Treatment With Immunological Checkpoint Inhibitors of HIV-infected Subjects With Cancer (PembroHIV)

It has been reported that peripheral and lymph node resident Cluster of Differentiation 4 (CD4)+ T cells expressing Programmed cell death protein 1 (PD-1) contribute to Human Immunodeficiency Virus (HIV) persistence during Antiretroviral Therapy (ART). In HIV-infected individuals, PD-1 expression on CD4+ T cells correlates with HIV disease progression, and loss of HIV-specific CD4+ T cell function can be reversed in vitro by PD-1 blockade. There are only a limited number of case reports describing the evolution of HIV-infected patients with concurrent oncological disease treated with immunological checkpoint inhibitors. However, this case provides very limited information on the effect of pembrolizumab on the HIV reservoir. Here, the investigators aim at describing changes in the HIV reservoir and in the HIV-specific immunity in HIV-infected patients on ART who receive immunological checkpoint inhibitors for the treatment of cancer, especially for metastatic melanoma.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Cancer

Detailed Description

Long-lived latently infected resting CD4+ T cells are the main reason why current antiretroviral therapy (ART) is unable to cure HIV infection. Recent work has suggested that the expression of immune checkpoint markers, such as the programmed death-1 (PD1) or the cytotoxic T-lymphocyte antigen 4 (CTL-4), may play a role in viral persistence on ART via either suppression of virus transcription and/or reduced HIV-specific T cell activity, but the in vivo role of immune checkpoint markers in HIV persistence on ART is not clear.

Immunological checkpoint inhibitors are humanized monoclonal Immunoglobulin G (IgG) antibodies directed against several cell surface receptors, including PD-1 that inhibits binding of PD-1, expressed on activated T cells to its ligands PD-L1, overexpressed on certain cancer cells, and PD-L2, which is primarily expressed on antigen presenting cells. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity antigen presenting cells. Immunological checkpoint inhibitors can also target CTL-4, which is constitutively expressed in Treg cells but only upregulated in conventional T cells after activation, a phenomenon which is particularly notable in cancers. These drugs are used to treat oncology diseases, including metastatic melanoma, and have been associated with multiple changes in immune function thought to enhance antitumor T cell function.

This exploratory study will include HIV-infected subjects with advanced melanoma or other oncological conditions in which the use of immunological checkpoint inhibitors is clinically indicated. The study is conceptually observational as the patients will be in regular clinical treatment with immunological checkpoint inhibitors for oncological conditions.

• Study Type: Observational
• Enrollment (Actual): 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

HIV-infected subjects with advanced melanoma or other oncological conditions in which the use of immunological checkpoint inhibitors is clinically indicated

Description

Inclusion Criteria:

• HIV-infected subjects with advanced melanoma or other oncological conditions in which the use of immunological checkpoint inhibitors is clinically indicated

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
PembroHIV; HIV-infected subjects with advanced melanoma or other oncological conditions in which the use of immunological checkpoint inhibitors is clinically indicated

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of total HIV DNA	Measurement of HIV viral latency by quantification of total HIV DNA in purified CD4+ T cells, using digital droplet PCR (ddPCR)	At the end of recruitment (up to one year after inclusion)
Quantification of cell-associated HIV RNA	Measurement of viral transcription by quantification of cell-associated unspliced HIV RNA in purified CD4+ T cells, using ddPCR	At the end of recruitment (up to one year after inclusion)
Quantification of ultrasensitive HIV viral load	Measurement of ultrasensitive viremia in plasma using single copy assay	At the end of recruitment (up to one year after inclusion)
Analysis of changes in HIV-specific cellular responses	Changes in the ability of Peripheral Blood Mononuclear Cells (PBMCs) to release Interferon gamma (IFNγ) in response to viral antigen stimulation (ELISPOT assay).	At the end of recruitment (up to one year after inclusion)
Analysis of changes in immune-phenotype of cellular populations	Study of changes in multiple cell membrane markers related with cell function, including T-cell activation and proliferation, T-cell exhaustion, T-cell subpopulations and release of specific cytokines in response to HIV stimuli (multicolor flow cytometry).	At the end of recruitment (up to one year after inclusion)
Analysis of changes in HIV inhibition capacity in vitro	Changes in the ex vivo ability of cluster of differentiation 8 (CD8)+ T cells to inhibit superinfected autologous CD4+ T cells (virus inhibition assay).	At the end of recruitment (up to one year after inclusion)
Supervision of changes on the standard blood analysis for oncologic follow-up	Blood analysis will be revised for oncologic follow-up	At the end of recruitment (up to one year after inclusion)
Analysis of changes in imaging of the oncological focus	Positron Emission Tomography (PET) scan will be analyzed for oncologic follow-up	At the end of recruitment (up to one year after inclusion)

Collaborators and Investigators

• Sponsor: IrsiCaixa
• Investigators: Principal Investigator: Javier Martinez-Picado, PhD, IrsiCaixa

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 26, 2018
• Primary Completion (ACTUAL): March 18, 2019
• Study Completion (ACTUAL): October 11, 2019

Study Registration Dates

• First Submitted: December 3, 2018
• First Submitted That Met QC Criteria: December 5, 2018
• First Posted (ACTUAL): December 6, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 15, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Cancer; HIV; Immunity; HIV reservoir; Checkpoint inhibitors
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: PembroHIV

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes