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CAR-T Cells for HIV Infection

Primary Purpose

HIV Infections

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
LVgp120duoCAR-T cells, low dose
LVgp120duoCAR-T cells, high dose
Analytic Treatment Interruption
Sponsored by
Steven Deeks
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring HIV, HIV/AIDS, CAR-T cells, HIV cure, HIV reservoir, Immunotherapy

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female, age ≥ 18 and ≤ 65 years
  • HIV-1 infection
  • On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days, and on a stable regimen that does not include a non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks or any long-acting ART drug that may be active in the participant after ART interruption for up to one year, without plans to modify ART during the study period
  • Screening plasma HIV RNA levels below the limit of quantification on all available determinations in past 12 months (isolated single values ≥ 40 but < 200 copies/mL will be allowed if they were preceded and followed by undetectable viral load determinations)
  • CD4+ T cell count nadir > 300 cells/mm3
  • Screening CD4+ T-cell count ≥ 500 cells/mm3
  • Available ART treatment history and the capacity to construct an effective antiretroviral treatment regimen
  • Willing to pause ART as part of the study

Exclusion Criteria:

  • Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
  • ART regimen that includes a long-acting anti-HIV drug and/or NNRTI that may be active in the participant for up to one year after ART interruption
  • ART regimen that includes protease inhibitor(s) and/or AZT. These drugs may increase the toxicity of cyclophosphamide.
  • Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers
  • History of or current active hepatitis B (HBV) infection defined as positive HBV surface antigen test. A positive anti-HBc regardless of HBsAg status.
  • Active hepatitis C (HCV) infection
  • Active or latent tuberculosis infection
  • Chronic liver disease
  • Active and poorly controlled atherosclerotic cardiovascular disease
  • Unwillingness to abstain from sex or use barrier protection for any sexual activity during the treatment interruption.

Sites / Locations

  • University of California, DavisRecruiting
  • Zuckerberg San Francisco GeneralRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Low Dose CAR-T Cells Only

Conditioning + Low Dose CAR-T Cells

Conditioning + High Dose CAR-T Cells

Arm Description

Participants will NOT undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.

Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.

Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 1 x 10^6 cells/kg LVgp120duoCAR-T cells will be infused into the participant. ART will be interrupted immediately after infusion.

Outcomes

Primary Outcome Measures

Number of participants reporting a new Grade 3 or greater adverse event that is definitely, probably, or possibly related to study treatment within 1 year of product administration.
The primary safety outcome will be the number of participants reporting a new Grade 3 or greater adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, including signs/symptoms, lab toxicity or clinical event, that is definitely, probably, or possibly related to study treatment within 1 year of product administration.
Number of participants achieving post-treatment control within 36 weeks of product administration.
The primary efficacy outcome will be the proportion of individuals who achieve study-defined post-treatment control. The investigators will define post-treatment control in two ways. First, participants who fail to show any consistent rebound above 400 copies RNA/mL between Weeks 12 and Week 36 will be considered as having achieved post-treatment control. Second, participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control.

Secondary Outcome Measures

Persistence of LVgp120duoCAR-T cells in blood during therapy
Real-time quantitative polymerase chain reaction (qPCR) will be used to monitor the frequency of circulating CD4+ and CD8+ T cells harboring the integrated LVgp120duoCAR-T gene longitudinally to determine product persistence. This measure will be performed on blood samples.
Persistence of LVgp120duoCAR-T cells in tissues during therapy
Real-time quantitative polymerase chain reaction (qPCR) will be used to monitor the frequency of circulating CD4+ and CD8+ T cells harboring the integrated LVgp120duoCAR-T gene longitudinally to determine product persistence. This measure will be performed on tissue samples collected from volunteers agreeing to lymph node sampling.
Change in quantitative virologic measures of the HIV reservoir pre- and post-therapy
The HIV reservoir will be measured using methods such as quantitative PCR (qPCR), ultra-sensitive PCR, and/or the intact proviral DNA assay (IPDA) at baseline and time points throughout the study. Changes in the number of copies per 10^6 T cells will be reported.

Full Information

First Posted
November 23, 2020
Last Updated
May 26, 2023
Sponsor
Steven Deeks
Collaborators
Caring Cross
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1. Study Identification

Unique Protocol Identification Number
NCT04648046
Brief Title
CAR-T Cells for HIV Infection
Official Title
Safety and Anti-HIV Activity of Autologous CD4+ and CD8+ T Cells Transduced With a Lentiviral Vector Encoding Bi-specific Anti-gp120 CAR Molecules (LVgp120duoCAR-T) in Anti-retroviral Drug-treated HIV-1 Infection
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2021 (Actual)
Primary Completion Date
December 31, 2026 (Anticipated)
Study Completion Date
December 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Steven Deeks
Collaborators
Caring Cross

