PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection
- Registration Number
- NCT03239899
- Lead Sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)
- Brief Summary
Background:
HIV affects millions of people. The disease may "hide" in the brain, even in people with well-controlled HIV without cancer. Then it may "wake up" and continue. The drug pembrolizumab uses the body's immune system to fight cells like cancer cells. It is approved to treat some cancers but not HIV. Researchers want to see if it is safe for HIV-positive people without cancer. This study is not for HIV treatment; only one dose of the drug will be used.
Objective:
To learn if the drug pembrolizumab, used to treat certain cancers, is safe for HIV-positive people.
Eligibility:
Adults ages 18 and older with HIV who are in another NIH protocol
Design:
Participants will be screened with:
* Medical history
* Physical and neurological exams
* Blood tests
* Lumbar puncture. The lower back will be numbed. A needle will remove fluid from between back bones.
* FDG-PET/CT. A radioactive sugar will be injected in a thin plastic tube (catheter) inserted in an arm vein. Participants will rest for an hour, urinate, then lie in the scanner. A mask will hold the head still.
* Leukapheresis. An optional procedure at baseline. White blood cells are removed from you using a serum cell separator machine
Women who can become pregnant cannot take pembrolizumab. Men who take it must use 2 kinds of contraception.
Participants will have up to 7 more visits, which repeat some screening tests.
At 1 visit, participants will get one dose of pembrolizumab by catheter for 30 minutes. They will get allergy and pain medicines.
At 2 visits, participants will have a brain MRI. They will get a contrast agent by catheter. They will lie in a metal cylinder that takes pictures for 1-2 hours. They will get earplugs for loud sounds.
- Detailed Description
Objective
In this Phase I, proof-of-concept study, we aim to determine the safety and tolerability of pembrolizumab, an FDA-approved monoclonal antibody against programmed cell death protein (PD)-1, in viremically suppressed human immunodeficiency virus-1 (HIV) positive patients. We are examining the correlation of immune activation and suppression markers in viremically suppressed HIV positive patients with the effects of pembrolizumab on immune restoration function (e.g. CD4 count, HIV viral load) and immune activation (e.g. HIV-specific T-cell responses).
Study Population
HIV is estimated to infect 37.6 million people globally, with 690,000 deaths and 1.5 million new infections occurring yearly. There is no cure. Opportunistic infections and neoplasms contribute to a large portion of mortality and morbidity within the HIV-positive population. Even in well- controlled, viremically suppressed patients, neurologic complications including HIV-associated neurocognitive disorder, continue to contribute to disease morbidity and mortality.
There is evidence that HIV reservoirs contribute to the inability to cure HIV infection. In the brain, macrophages and astrocytes harbor HIV. It is theorized that the brain is a potential reservoir for replication competent HIV. PD-1 expression is elevated in patients with HIV compared to uninfected controls. Upregulated PD-1 expression is associated with higher viral load and increased mortality in infections.1 PD-1 co-expression on regulatory T-cells has been shown to correlate with disease progression in perinatally-infected HIV-positive children. Drugs targeting the PD-1 pathway in HIV infection have shown upregulation of T-cell responses that are potentially critical to eradication of infection. Pembrolizumab is an attractive option due to its mechanism of action, although it has been rarely used in the HIV population.
Design
In this single-center, single-arm, open label, baseline-versus-treatment phase I clinical trial, twelve patients with HIV-1 infection receive a one-time dose of 200mg pembrolizumab with a baseline study period of 3 weeks, a one-day treatment phase, and a 6-month post treatment phase. Outcome measures are collected every 3 to 6 weeks for the duration of the study.
Outcome Measures
The primary outcome is the safety and tolerability of pembrolizumab, which is measured by clinical exam, laboratory studies and adverse event tabulations using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
In addition, viral and immunologic outcome measures investigating the impact of pembrolizumab on HIV-1 biology and its effects on immune function is measured in the CSF and periphery, including single copy HIV analysis, CD4+ T-cell count, PD-1 lymphocyte expression and T-cell phenotype analysis, T-cell proliferation against HIV-proteins, CSF cytokine analysis and/or CSF antibody profiling (LIPS). These additional studies offer indirect proof of a HIV viral reservoir in the CNS as well as potential efficacy of pembrolizumab in reversing immune exhaustion against latent HIV
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 13
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description HIV Participants Pembrolizumab Participants who received 200 mg of Pembrolizumab administered as a one-time intravenous infusion over 30 minutes during the treatment phase of the study.
- Primary Outcome Measures
Name Time Method Frequency of Grade 3 or Higher Adverse Events study duration (up to 52 weeks post infusion) The frequency of Grade 3 and higher Adverse Events (AEs) that are probably or definately causal to pembrolizumab was calculated for the duration of the study, i.e., up to 52 weeks following infusion of pembrolizumab.
- Secondary Outcome Measures
Name Time Method Change in HIV-specific Antibody Responses in the CSF and Serum Using LIPS Assay. 3 weeks after infusion Analysis of the effects of pembrolizumab on various immunologic responses (antigens) was conducted at baseline and 3 weeks after infusion of pembrolizumab.
Antibody responses have been correlated with cure responses in the "Berlin patient". Utilizing the "Berlin patient's" antibody levels as a benchmark for the post-treatment of the study participants, a change in the following antigens was analyzed at 3 weeks post-infusion of pembrolizumab, in CSF and serum: p24, Matrix, gp120, Reverse transcriptase, Integrate, Protease, and pg41. A positive value suggests exposure to the HIV protein; while a negative value suggests no exposure to the HIV protein.Peripheral CD4 Counts 3 weeks after infusion A change in peripheral CD4 counts was measured from baseline to 3 weeks post-infusion of pembrolizumab. CD4 T cells help coordinate the immune response by stimulating other immune cells, such as macrophages, B lymphocytes (B cells), and CD8 T lymphocytes (CD8 cells), to fight infection. HIV weakens the immune system by destroying CD4 cells. CD4 counts in the blood were measured at baseline and 3 weeks after infusion of pembrolizumab. A positive value suggests an increase in the CD4 count while a negative value suggests a decrease in the CD4 count.
Change in CSF Cytokine Profile Post-study Drug 3 weeks after infusion A change in CSF cytokine profile was measured between baseline and 3 weeks after infusion of pembrolizumab. Cytokines are proteins that communicate with and trigger the immune system to attack invaders in the body. An increase in an individual cytokine level after 3 weeks suggests an immune reaction.
HIV RNA in Plasma and CSF 3 weeks after infusion Change in HIV RNA levels was measured in plasma and CSF from baseline to 3 weeks after pembrolizumab infusion. A positive change value suggests an increase in viral load, while a negative change value suggests a decrease in viral load.
Change in FDG-PET/CT Metabolic Uptake in CNS 3 weeks after infusion Change in FDG-PET/CT metabolic uptake in the CNS from baseline to 3 weeks after infusion of pembrolizumab was measured. A change reflecting an increase in update might suggest higher metabolic activity in that brain region, while a change reflecting a decrease in uptake might suggest lower metabolic activity in that brain region.
Change in PD-1 Expression in the CSF and Blood Cells 3 weeks after infusion A change in PD-1 expression on CD4 and CD8 T cells in the CSF and blood cells, was measured from baseline to 3 weeks after infusion of Pembrolizumab. A decline in PD-1 expression on CD4 and CD8 T cells suggests more potential T cell targeting response.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States