Gene Transfer for HIV Using Autologous T Cells

• Patient Safety [ Time Frame: Every 3 months for the first year, then twice yearly until year 5, and then yearly until year 15 after treatment ] [ Designated as safety issue: Yes ]
  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.
• Feasibility [ Time Frame: Every 3 months for the first year, then twice yearly until year 5, and then yearly until year 15 after treatment ] [ Designated as safety issue: Yes ]
  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.

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).

Study Design 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) as defined by HIV levels or by intolerance to drug therapy. The lentivirus vector induces 3 forms of anti-HIV RNA: RNAi in the form of a short hairpin RNA (shRNA) targeted to an exon in HIV-1 tat/rev (shI), a decoy for HIV TAT-activated RNA (TAR), and a ribozyme that targets the host T cell CCR5 cytokine receptor (CCR5RZ). The vector is called rHIV7-shI-TAR-CCR5RZ and will be used in the transduction and expansion of autologous CD4-enriched T cells. Doses of 1 x 109 T cells will be given at 0, +6, and +12 weeks to the first cohort of 3 subjects. Following completion of this cohort, if no serious adverse events have occurred within 3 weeks of the last infusion, then the next cohort will receive 10 x 109 T cells at 0, +6, and +12 weeks using the same 8 week spacing between subjects.

Study Endpoints:

The primary endpoints of this pilot study are patient safety and study feasibility. Safety will be determined by clinical and laboratory observation and grading of adverse events, analysis of T cell repertoire clonality, and evaluation of HIV isolates for evidence of vector recombination. 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.

Subject Eligibility and Number. Subjects must be HIV-1 infected adults ≥18 and ≤60 years of age who have been on HAART therapy for at least one year and have evidence of virologic failure defined by >5000 HIV RNA genome copies (gc) per mL in blood. Subjects must have a CD4 count of at least 200 CD4+ T cells/mL. This pilot study is expected to accrue five evaluable patients.

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Inclusion Criteria:

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.

Exclusion Criteria:

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.