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a limited-center, open-label dose escalating phase I/IIa study of autologous T cells expressing LVgp120duoCAR molecules in people with HIV infection. It will follow a 3+3 design. Dose escalation decisions will be made when a minimum of three participants have completed the safety-evaluation period (45 days) at a given dose level. Cohort 1 will undergo infusion of a single low-dose regimen of LVgp120duoCAR-T cells. Cohort 2 will undergo non-ablative conditioning with cyclophosphamide, followed by infusion of a single low-dose regimen of LVgp120duoCAR-T cells. Cohort 3 will undergo non-ablative conditioning with cyclophosphamide, followed infusion of a single high-dose regimen of LVgp120duoCAR-T cells. Following administration of the experimental therapy, HIV medications will be paused for participants in each group during an analytic treatment interruption.
Detailed Description
A limited-center, open-label dose escalating phase I/IIa study of autologous T cells expressing LVgp120duoCAR molecules will be performed. Participants will be enrolled sequentially in up to three cohorts following a 3+3 design. Dose escalation decisions will be made when a minimum of three participants have completed the safety-evaluation period (45 days) at a given dose level. No dose escalation will be allowed in an individual participant, and participants who have dose limiting adverse events will reinstate ART therapy at first available opportunity. Following a 3+3 design, each cohort will enroll at least 3 participants. If there are no safety issues with dosing in a cohort, the investigators will proceed to the following cohort. If one participant in a cohort experiences a safety issue, an additional 3 individuals will be enrolled in that cohort to assess safety prior to proceeding to the next cohort. See below for Dose Escalation Procedures. The first 3 participants start at Cohort 1. Data from Cohort 1 will be submitted for FDA review prior to dosing Cohorts 2 and 3 to determine if cyclophosphamide conditioning is needed. Cohort 1: Participants will NOT undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 105 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion. Cohort 2: Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 105 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion. Cohort 3: Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 1 x 106 cells/kg LVgp120duoCAR-T cells will be infused into the participant. ART will be interrupted immediately after infusion. Dose Escalation Procedures: If, after 45 days of study treatment, no participant out of the initial 3 in a cohort exhibits a study treatment-related DLT, then the next cohort of participants will be treated at the subsequent cohort. If, after 45 days of study treatment, 1 participant out of the initial 3 in a cohort exhibits a study treatment-related DLT, then up to 3 additional participants will be added at that dose level. If no additional participant develops a study treatment-related DLT (i.e., 1/6 participants with DLT at that dose level), then the next cohort of participants will be treated at the next higher dose level. However, if a second participant develops a study treatment-related DLT, even if it is before there are 6 total participants on that level, then the maximum tolerated dose (MTD) has been exceeded and no additional participants should be added to this or any higher doses. A total of 6 participants should then be treated on the next lowest dose level to ensure its tolerability and to better define the MTD. Thus, the MTD is defined as the highest assigned dose level at which < 2/6 participants have a DLT. If 2 participants in Cohort 1 experience a related DLT, the MTD will have been exceeded and no additional participants will be added at any higher level. If the investigators experience DLTs in Cohort 1, the investigators will de-escalate the dose to 1 x 10^5 cells per kg. If the investigators experience DLTs at the de-escalated dose of 1 x 10^5 cells per kg, the study will stop.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
HIV, HIV/AIDS, CAR-T cells, HIV cure, HIV reservoir, Immunotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
The clinical trial is an open-label dose escalating phase I/IIa study of autologous T cells expressing LVgp120duoCAR molecules that target and kill HIV-1 gp120 expressing cells. Participants will be enrolled sequentially in up to three sequentially enrolled cohorts in a 3+3 design. Dose escalation decisions will be made when a minimum of three participants have completed the safety-evaluation period (45 days) at a given dose level. No dose escalation will be allowed in an individual participant, and participants who have dose limiting adverse events will reinstate ART therapy at first available opportunity. There are 3 dose escalation cohorts with the first 3 participants starting at Cohort 1.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Low Dose CAR-T Cells Only
Arm Type
Experimental
Arm Description
Participants will NOT undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
Arm Title
Conditioning + Low Dose CAR-T Cells
Arm Type
Experimental
Arm Description
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
Arm Title
Conditioning + High Dose CAR-T Cells
Arm Type
Experimental
Arm Description
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 1 x 10^6 cells/kg LVgp120duoCAR-T cells will be infused into the participant. ART will be interrupted immediately after infusion.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Non-ablative conditioning with cyclophosphamide.
Intervention Type
Biological
Intervention Name(s)
LVgp120duoCAR-T cells, low dose
Intervention Description
A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused.
