CD4⁺ T cell count > 200 cells/μL.
- •Adequate hematologic function defined as:
- •Hemoglobin ≥ 90 g/L;
- •Platelet count ≥ 75 × 10⁹/L;
- •Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L;
- •White blood cell count ≥ 2 × 10⁹/L.
- •Adequate hepatic and renal function defined as:
- •Serum creatinine ≤ 1.5 × upper limit of normal (ULN);
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN;
- •Total bilirubin ≤ 2 × ULN;
- •Prothrombin time (PT) prolongation < 3 seconds.
- •Hemodynamically stable with a left ventricular ejection fraction (LVEF) ≥ 45%.
- •Negative serum or urine pregnancy test for females of childbearing potential.
- •Willingness of the participant to:
- •Practice effective contraception during the study period and for one year following completion of the trial;
- •Voluntarily provide written informed consent and comply with scheduled follow up visits and study procedures.
排除标准
- •Participants meeting any of the following criteria will be excluded from study participation:
- •Presence of severe cardiovascular, respiratory, or hematologic disease; active infectious disease (other than controlled HIV infection); or active malignancy.
- •Positive serology for hepatitis B surface antigen (HBsAg) or detectable hepatitis C virus RNA (HCV RNA).
- •Diagnosis of chronic kidney disease (CKD).
- •History or presence of acute or chronic pancreatitis.
- •Active severe peptic ulcer disease.
- •Current severe neurologic or psychiatric disorder.
- •History of alcohol abuse or illicit substance use disorder.
- •Known allergic diathesis or hypersensitivity to any component of the investigational agents.
- •Female participants who are pregnant, lactating, or of childbearing potential and unwilling to adhere to required contraceptive measures.
- •Concurrent use of immunosuppressive agents.
- •Any other condition that, in the opinion of the investigator, renders the participant unsuitable for study participation.
研究者
Biao Zhu
Chief Physician
First Affiliated Hospital of Zhejiang University