Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728 for HIV

NCT00842634 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 806383
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief 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 common types of HIV (CCR5 tropic) to enter into and infect T-cells. T-cells are one of the white blood cells used by the body to fight HIV. The most important T-cells are those 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). In order to delete the CCR5 protein on the T cells, this study will isolate large numbers of T-cells from subjects, and then deliver the ZFNs using a delivery vehicle called a viral vector. The viral vector used in this study is called an adenoviral vector. The vector is added to the cells at the beginning of the manufacture process and the ZFNs knock out the CCR5 protein. By the time T-cells are returned to subjects, there is minimal adenovirus or ZFN present. The removal of the CCR5 protein on the T-cells subjects receive, however, is permanent. The purpose of this research study is to find out whether "zinc finger" modified T-cells are

1. 1.safe to give to humans and
2. 2.find how "zinc finger" modified T cell affects HIV

Conditions

HIV; HIV Infections

Keywords

HIV; Treatment Experienced

Outcome Measures

Primary Outcomes (1)

• Safety - Treatment related adverse events

  Cohort 1, Cohort 3 approximately 1 year from screening. Cohort 2 approximately 40 weeks from screening

Secondary Outcomes (7)

• Compare the percent of CD4+ and CD8+ T cells that secrete cytokines as a response to stimulation by HIV-specific antigens after the infusion of αCCR5 ZFN-modified autologous T cells

  8 weeks after the infusion of αCCR5 ZFN-modified autologous T cells

• Compare the CD4+ and CD8+ T cells response following stimulation by HIVspecific antigens, at baseline and 8 weeks after the infusion of CCR5 ZFN-modified autologous T cells.

  8 weeks after the infusion of CCR5 ZFN-modified autologous T cells

• To evaluate the change between baseline CD4+ T-cell count and the average of two consecutive CD4+ T-cell count values after dosing and just prior to initiation of a new drug regimen or at weeks 8 and 12, whichever comes first.

  week 8 or 12

• Cohort 1: To evaluate the change between baseline log10 HIV-1 RNA level and the average of two consecutive viral load measurements of log10 HIV-1 RNA levels after dosing.

  weeks 8 and 12

• Cohort 2: To evaluate the time to recrudescence to >500 copies/ml viral load, and viral set point following STI as defined by the average of week 12 and 16 readings (week 8 and 12 post STI).

  Week 8 and Week 12

Study Arms (3)

Cohort 1

EXPERIMENTAL

Patients who have failed two more HAART regimens

Biological: ZFN modified T cells

Cohort 2

EXPERIMENTAL

Patients doing well on a stable antiretroviral medication

Biological: ZFN modified T cells; Other: Structured Treatment Interruption

Cohort 3

EXPERIMENTAL

Patients who have an undetectable viral load on HAART who have exhibited suboptimal CD4+ T cell gains during long term antiretroviral therapy. This group will not participate in the structured treatment interruption.

Biological: ZFN modified T cells

Interventions

ZFN modified T cells BIOLOGICAL

A single infusion of 5-10 billion ZFN Modified CD4+ T Cells

Cohort 1; Cohort 2; Cohort 3

Structured Treatment Interruption OTHER

Stop Taking HAART Medication for up to 12 weeks (4 weeks after infusion to 16 weeks after infusion)

Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cohort 1 Only:
• Patients who have been on two more HAART regimens and have failed due to resistance or tolerance (no changes to treatment within 4 weeks of study entry), and who have no viable treatment options likely to result in complete viral suppression.
• CD4+ T cell count of ≥200 cells/mm3
• HIV-1 RNA ≥2000 copies/mL obtained within 60 days prior to study entry performed with an ultrasensitive HIV-1 PCR assay.
• Two HIV-1 RNA levels \<150,000 copies/mL obtained within 60 days prior to study entry performed with an ultrasensitive HIV-1 PCR assay. These HIV-1 RNA measurements must be at least 48 hours apart and may include the HIV-1 RNA measurement done at the time of the screening visit.
• Ongoing treatment with HIV entry inhibitors such as enfurvitide or maraviroc are excluded
• Cohort 2 Only:
• On a stable antiretroviral medication (no changes to treatment within 4 weeks of study entry) and be willing to continue on current antiretroviral therapy for the duration of the study until undergoing structured treatment interruption.
• CD4+ T cell count of ≥450 cells/mm3 at screen; and a documented CD4 nadir of not lower than 300 cells/mm.
• HIV-1 RNA undetectable by ultrasensitive HIV PCR assay obtained within 60 days prior to study entry performed with an ultrasensitive HIV-1 PCR assay.
• Cohort 3 only:
• On a stable antiretroviral medication (no changes to treatment within 4 weeks of study entry) and be willing to continue on current antiretroviral therapy for the duration of the study.
• CD4+ T cell count that is persistently \<500 cells/mm3 despite at least 2 years of stable HAART and \>200 cells/mm3 at screen
• Subjects must have received at least 2 continuous years of therapy and have had undetectable viral loads by ultrasensitive assay since 6 months of therapy. Subjects who have had a single viral load blip at any point in this time, or who experience intermittent isolated episodes of detectable low-level viremia (detectable but \<1000 copies RNA/mL; blips) will remain eligible.
• Subjects who are currently taking maraviroc or have received maraviroc within 6 months of study entry are excluded.

You may not qualify if:

• Acute or chronic hepatitis B or hepatitis C infection
• Current or prior AIDS diagnosis (Cohort 1 and 2 only)
• History of cancer or malignancy, (basal cell or squamous cell carcinoma of the skin allowed)
• History or problems with uncontrolled heart disease, bleeding or hemodynamic instability.
• Have been previously treated with any HIV experimental vaccine within 6 months prior to screening, or any previous gene therapy using an integrating vector.
• Use of the following medications within the last 30 days: chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g., interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, etc.)
• Breast-feeding, pregnant, or unwilling to use acceptable methods of birth control.
• Use of aspirin, dyprydamole, 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 that in the opinion of the investigator, would interfere with adherence to study requirements
• Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry.
• Receipt of a vaccination within 30 days prior to study entry.
• Have an allergy or hypersensitivity to study product excipients (human serum albumin, DMSO and Dextran 40).
• Currently taking medications called HIV entry inhibitors such as enfuvirtide or maraviroc

Sponsors & Collaborators

• University of Pennsylvania: lead
• Sangamo Therapeutics: collaborator

Study Sites (2)

Jacobi Medical Cener

The Bronx, New York, 10461, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014 Mar 6;370(10):901-10. doi: 10.1056/NEJMoa1300662.

  PMID: 24597865 DERIVED

Related Links

• Clinical Trials Listing for UPENN HIV Clinical Trials Unit

MeSH Terms

Conditions

HIV Infections

Interventions

Treatment Interruption

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Treatment Adherence and Compliance; Attitude to Health; Delivery of Health Care; Health Care Quality, Access, and Evaluation

Study Officials

• Pablo Tebas, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• David Stein, MD

  Jacobi Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2009
• First Posted: February 12, 2009
• Study Start: January 1, 2009
• Primary Completion: January 1, 2013
• Study Completion: January 1, 2013
• Last Updated: February 8, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)