A Phase I Study of T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728mR in HIV-Infected Patients

NCT02388594 | Completed Phase 1 DMC

• 2 other identifiers: SB-728mRU01AI104400
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This is a triple cohort, open-label pilot study of the safety and antiviral activity of a single infusion of autologous CD4+ T cells genetically modified at the CCR5 gene by Zinc Finger Nucleases SB-728mR (ZFN Modified CD4+ T Cells) using electroporated mRNA with or without the prior administration of two different doses of cyclophosphamide.

Conditions

Human Immunodeficiency Virus (HIV)

Outcome Measures

Primary Outcomes (1)

• Number of participants with adverse events

  6 months post treatment

Study Arms (2)

ZFN Modified CD4+ T Cell

EXPERIMENTAL

ZFN Modified CD4+ T Cell

Drug: ZFN Modified CD4+ T Cells

ZFN Modified CD4+ T Cell with Cyclophosphamide

EXPERIMENTAL

ZFN Modified CD4+ T Cell with Cyclophosphamide

Drug: ZFN Modified CD4+ T Cells; Drug: Cyclophosphamide

Interventions

ZFN Modified CD4+ T Cells DRUG

Also known as: SB-728mR

ZFN Modified CD4+ T Cell; ZFN Modified CD4+ T Cell with Cyclophosphamide

Cyclophosphamide DRUG

ZFN Modified CD4+ T Cell with Cyclophosphamide

Eligibility Criteria

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

You may qualify if:

• HIV-1 infection, as documented by a rapid HIV test or any FDA-approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western blot at any time prior to study entry or HIV antigen, plasma HIV-1 RNA, or second antibody test by a method other than rapid HIV and E/CIA. Alternatively, if a rapid HIV test or any FDA-approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit is not available, two HIV-1 RNA values ≥ 2000 copies/mL at least 24 hours apart performed by any laboratory that has CLIA certification, or its equivalent, may be used to document infection.
• CD4+ T cell count of ≥450 cells/mm3 at screen; and a documented CD4 nadir of not lower than 200 cells/mm3.
• Adequate venous access and no other contraindications for leukapheresis.
• Laboratory values obtained at screen:
• Hemoglobin: ≥ 10.0 (males); ≥ 9.5 (females) g/dL
• Absolute neutrophil count (ANC): ≥ 1000/mm3
• Platelet count: ≥ 100,000/mm3
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): ≤ 2.5 times the upper limit of normal (ULN).
• Subjects must be willing to comply with study-mandated evaluations; including not changing their antiretroviral regimen (unless medically indicated) for 2 months in step 2 or until undergoing the analytical treatment interruption.
• Be male or female, 18 years of age and older.
• Ability and willingness of subject to provide informed consent.
• Have a Karnofsky Performance Score of 70 or higher.
• Have no polymorphisms in the CCR5 ZFN target region as determined by Cel I snp assay at screening.
• Subjects in Cohorts 2 and 3: LVEF \> or equal to 40%
• Clinically stable on their first or second HAART regimen. Changes while the patient HIV viral load is undetectable does not count toward the number of ART regimens used, only changes made for virologic failure (for example an individual switching from an NNRTI-based regimen to an integrase inhibitor based regimen while the HIV viral load is undetectable will still be in their first regimen). Site investigator anticipates that a fully active alternative ART regimen could be constructed in the event of virologic failure on the current ART regimen. The current regimen should have no changes within 4 weeks of enrollment. Subjects must be willing to continue on current antiretroviral therapy for the duration of the study except for the duration of the 16 week analytical treatment interruption. NOTE: Subject's ART regimen must be in accordance with the Department of Health and Human Services Document "Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents."

You may not qualify if:

• Acute or chronic hepatitis B or hepatitis C infection (as further defined in section 6.3.4 and 6.3.8 of this protocol)
• Current or prior AIDS diagnosis.
• History of cancer or malignancy, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin
• History or any features on physical examination indicative of active or unstable cardiac disease or hemodynamic instability. NOTE: subjects with a history of cardiac disease may participate with a physician's approval.
• History or any features on physical examination indicative of a bleeding diathesis.
• Have been previously treated with any HIV experimental vaccine within 6 months prior to screening, or any previous gene therapy using an integrating vector. Note: Subjects treated with placebo in an HIV vaccine study will not be excluded if documentation that they received placebo is provided.
• Breast-feeding, pregnant, or unwilling to use acceptable methods of birth control.
• Anticipated 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 site investigator, would interfere with adherence to study requirements.
• Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study screening visit.
• Receipt of vaccination within 30 days prior to study screening visit. NOTE: It is recommended that subjects enrolling into this study should have completed their routine vaccinations (hepatitis A, hepatitis B, pneumococcus, and tetanus diphtheria booster) at least 30 days prior to screening for the study.
• Have an allergy or hypersensitivity to study product excipients (human serum albumin, DMSO and Dextran 40).

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Tebas P, Jadlowsky JK, Shaw PA, Tian L, Esparza E, Brennan AL, Kim S, Naing SY, Richardson MW, Vogel AN, Maldini CR, Kong H, Liu X, Lacey SF, Bauer AM, Mampe F, Richman LP, Lee G, Ando D, Levine BL, Porter DL, Zhao Y, Siegel DL, Bar KJ, June CH, Riley JL. CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication. J Clin Invest. 2021 Apr 1;131(7):e144486. doi: 10.1172/JCI144486.

  PMID: 33571163 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

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 24, 2015
• First Posted: March 17, 2015
• Study Start: April 1, 2015
• Primary Completion: September 1, 2018
• Study Completion: March 1, 2019
• Last Updated: April 10, 2019

Record last verified: 2019-04

Locations

US (1)