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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment, LVgp120duoCAR-T cells (a type of CAR-T cell therapy), to determine its effectiveness against HIV infection. Participants will be divided into groups to test different doses and methods of administration. Some groups will undergo a conditioning step with cyclophosphamide to enhance the treatment's effectiveness. Individuals who have been on stable HIV medication for over a year and maintain good immune cell levels might be suitable for this study. Participants should be willing to pause their HIV medication as part of the trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CAR-T cell therapy, like the one being tested for HIV, holds promise in early studies. These specially designed cells can target and fight HIV in lab settings, suggesting they might control the virus and eliminate infected cells.

Regarding safety, earlier research suggests that this therapy is generally well-tolerated, though side effects can occur. Common side effects include fever, tiredness, or low blood counts, typical for treatments that alter immune system function. Since this trial is in an early stage, it focuses on determining the right dose and ensuring the treatment's safety for participants.

The trial tests different doses of the treatment, sometimes with additional medications to prepare the body. The safety of these doses remains under study, but the trial is carefully designed for close monitoring. Participants receive close observation to quickly address any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CAR-T cell therapy for HIV because it represents a novel approach compared to existing treatments like antiretroviral therapy (ART), which requires lifelong adherence and primarily controls the virus without eliminating it. This therapy uses genetically modified T cells, known as LVgp120duoCAR-T cells, to specifically target and destroy HIV-infected cells, potentially offering a functional cure. Unlike standard ART, which suppresses the virus, CAR-T cells aim to eradicate it, which could revolutionize HIV treatment by reducing or eliminating the need for continuous medication. The excitement also stems from the potential to interrupt ART immediately after infusion, suggesting a significant shift towards more sustainable long-term solutions for managing HIV.

What evidence suggests that this trial's treatments could be effective for HIV?

Research shows that a new treatment, called LVgp120duoCAR-T cells, holds promise in fighting HIV. Participants in this trial will receive either a low or high dose of LVgp120duoCAR-T cells, with some undergoing conditioning with cyclophosphamide. Early animal studies demonstrated that these cells can control HIV and protect important immune cells. They also strongly suppressed HIV and destroyed cells carrying the virus. These initial findings suggest that LVgp120duoCAR-T cells might effectively target and eliminate HIV-infected cells. Early safety results from human treatments are encouraging as well. ^{1 3 6 7 8}

Who Is on the Research Team?

Steven J Deeks, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04648046

Study Details | NCT04648046 | CAR-T Cells for HIV Infection 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.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7136029/

Multi-specific anti-HIV duoCAR-T cells display broad ... Furthermore, multi-specific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4+ T ...

3. health.ucdavis.edu health.ucdavis.edu/news/headlines/clinical-trial-begins-using-car-t-cells-to-potentially-cure-hiv/2023/04

Clinical trial begins using CAR T cells to potentially cure HIV Pre-clinical research investigating the CAR T-cell therapy demonstrated an ability to potently suppress HIV and eliminate HIV-expressing cells ...

4. natap.org natap.org/2023/HIV/051223_03.htm

First two patients receive CAR T cell therapy for HIV The first patient received LVgp120duoCAR-T cells in August of 2022. The safety signals are encouraging, with Mehrdad Abedi, who leads the trial at the ...

5. withpower.com withpower.com/trial/phase-2-communicable-diseases-2-2021-0d444

CAR-T Cell Therapy for HIV 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10057306/

Opportunities for CAR-T Cell Immunotherapy in HIV Cure - PMC A recent study showed that multiple-site targeting CAR-T cells consistently demonstrated greater suppressive activity against HIV-1 in vitro and ...

7. trialx.com trialx.com/clinical-trials/listings/276473/car-t-cells-for-hiv-infection/

CAR-T Cells for HIV Infection | Clinical Research Trial ... This is a limited-center, open-label dose escalating phase I/IIa study of autologous T cells expressing LVgp120duoCAR molecules in people with ...

8. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT04648046

CAR-T Cells for HIV Infection 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.