Autologous CD4 T-Cells in HIV (C34-CXCR4)

Study Overview
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Brief Summary
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A single cohort, open-label pilot study of the safety and tolerability of a single infusion of autologous CD4+ T-cells genetically modified with an HR2, C34-peptide conjugated to the CXCR4 N-terminus using a lentiviral vector in HIV-infected subjects. This is a first in human study of C34-CXCR4 T cells

Detailed Description
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There will be a single cohort in this study, which consists of subjects with well-controlled HIV replication on HAART. Within this cohort will be 3 escalating doses of T-cell infusions. A modified 3+3+3 dose-escalation design will be followed, in which the standard dose-escalation algorithm is stopped when a maximum of 9 evaluable subjects or a DLT stopping point has been reached, whichever comes first. At each dose level, three patients are treated. For dose levels 1 and 2, if 0/3 subjects have a dose limiting toxicity (DLT), then the dose is escalated. If 1/3 has a DLT (grade 3 or higher unexpected, related adverse event [AE]) at a dose level then 3 additional patients are treated at that dosage before escalating, and if <2/6 have DLT (i.e. no additional DLT is observed) then the dose is escalated to the next planned dose level and patients treated until a maximum of 9 evaluable subjects has been reached. The study will comprise of 5 steps: Step 1, all participants will undergo leukapheresis to obtain CD4 positive T-cells that will be genetically modified. A second leukapheresis and a rectal biopsy will provide baseline specimens to evaluate the size of the HIV reservoir Step 2, all participants will receive a single infusion of C34-CXCR4-modified CD4+ T-cells at one of 3 dose levels. The first 3 subjects will receive dose level 1 of 0.8-1x109 transduced CD4+T-cells. Provided no dose limiting toxicity (DLT) is seen at the first dose level, the next 3 subjects will receive infusion at the 2nd dose level of 2.4-3x109 transduced CD4+ T-cells. If no DLT occurs at that dose, the final 3 subjects will receive the 3rd dose level of 0.8-1x1010 transduced CD4+ T-cells. In the event of a DLT (grade 3 or higher unexpected, related AE) recruitment will be paused pending DSMB decision. Step 3 all participants will participate in a 16-week analytical treatment interruption beginning 4 weeks after T-cell infusion. At the end of step 3 all participants will undergo mini-leukapheresis and rectal biopsy Step 4 all participants will be advised to resume antiretroviral therapy and will be followed until plasma HIV RNA falls below the limit of detection. In Step 5 all participants will undergo leukapheresis and rectal biopsy at 52 weeks post infusion. At the completion of the study, participants will be asked to participate in a long-term follow-up study as required by regulatory authorities.

Official Title
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A Pilot Study to Evaluate the Safety and Tolerability of Escalating Doses of Autologous CD4 T-Cells Modified With Lentiviral Vector Expressing an HR2, C34-peptide Conjugated to the CXCR4 N-terminus in HIV-infected Subjects