Intervention Type
Biological
Intervention Name(s)
LVgp120duoCAR-T cells, high dose
Intervention Description
A single dose of 1 x 10^6 cells/kg LVgp120duoCAR-T cells will be infused.
Intervention Type
Other
Intervention Name(s)
Analytic Treatment Interruption
Intervention Description
HIV antiretroviral therapy medications will be paused.
Primary Outcome Measure Information:
Title
Number of participants reporting a new Grade 3 or greater adverse event that is definitely, probably, or possibly related to study treatment within 1 year of product administration.
Description
The primary safety outcome will be the number of participants reporting a new Grade 3 or greater adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, including signs/symptoms, lab toxicity or clinical event, that is definitely, probably, or possibly related to study treatment within 1 year of product administration.
Time Frame
Within 1 year of product administration
Title
Number of participants achieving post-treatment control within 36 weeks of product administration.
Description
The primary efficacy outcome will be the proportion of individuals who achieve study-defined post-treatment control. The investigators will define post-treatment control in two ways. First, participants who fail to show any consistent rebound above 400 copies RNA/mL between Weeks 12 and Week 36 will be considered as having achieved post-treatment control. Second, participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control.
Time Frame
Week 36
Secondary Outcome Measure Information:
Title
Persistence of LVgp120duoCAR-T cells in blood during therapy
Description
Real-time quantitative polymerase chain reaction (qPCR) will be used to monitor the frequency of circulating CD4+ and CD8+ T cells harboring the integrated LVgp120duoCAR-T gene longitudinally to determine product persistence. This measure will be performed on blood samples.
Time Frame
Week 12 through Week 36
Title
Persistence of LVgp120duoCAR-T cells in tissues during therapy
Description
Real-time quantitative polymerase chain reaction (qPCR) will be used to monitor the frequency of circulating CD4+ and CD8+ T cells harboring the integrated LVgp120duoCAR-T gene longitudinally to determine product persistence. This measure will be performed on tissue samples collected from volunteers agreeing to lymph node sampling.
Time Frame
Week 12 through Week 36
Title
Change in quantitative virologic measures of the HIV reservoir pre- and post-therapy
Description
The HIV reservoir will be measured using methods such as quantitative PCR (qPCR), ultra-sensitive PCR, and/or the intact proviral DNA assay (IPDA) at baseline and time points throughout the study. Changes in the number of copies per 10^6 T cells will be reported.
Time Frame
Baseline and 36 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female, age ≥ 18 and ≤ 65 years HIV-1 infection On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days, and on a stable regimen that does not include a non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks or any long-acting ART drug that may be active in the participant after ART interruption for up to one year, without plans to modify ART during the study period Screening plasma HIV RNA levels below the limit of quantification on all available determinations in past 12 months (isolated single values ≥ 40 but < 200 copies/mL will be allowed if they were preceded and followed by undetectable viral load determinations) CD4+ T cell count nadir > 300 cells/mm3 Screening CD4+ T-cell count ≥ 500 cells/mm3 Available ART treatment history and the capacity to construct an effective antiretroviral treatment regimen Willing to pause ART as part of the study Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study ART regimen that includes a long-acting anti-HIV drug and/or NNRTI that may be active in the participant for up to one year after ART interruption ART regimen that includes protease inhibitor(s) and/or AZT. These drugs may increase the toxicity of cyclophosphamide. Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers History of or current active hepatitis B (HBV) infection defined as positive HBV surface antigen test. A positive anti-HBc regardless of HBsAg status. Active hepatitis C (HCV) infection Active or latent tuberculosis infection Chronic liver disease Active and poorly controlled atherosclerotic cardiovascular disease Unwillingness to abstain from sex or use barrier protection for any sexual activity during the treatment interruption.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Rebecca Hoh
Phone
415-476-4082
Ext
139
Email
rebecca.hoh@ucsf.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Deeks, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, Davis
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christina Dyner, RN
Email
cjdyer@ucdavis.edu
First Name & Middle Initial & Last Name & Degree
Mehrdad Abedi
Facility Name
Zuckerberg San Francisco General
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rebecca Hoh, MS
Phone
415-476-4082
Ext
139
Email
rebecca.hoh@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Steven Deeks, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36345941
Citation
Anthony-Gonda K, Ray A, Su H, Wang Y, Xiong Y, Lee D, Block A, Chilunda V, Weiselberg J, Zemelko L, Wang YY, Kleinsorge-Block S, Reese JS, de Lima M, Ochsenbauer C, Kappes JC, Dimitrov DS, Orentas R, Deeks SG, Rutishauser RL, Berman JW, Goldstein H, Dropulic B. In vivo killing of primary HIV-infected cells by peripheral-injected early memory-enriched anti-HIV duoCAR T cells. JCI Insight. 2022 Nov 8;7(21):e161698. doi: 10.1172/jci.insight.161698.
Results Reference
derived

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CAR-T Cells for HIV Infection

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