CAR-T Cell Therapy for HIV

Recruiting at 1 trial location

Overseen By Rebecca Hoh

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Steven Deeks

Must be taking: Antiretrovirals

Must not be taking: NNRTIs, Protease inhibitors, AZT

Disqualifiers: HIV malignancy, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 45 days per cohort

18 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

Participants will need to pause their HIV medications during the study as part of an analytic treatment interruption. However, the trial does not specify if other medications need to be stopped.

What data supports the effectiveness of the CAR-T cell therapy for HIV?

Research shows that CAR-T cell therapy can target and kill HIV-infected cells in humanized mice, and similar therapies have been effective in increasing specific immune cells in humans, suggesting potential for controlling HIV. ^{1 2 3 4 5}

Is CAR-T cell therapy for HIV safe for humans?

Research on CAR-T cell therapy for HIV shows that it is generally safe in humans. In a Phase 1 trial, there were no serious adverse events, and all side effects were mild. Another study found no severe adverse effects, and any minor issues resolved without medical help. ^{1 3 6 7 8}

How is the CAR-T cell treatment for HIV different from other treatments?

The CAR-T cell treatment for HIV is unique because it uses genetically modified immune cells to specifically target and kill HIV-infected cells, potentially offering a functional cure by eliminating the virus from the body, unlike standard antiretroviral therapy which only suppresses the virus. ^{1 9 10 11 12}

Research Team

Steven J Deeks, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults aged 18-65 with HIV who've been on stable antiretroviral therapy (ART) without interruptions for at least a year. They must have undetectable viral loads, a history of good immune health indicated by CD4+ T cell counts, and be willing to pause their ART during the study. Excluded are pregnant or breastfeeding individuals, those unwilling to use birth control, people with certain cancers or hepatitis infections, and anyone on specific ART drugs that may interact poorly with the trial medications.

Inclusion Criteria

Screening CD4+ T-cell count ≥ 500 cells/mm3

I am infected with HIV-1.

I've been on stable HIV treatment for over a year without breaks longer than 2 weeks.

Exclusion Criteria

I have a long-term liver condition.

I have had a cancer linked to HIV, like Kaposi's sarcoma or lymphoma.

Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive autologous T cells expressing LVgp120duoCAR molecules, with dose escalation based on safety evaluation

45 days per cohort

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including post-treatment control and persistence of CAR-T cells

36 weeks

Regular visits for monitoring and sample collection

Long-term Follow-up

Participants are monitored for adverse events and long-term outcomes

1 year

Treatment Details

Interventions

• Cyclophosphamide
• LVgp120duoCAR-T cells, high dose
• LVgp120duoCAR-T cells, low dose

Trial Overview The study tests LVgp120duoCAR-T cells in three escalating doses to see how they affect HIV infection. Participants will either receive low-dose CAR-T cells alone or combined with cyclophosphamide conditioning; another group gets high-dose CAR-T after conditioning. The treatment's impact will be assessed during an analytic treatment interruption where standard HIV meds are paused.

Participant Groups

Group I: Low Dose CAR-T Cells Only Experimental Treatment 2 Interventions

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.

Group II: Conditioning + Low Dose CAR-T Cells Experimental Treatment 3 Interventions

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.

Group III: Conditioning + High Dose CAR-T Cells Experimental Treatment 3 Interventions

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.

LVgp120duoCAR-T cells, high dose is already approved in United States, European Union for the following indications:

Approved in United States as CAR-T cells for:

• Acute Lymphoblastic Leukemia
• Non-Hodgkin Lymphoma
• Multiple Myeloma

Approved in European Union as CAR-T cells for:

• Acute Lymphoblastic Leukemia
• Non-Hodgkin Lymphoma
• Multiple Myeloma

Who Is Running the Clinical Trial?

Steven Deeks

Lead Sponsor

Trials

2

Recruited

70+

Caring Cross

Collaborator

Trials

1

Recruited

20+

Findings from Research

Anti-HIV duoCAR T cell therapy has shown promising efficacy in eliminating HIV-infected cells in humanized mice, indicating its potential to target and destroy reactivated HIV-infected cells in people with HIV.

The therapy effectively localizes to lymphoid tissues and demonstrates the ability to kill HIV-infected CD4+ T cells and monocytes/macrophages, supporting its safety and efficacy as it moves into clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo killing of primary HIV-infected cells by peripheral-injected early memory-enriched anti-HIV duoCAR T cells. Anthony-Gonda, K., Ray, A., Su, H., et al.[2023]

In a study of 90 people living with HIV-1 on long-term combined antiretroviral therapy (cART), researchers found that CD8+ T cells specific to a wide range of HIV-1 epitopes were maintained, suggesting a potential for these cells in curative treatments.

Long-term cART not only preserved these HIV-1-specific T cells but also enhanced their ability to proliferate in laboratory conditions, indicating that they could serve as effective effector cells in future 'shock and kill' strategies against HIV-1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8+ T cells. Kuse, N., Gatanaga, H., Zhang, Y., et al.[2023]

AGT103-T, a genetically engineered cell therapy, was found to be safe with no serious adverse events reported in a Phase 1 clinical trial involving participants with chronic HIV, who received either low or high doses of the treatment.

The therapy significantly increased Gag-specific CD4+ T cells by 9 to 300-fold and Gag-specific CD8+ T cells by 1.7 to 10-fold within weeks of infusion, indicating its efficacy in enhancing the immune response against HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and durability of AGT103-T autologous T cell therapy for HIV infection in a Phase 1 trial. Muvarak, N., Li, H., Lahusen, T., et al.[2022]

Engineering T cells to express HIV-specific chimeric antigen receptors (CARs) combined with a cytomegalovirus (CMV) vaccine can enhance T cell activation and persistence, particularly during low HIV antigen levels seen in antiretroviral therapy (ART).