Conditions
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Hiv

Intervention / Treatment
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* Biological: Autologous CD4 T-Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to enrollment and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA VL. Ability and willingness of subject to provide informed consent. Men and women ages ≥18 years. 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: changes to safely begin the treatment interruption are permitted). Screening HIV-1 RNA that is ≤50 copies/mL using a FDA-approved assay performed by any laboratory that has a CLIA certification or its equivalent within 30 days prior to enrollment. HIV-1 RNA ≤50 copies/mL using a FDA-approved assay for at least 24 weeks prior to enrollment performed by any laboratory that has a CLIA certification or its equivalent. NOTE: HIV-RNA must be measured at least once in the last 24 weeks and at least 3 days before the screening measure. Single determinations that are between >50 and <400 copies/mL (ie, blips) are allowed as long as the preceding and subsequent determinations are ≤50 copies/mL. The screening value may serve as the subsequent determination ≤50 copies/mL following a blip NOTE: subjects who have participated in other trials using ATI's will be permitted since detectable virus during the interruption does not represent virologic failure. These subjects should have at least 24 weeks of VL <50 copies/mL. Screening CD4+ T-cell count ≥450 cells/ mm3 within 30 days of enrollment. Started ART with nadir CD4+ ≥200 cells/ mm3. The following laboratory values obtained within 30 days prior to enrollment meeting the following criteria: Absolute neutrophil count (ANC) ≥1000 cells/mm3 Hemoglobin:≥10.0(males); ≥9.5 (females) g/dL Platelet count: 100,000/mm3 Calculated creatinine clearance ≥50 mL/min estimated by the Cockcroft-Gault equation Alanine aminotransferase (ALT) ≤ 2.0 x ULN Negative HBsAg within 6 months prior to enrollment. Negative HCV serology, or if positive, negative HCV RNA within 6 months prior to enrollment Adequate venous access and no other contraindications for leukapheresis. Have a Karnofsky Performance Score of 70 or higher. Have a recorded viral load set point prior to starting antiretroviral therapy Exclusion Criteria: Acute or chronic hepatitis B or hepatitis C infection 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 enrollment, 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. Use of chronic systemic corticosteroids, hydroxyurea, or immunomodulating agents (e.g., interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, etc.) within 30 days prior to enrollment. NOTE: Recent or current use of inhaled steroids is not exclusionary. If subjects are prescribed a brief course of oral corticosteroids, the use should be limited to less than 7 days. Use of steroids before apheresis and immune assessment blood draws should be discouraged as it will affect white blood cell function. Breast-feeding, pregnant, or unwilling to use acceptable methods of birth control. Anticipated use of aspirin, dipyridamole, 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 enrollment Asymptomatic baseline serum chemistry elevations in LFTs, bilirubin, and serum creatinine due to HAART medication are not exclusionary, when in the opinion of the investigator, the abnormalities are not attributable to intrinsic hepatorenal disease. Such baseline elevations must be due to HAART. Receipt of vaccination within 30 days prior to enrollment. 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 enrollment Have an allergy or hypersensitivity to study product excipients (human serum albumin, DMSO and Dextran 40).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose level 1:<br>Autologous CD4 T-Cells0.8-1x10^9 transduced CD4+T-cells administered IV as a single dose | Biological: Autologous CD4 T-Cells<br>* all participants will receive a single infusion of C34-CXCR4-modified CD4+ T-cells at one of 3 dose levels. The first 3 subjects will receive dose level 1 of 0.8-1x109 transduced CD4+T-cells. Provided no dose limiting toxicity (DLT) is seen at the first dose level, the next 3 subjects will receive infusion at the 2nd dose level of 2.4-3x109 transduced CD4+ T-cells. If no DLT occurs at that dose, the final 3 subjects will receive the 3rd dose level of 0.8-1x1010 transduced CD4+ T-cells. In the event of a DLT (grade 3 or higher unexpected, related AE) recruitment will be paused pending DSMB decision<br>|
| Active Comparator: Dose level 2<br>Autologous CD4 T-Cells 2.4-3x10^9 transduced CD4+ T-cells administered IV as a single dose | Biological: Autologous CD4 T-Cells<br>* all participants will receive a single infusion of C34-CXCR4-modified CD4+ T-cells at one of 3 dose levels. The first 3 subjects will receive dose level 1 of 0.8-1x109 transduced CD4+T-cells. Provided no dose limiting toxicity (DLT) is seen at the first dose level, the next 3 subjects will receive infusion at the 2nd dose level of 2.4-3x109 transduced CD4+ T-cells. If no DLT occurs at that dose, the final 3 subjects will receive the 3rd dose level of 0.8-1x1010 transduced CD4+ T-cells. In the event of a DLT (grade 3 or higher unexpected, related AE) recruitment will be paused pending DSMB decision<br>|
| Active Comparator: Dose level 3<br>Autologous CD4 T-Cells 0.8-1x10^10 transduced CD4+ T-cells administered IV as a single dose | Biological: Autologous CD4 T-Cells<br>* all participants will receive a single infusion of C34-CXCR4-modified CD4+ T-cells at one of 3 dose levels. The first 3 subjects will receive dose level 1 of 0.8-1x109 transduced CD4+T-cells. Provided no dose limiting toxicity (DLT) is seen at the first dose level, the next 3 subjects will receive infusion at the 2nd dose level of 2.4-3x109 transduced CD4+ T-cells. If no DLT occurs at that dose, the final 3 subjects will receive the 3rd dose level of 0.8-1x1010 transduced CD4+ T-cells. In the event of a DLT (grade 3 or higher unexpected, related AE) recruitment will be paused pending DSMB decision<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Subjects With Treatment Related Adverse Events | assessed by DAIDS AE grading table v2.0 November 2014 | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the Percentage of Enriched Modified Cells C34-CXCR4 Modifiec T- Cells |  | 2 weeks post infusion, prior to ARV reinitiation, weeks 12, 16 and 20 | 
| Compare the Change Between CD4 Count |  | Baseline, week 2 post infusion, prior to ARV initiation, weeks 12, 16 20 | 
| Compare Viral Set Point Log 10 HIV RNA Level |  | week 2 post infusion, prior to ARV initiation, week 12, 16, 20 | 
| Evaluate Cell Mediated Response (Immunogenicity) Using Flow Cytometry |  | baseline through 1 year |