Modified T Cells for HIV Therapy

Overseen By Su Kyung Kim, PhD, CRNP, WHNP-BC

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must be taking: HAART

Must not be taking: Corticosteroids, Hydroxyurea, NNRTI, others

Disqualifiers: Hepatitis, AIDS, Cancer, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 1 day for Cohort 1, 8 weeks for Cohort 2

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is being carried out to study a new way to possibly treat HIV. As part of this study, doctors will take some of your own white blood cells, called T-cells, and modify them so that they can identify and target your HIV cells. The purpose of the study is to evaluate the safety of these modified T cells and determine whether they have any effect on HIV infection.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot be taking a non-nucleoside reverse transcriptase inhibitor (NNRTI) or certain medications affecting blood clotting before the procedure. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the treatment CD4 CAR+CCR5 ZFN T-cells for HIV therapy?

Research shows that CCR5 gene-edited CD4+ T cells can delay the return of the virus after stopping regular HIV medication and enhance the body's immune response against HIV. Additionally, using zinc-finger nucleases (ZFN) to modify CCR5 in T cells has been shown to provide resistance to HIV infection, leading to lower viral loads and higher T-cell counts in animal studies. ^{1 2 3 4 5}

Is the treatment with modified T cells for HIV therapy safe for humans?

Studies show that using modified T cells, specifically CCR5 gene-edited CD4+ T cells, is generally safe in humans. Clinical trials reported no serious adverse events, and in vivo toxicity studies showed no detectable toxicity or harmful transformation of T cells. ^{1 3 4 6 7}

How is the treatment CD4 CAR+CCR5 ZFN T-cells unique for HIV therapy?

This treatment is unique because it uses gene editing to modify T-cells, making them resistant to HIV by disrupting the CCR5 gene, which HIV uses to enter cells. This approach aims to create a population of HIV-resistant T-cells, potentially offering a long-term solution compared to traditional antiretroviral therapies that require continuous use. ^{1 2 4 6 8}

Research Team

Pablo Tebas, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for adults over 18 with HIV who've had a stable viral load (≤50 copies/mL) for at least 24 weeks, are on their first or second antiretroviral therapy, and have certain levels of T cells. They must not have hepatitis B/C, AIDS, cancer history (except some skin cancers), heart disease without approval, bleeding disorders, recent gene therapy or experimental vaccines for HIV.

Inclusion Criteria

I am infected with HIV-1.

Negative HBsAg (hepatitis B) within 6 months prior to enrollment

Have a recorded viral load set point prior to starting antiretroviral therapy

Exclusion Criteria

I have a condition that causes unusual bleeding.

I don't have active or unstable heart problems, or if I do, my doctor approves my participation.

Breast-feeding, pregnant, or unwilling to use acceptable methods of birth control

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Subjects receive a single infusion of CD4 CAR+CCR5 ZFN modified T cells

1 day for Cohort 1, 8 weeks for Cohort 2

1 visit (in-person)

Analytical Treatment Interruption (ATI)

Participants undergo a 16-week ATI, with monitoring of viral load and CD4 count

Up to 16 weeks

Regular monitoring visits

Extension of ATI

Participants with viral loads ≤1000 copies/ml continue ATI until specific criteria are met

Variable

Reinitiation of Antiretroviral Therapy

Participants restart antiretroviral therapy with monthly visits until HIV RNA is below quantification limit

Variable

Monthly visits

Secondary Follow-up

All subjects are followed for safety for up to 5 years post-infusion

Up to 5 years

Treatment Details

Interventions

• CD4 CAR+CCR5 ZFN T-cells

Trial Overview The study tests modified T-cells designed to fight HIV. Participants' own T-cells will be taken and genetically altered using CD4 CAR+CCR5 ZFN technology to target the virus. The goal is to assess safety and impact on the infection.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

Cohort 2 subjects will begin treatment interruption approximately 8 weeks after they receive the modified T-cells. All other study procedures are the same as Cohort 1.

Group II: Cohort 1 Experimental Treatment 1 Intervention

Cohort 1 subjects will begin treatment interruption approximately 24 hours after they receive the modified T-cells. All other study procedures are the same as Cohort 2.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

Dual-CAR T cells, which express both 4-1BB/CD3-ζ and CD28/CD3-ζ endodomains, showed superior expansion and effectiveness in preventing CD4+ T cell loss in HIV-infected humanized mice compared to traditional CAR T cells.

When protected from HIV infection, Dual-CAR T cells significantly reduced viral levels and improved HIV suppression during antiretroviral therapy, highlighting their potential as a powerful treatment strategy for HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo. Maldini, CR., Claiborne, DT., Okawa, K., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells invivo. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Targeting of HIV Reservoirs: How to Give T Cells a New Direction. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo. [2023]