HIV-1 InfectionEarly Phase 1Gene TransferNCT01153646
Gene Transfer for HIV Using Autologous T Cells
A Early Phase 1 study testing pHIV7-shI-TAR-CCR5RZ treated CD4 cells in people with HIV-1 Infection, run by City of Hope Medical Center at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- HIV-1 Infection
- What is being tested?
- pHIV7-shI-TAR-CCR5RZ treated CD4 cells
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2010to Jan 2011
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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%.
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- 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.
Who cannot join
- 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.
Show all 14Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Beckman Research Institute of City of Hope
Duarte, California, 91010
About this study
Official title: A Pilot Study of Safety and Feasibility of T-Cell Immunotherapy Using Lentivirus Vector-Expressed RNAi in Autologous T-Cells of HIV-1 Infected Patients Who Have Failed Anti-Retroviral Therapy
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).
Read the detailed description
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.
- Conditions
- HIV-1 Infection
- Being tested
- pHIV7-shI-TAR-CCR5RZ treated CD4 cells
- Keywords
- HIV, Gene Transfer, T-Cell Immunotherapy, HIV-1 infected patients who have failed anti-retroviral therapy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
pHIV7-shI-TAR-CCR5RZ treated CD4 cellsGenetic
Single dose administration x 3 of genetically modified T-cells given at 3 infusions at 6 week intervals.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1: 1x10e9 and Cohort 2: 1x10e10 T cells per infusion | Experimental | Group of patients receiving genetically modified T-cells Receives: Genetic: pHIV7-shI-TAR-CCR5RZ treated CD4 cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: During time of follow-up years 0-2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jun 2010 (estimated)
- Study startApr 2010
- Primary completionJan 2011
- Study completionJan 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for HIV-1 InfectionStudies of the same condition, open and under way.
- More trials run by City of Hope Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (estimated)
Sponsor and investigators
- Lead sponsor
- City of Hope Medical Center
- Sponsor type
- University, hospital or other
- Investigators
- John A. Zaia, MD, Principal investigator, Beckman Research Institute of City of Hope
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01153646
- Sponsor's protocol ID
- 03161
- Other IDs
- IND #14146
- Acronym
- Gene Transfer
- Status last verified
- Jan 2011
- First submitted
- 28 Jun 2010
- Last updated
- 19 Jan 2011
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 11786906Sarver 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.
PubMed 2107573Bai 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.
PubMed 10933940Bauer 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.
PubMed 9116267Lee 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.
PubMed 11981565Li 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.
PubMed 12907142Li 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.
PubMed 16115802
Study at a glance
From the registry record, last updated by the sponsor on 19 Jan 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of Safety and Feasibility of T-Cell Immunotherapy Using Lentivirus Vector-Expressed RNAi in Autologous T-Cells of HIV-1 Infected Patients Who Have Failed Anti-Retroviral Therapy
- ClinicalTrials.gov ID
- NCT01153646
- Acronym / sponsor ID
- Gene Transfer / 03161
- Conditions
- HIV-1 Infection
- Keywords
- HIV, Gene Transfer, T-Cell Immunotherapy, HIV-1 infected patients who have failed anti-retroviral therapy
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 5 participants (estimated)
- Lead sponsor
- City of Hope Medical CenterUniversity, hospital or other
- Study start
- Apr 2010
- Primary completion
- Jan 2011 (actual)
- Study completion
- Jan 2011 (actual)
- First posted
- 30 Jun 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
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.
Study design
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Cohort 1: 1x10e9 and Cohort 2: 1x10e10 T cells per infusion | Experimental | Genetic: pHIV7-shI-TAR-CCR5RZ treated CD4 cellsGroup of patients receiving genetically modified T-cells |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (13 listed)
- 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%.
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| pHIV7-shI-TAR-CCR5RZ treated CD4 cellsSingle dose administration x 3 of genetically modified T-cells given at 3 infusions at 6 week intervals. | Genetic | Cohort 1: 1x10e9 and Cohort 2: 1x10e10 T cells per infusion |
Primary outcome
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
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
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.
1 secondary outcome
Genetic marking in peripheral blood using vector-specific PCR assay.
Time frame: During time of follow-up years 0-2
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jan 2011.
- Background: PubMed 11786906Levine 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.
- Background: PubMed 2107573Sarver 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.
- Background: PubMed 10933940Bai 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.
- Background: PubMed 9116267Bauer 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.
- Background: PubMed 11981565Lee 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.
- Background: PubMed 12907142Li 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.
- Background: PubMed 16115802Li 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John A. Zaia, MD principal investigator
Beckman Research Institute of City of Hope
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing pHIV7-shI-TAR-CCR5RZ treated CD4 cells in people with HIV-1 Infection, run by City of Hope Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 19 Jan 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01153646, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jan 2011.