In a humanized HIV mouse model, CMV vaccination during ART led to increased expansion of CMV-HIV CAR T cells, which correlated with better control of HIV viral load and reduced presence of HIV-infected cells in the bone marrow, suggesting a promising strategy for HIV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-clinical data supporting immunotherapy for HIV using CMV-HIV-specific CAR T cells with CMV vaccine. Guan, M., Lim, L., Holguin, L., et al.[2023]

In a study involving 4 ART-suppressed rhesus macaques, the infusion of virus-specific CD4CAR T cells followed by supplemental HIV-1 envelope (Env) led to significant expansion of CAR T cells and delayed viral rebound after ART interruption, demonstrating a novel approach to enhance CAR T cell efficacy in low-antigen environments.

The use of anti-PD-1 antibody to reverse immune exhaustion in CAR T cells resulted in further expansion and reduced viral loads to undetectable levels, highlighting the potential of combining CAR T cell therapy with immune checkpoint blockade for better outcomes in HIV-1 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates. Rust, BJ., Kean, LS., Colonna, L., et al.[2021]

The T cell therapy targeting HLA-A02 restricted HIV antigen epitopes was found to be safe, with only two mild adverse effects reported that resolved without medical intervention among 28 HIV+ participants.

The therapy showed a downregulation of PD-1 and CD95 molecules on CD8+ T cells post-treatment, suggesting a potential impact on immune suppression, although there were no significant differences in symptoms or lab tests compared to the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T Cell Therapy Targeted on HLA-A02 Restricted HIV Antigen Epitopes: An Open Label Cellular Therapy Trial Using CD8+ T Cell. Liu, S., Sun, J., Li, Z., et al.[2021]

The study developed a novel CAR-T therapy using duoCARs that target multiple conserved sites on the HIV-1 envelope, showing a remarkable ability to reduce HIV infection by up to 99% in vitro and over 97% in vivo.

Transduced T cells demonstrated long-term control of HIV infection and protection against diverse HIV-1 strains, suggesting that this approach could effectively treat HIV-1 in patients and prevent the loss of crucial CD4+ T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model. Anthony-Gonda, K., Bardhi, A., Ray, A., et al.[2020]

The development of a universal CAR-NK cell that targets 2,4-dinitrophenyl (DNP) allows for flexible targeting of various HIV envelope epitopes, potentially overcoming the virus's diversity and mutability.

This CAR-NK cell effectively recognizes and kills HIV-infected cells expressing different subtypes of the gp160 protein, demonstrating its efficacy in targeting both mimic cell lines and primary human CD4+ T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Universal CAR-NK Cell Targeting Various Epitopes of HIV-1 gp160. Lim, RM., Rong, L., Zhen, A., et al.[2021]

Anti-HIV chimeric antigen receptor (CAR) T cells have the potential to provide a cure for HIV by specifically targeting and eliminating virus-producing cells, even in patients undergoing successful antiretroviral therapy.

The review highlights advancements in CAR design aimed at improving their effectiveness and targeting precision, while also addressing ongoing challenges that must be overcome to make this treatment a viable option for curing HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status and future development of anti-HIV chimeric antigen receptor T-cell therapy. Mao, Y., Zhao, C., Zheng, P., et al.[2022]

Chimeric antigen receptor (CAR) cell therapy shows promise as a potential strategy for enhancing immunity against HIV-1, aiming for virus control or elimination without the need for lifelong antiretroviral therapy (ART).

Recent advancements in CAR cell therapy over the past two decades include engineering modifications to protect these cells from HIV-1 infection, with several therapies currently progressing to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in HIV-1-specific chimeric antigen receptor cells to target the HIV-1 reservoir. Choudhary, MC., Cyktor, JC., Riddler, SA.[2023]

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]

Antiretroviral therapy (ART) can reduce HIV viral load to undetectable levels, but it cannot eliminate the virus due to its integration into the host's genome, leading to persistent viral reservoirs.

Chimeric antigen receptor (CAR) therapy is emerging as a promising strategy to enhance immunity against HIV and potentially eliminate these reservoirs, with various CAR structures and cell types being explored for clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the HIV reservoir: chimeric antigen receptor therapy for HIV cure. Li, S., Wang, H., Guo, N., et al.[2023]

References

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

In vivo killing of primary HIV-infected cells by peripheral-injected early memory-enriched anti-HIV duoCAR T cells. [2023]

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

Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8+ T cells. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and durability of AGT103-T autologous T cell therapy for HIV infection in a Phase 1 trial. [2022]

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

Pre-clinical data supporting immunotherapy for HIV using CMV-HIV-specific CAR T cells with CMV vaccine. [2023]

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

Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

T Cell Therapy Targeted on HLA-A02 Restricted HIV Antigen Epitopes: An Open Label Cellular Therapy Trial Using CD8+ T Cell. [2021]

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

Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model. [2020]

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

A Universal CAR-NK Cell Targeting Various Epitopes of HIV-1 gp160. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Current status and future development of anti-HIV chimeric antigen receptor T-cell therapy. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Advances in HIV-1-specific chimeric antigen receptor cells to target the HIV-1 reservoir. [2023]

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

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

12. China pubmed.ncbi.nlm.nih.gov

Targeting the HIV reservoir: chimeric antigen receptor therapy for HIV cure. [2023]