Gene Transfer for HIV Using Autologous T Cells

NCT01153646 | Terminated Early Phase 1 DMC

• 2 other identifiers: 03161IND #14146
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This is a pilot study to determine the safety and feasibility of lentivirus-transduced T-cell immunotherapy in patients who have failed highly active anti-retrovirus therapy (HAART).

Conditions

HIV-1 Infection

Keywords

HIV; Gene Transfer; T-Cell Immunotherapy; HIV-1 infected patients who have failed anti-retroviral therapy

Outcome Measures

Primary Outcomes (2)

• Patient Safety

  Patient safety will be determined by clinical and laboratory observation and grading of adverse events using the CTCAE v.3. Assays: analysis of T cell repertoire clonality, and evaluation of HIV isolates for evidence of vector recombination.

  Every 3 months for the first year, then twice yearly until year 5, and then yearly until year 15 after treatment

• Feasibility

  Feasibility will be determined by the ability to obtain suitable numbers of expanded T cells and expression of the RNA transgenes in these cells. The secondary endpoints are the duration of T cell circulation in blood post-infusion and the effect of the T cell infusion on CD4 count and on HIV load. Conventional CD4 counts and HIV RNA levels in blood will be determined at follow-up intervals.

  Every 3 months for the first year, then twice yearly until year 5, and then yearly until year 15 after treatment

Secondary Outcomes (1)

• Genetic marking in peripheral blood using vector-specific PCR assay.

  During time of follow-up years 0-2

Study Arms (1)

Cohort 1: 1x10e9 and Cohort 2: 1x10e10 T cells per infusion

EXPERIMENTAL

Group of patients receiving genetically modified T-cells

Genetic: pHIV7-shI-TAR-CCR5RZ treated CD4 cells

Interventions

pHIV7-shI-TAR-CCR5RZ treated CD4 cells GENETIC

Single dose administration x 3 of genetically modified T-cells given at 3 infusions at 6 week intervals.

Cohort 1: 1x10e9 and Cohort 2: 1x10e10 T cells per infusion

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patient must:
• Be Age ≥ 18 years ≤ 60 years.
• Be HIV seropositive and have been treated with a potent antiretroviral chemotherapy regimen for at least one year and with an HIV plasma RNA \>5000 gc/ml.
• Have available genotypic evidence of resistance and prior HAART modifications must have been consistent with current recommendations.
• Have a CD4 count \>200 cells/mL and a CD4/CD8 ratio \>0.2, with hemoglobin, WBC, and platelet count within 1.5x normal limits.
• Have a Karnofsky performance status \>/= 70%.
• Have pretreatment SGOT, SGPT, and serum bilirubin \<2.5 times the institutional upper limit of normal (ULN) with no extrinsic hepatobiliary disease and no HBV surface antigen and no hepatitis C virus antibody.
• Have PT/PTT \<2 times the ULN.
• Have serum creatinine \< 2 x ULN.
• Females Only: Must not be pregnant based on a pregnancy test within the past 7 days.
• Have CD4 counts are ≤ 200, is the patient on a prophylactic regimen for pneumocystis pneumonia or have they agreed to begin such treatment.
• Agree to use effective birth control to prevent pregnancy.
• Voluntarily consent and comply with the treatment and required tests.

You may not qualify if:

• Patients are ineligible if:
• The patient has an active bacterial or fungal infection.
• The patient has been successfully treated AIDS related opportunistic infections within the past year.
• The patient has active CMV retinitis or other active CMV-related organ dysfunction (excluding completely treated CMV infections).
• The patient has evidence of clinically significant neuropathy.
• The patient has had a relapse of pneumocystis carinii pneumonia within the past year.
• The patient has intractable and severe diarrhea as defined as \>1500 cc diarrheal fluid per day or diarrhea causing persistent severe electrolyte abnormalities or hypoalbuminemia.
• The patient has other AIDS-related syndromes, infections or other illness that would preclude autologous HCT as determined by the Principle Investigator.
• The patient has taken any immunosuppressive medications in the past 30 days.
• Has any prior malignancy, except those treated with curative intent that are five years from treatment, cervical and anal squamous cell cancers and superficial basal cell and squamous cell cancers of the skin.
• The patient has auto-antibodies.
• The patient has had a leukapheresis in the past 3 months.
• The patient has a known allergy to human serum albumin, Dextran 40 or DMSO.
• The patient has ever been on a gene therapy trial.

Sponsors & Collaborators

• City of Hope Medical Center: lead

Study Sites (1)

Beckman Research Institute of City of Hope

Duarte, California, 91010, United States

Location

Related Publications (7)

• Levine BL, Bernstein WB, Aronson NE, Schlienger K, Cotte J, Perfetto S, Humphries MJ, Ratto-Kim S, Birx DL, Steffens C, Landay A, Carroll RG, June CH. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med. 2002 Jan;8(1):47-53. doi: 10.1038/nm0102-47.

  PMID: 11786906 BACKGROUND

• Sarver N, Cantin EM, Chang PS, Zaia JA, Ladne PA, Stephens DA, Rossi JJ. Ribozymes as potential anti-HIV-1 therapeutic agents. Science. 1990 Mar 9;247(4947):1222-5. doi: 10.1126/science.2107573.

  PMID: 2107573 BACKGROUND

• Bai J, Gorantla S, Banda N, Cagnon L, Rossi J, Akkina R. Characterization of anti-CCR5 ribozyme-transduced CD34+ hematopoietic progenitor cells in vitro and in a SCID-hu mouse model in vivo. Mol Ther. 2000 Mar;1(3):244-54. doi: 10.1006/mthe.2000.0038.

  PMID: 10933940 BACKGROUND

• Bauer G, Valdez P, Kearns K, Bahner I, Wen SF, Zaia JA, Kohn DB. Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stimulating factor-mobilized CD34+ cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes. Blood. 1997 Apr 1;89(7):2259-67.

  PMID: 9116267 BACKGROUND

• Lee NS, Dohjima T, Bauer G, Li H, Li MJ, Ehsani A, Salvaterra P, Rossi J. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol. 2002 May;20(5):500-5. doi: 10.1038/nbt0502-500.

  PMID: 11981565 BACKGROUND

• Li MJ, Bauer G, Michienzi A, Yee JK, Lee NS, Kim J, Li S, Castanotto D, Zaia J, Rossi JJ. Inhibition of HIV-1 infection by lentiviral vectors expressing Pol III-promoted anti-HIV RNAs. Mol Ther. 2003 Aug;8(2):196-206. doi: 10.1016/s1525-0016(03)00165-5.

  PMID: 12907142 BACKGROUND

• Li MJ, Kim J, Li S, Zaia J, Yee JK, Anderson J, Akkina R, Rossi JJ. Long-term inhibition of HIV-1 infection in primary hematopoietic cells by lentiviral vector delivery of a triple combination of anti-HIV shRNA, anti-CCR5 ribozyme, and a nucleolar-localizing TAR decoy. Mol Ther. 2005 Nov;12(5):900-9. doi: 10.1016/j.ymthe.2005.07.524. Epub 2005 Aug 22.

  PMID: 16115802 BACKGROUND

Study Officials

• John A. Zaia, MD

  Beckman Research Institute of City of Hope

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: June 28, 2010
• First Posted: June 30, 2010
• Study Start: April 1, 2010
• Primary Completion: January 1, 2011
• Study Completion: January 1, 2011
• Last Updated: January 19, 2011

Record last verified: 2011-01

Locations

US (1)