Phase 1 Dose Escalation Study of Autologous T-cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases in HIV-Infected Patients

HIV Infections Clinical Trial

Official title:

A Phase 1 Dose Escalation, Single Dose Study of Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-278 in HIV-Infected Patients Who Have Exhibited Suboptimal CD4+ T-Cell Gains During Long-Term Antiretroviral Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01044654
• Other study ID #: SB-728-0902
• Status: Completed
• Phase: Phase 1
• First received: January 6, 2010
• Last updated: March 11, 2015
• Start date: December 2009
• Est. completion date: December 2014

Study information

• Verified date: March 2015
• Source: Sangamo Biosciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This research study is being carried out to study a new way to possibly treat HIV. This agent is called a "Zinc Finger Nuclease" or ZFN for short. ZFNs are proteins that can delete another protein named CCR5. This CCR5 protein is required for certain types of HIV (CCR5 tropic) to enter into and infect your T-cells. T cells are one of the white blood cells used by the body to fight HIV. The most important of these are called "CD4 T-cells."

Some People are born without CCR5 on their T-cells. These people remain healthy and are resistant to infection with HIV. Other people have a low number of CCR5 on their T-cells, and their HIV disease is less severe and is slower to cause disease (AIDS).

Even with no detectable levels of HIV in the blood, HIV remains in some tissues in the body, primarily the gut tissue. HIV infects the CD4+ T-cells including in the blood and gut. The new treatment to be studied will involve removing white blood cell from the blood that contains CD4+ T-cells. The extracted CD4+ T-cells are then genetically modified by the ZFNs to be resistant to infection by HIV by removing the CCR5 gene from the surface of the CD4+ T cell where HIV enters the cell. Additional genetically modified cells are manufactured and then re-infused back into you. Researchers hope that these genetically modified cells will be resistant to infection by HIV and will be able to reproduce additional resistant CD4+ T-cells in your body.

Laboratory studies have shown that when CD4+ T-cells are modified with ZFNs, HIV is prevented from killing the CD4+ T-cells. On the basis of these laboratory results, thre is the potential that ZFNs may work in humans infected with HIV and improve their immune system by allowing their CD4+ T-cells to survive longer.

The purpose of this research study is to find out whether "zinc finger" modified CD4+ T-cells are safe to give to humans and find how "zinc finger" modified T-cell affects HIV.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Documented HIV infection prior to study entry

• Must be willing to comply with study-mandated evaluations; including not changing their antiretroviral regimen (unless medically indicated) during the study period.

Cohort 1, 2 and 3 (Enrollment Completed)

Cohort 5:

• Must have received HAART therapy, and had undetectable viral loads for at least 1 year.

• HIV-1 RNA < 50 copies/mL obtained within 60 days prior to study entry performed with an ultrasensitive HIV-1 PCR assay.

• CD4+ T cell count >500 cells/mm3

• Heterozygous for the CCR5 delta-32 mutation

• On stable antiretroviral medication (no changes to treatment within 4 weeks of screening and willing to discontinue current antiretroviral therapy during the structured therapy interruption

Cohort 4

• On stable antiretroviral medication (no changes to treatment within 4 weeks of screening and willing to continue on current antiretroviral therapy through week 8 after infusion

• CD4+ T cell count >350 cells/mm3.

• HIV-1 >1,000 copies/mL at screen and not responding to current antiviral therapy (i.e. HIV-RNA plasma levels > 1000 copies/ml after at least 12 weeks of stable, unchanged ARV therapy).

Exclusion Criteria:

• Acute or chronic hepatitis B or hepatitis C infection

• Active or recent (in prior 6 months) AIDS defining complication.

• Any cancer or malignancy within the past 5 years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin or low grade (0 or 1) anal or cervical dysplasia.

• Current diagnosis of NYHA grade 3 or 4 CHF, uncontrolled angina or uncontrolled arrhythmias.

• History or any features on physical examination indicative of a bleeding diathesis.

• Previous treatment with any HIV experimental vaccine within 6 months prior to screening, or any previous gene therapy using an integrating vector.

• Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g., interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, etc.) within 30 days prior to enrollment

• Breast-feeding, pregnant or unwilling to use acceptable methods of birth control for 6 months following the last infusion of SB-728-T cells.

• warfarin or any other medication that is likely to affect platelet function or other aspects of blood coagulation during the 2 week period prior to leukapheresis.

• Active drug or alcohol use or dependence

• Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry.

• Recent vaccination or intercurrent illness (within 5 weeks prior to infusion)

• Have an allergy or hypersensitivity to study product excipients (human serum albumin, DMSO and Dextran 40).

• Subjects who are currently taking maraviroc or have received maraviroc within 6 months prior to screening.

Cohort 4 only:

• HIV-1 RNA >1,000 copies/mL at screen and not responding to current antiviral therapy

• CD4+ T cell count >350 cells/mm3

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infection
• HIV Infections
• Infection

Intervention

Genetic:
• SB-728-T
Each infusion will be 5-30 billion ZFN modified CD4+ T-cells

Locations

Country	Name	City	State
United States	Gordon Crofoot, MD, PA	Houston	Texas
United States	UCLA Center for AIDS Research and Education	Los Angeles	California
United States	Ricky K Hsu, MD, PC	New York	New York
United States	Orange Coast Medical Group	Newport Beach	California
United States	Circle CARE Center, LLC	Norwalk	Connecticut
United States	Orlando Immunology Center	Orlando	Florida
United States	Quest Clinical Research	San Francisco	California
United States	Southwest CARE Center	Santa Fe	New Mexico
United States	Central West Clinical Research, Inc.	St Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Sangamo Biosciences

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety - Treatment related adverse events		12 months after the first infusion	Yes
Secondary	Evaluate the long-term persistence and activity of CCR5 ZFN-modified autologous T-Cells		12 months after the first infusion	No