CAR T Cells for HIV

Recruiting at 1 trial location

Overseen By Steven Hendrickx

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: City of Hope Medical Center

Must be taking: Antiretrovirals

Disqualifiers: Concurrent illness, Antiretroviral resistance, others

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

Compensation: Varies

Number of Visits: 3

Duration: 1 day

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to interrupt their ART regimen for 4 days before a procedure called leukapheresis (a process to collect blood cells). Other current medications are not specified in the protocol.

What data supports the effectiveness of the treatment CMV/HIV-CAR T Cells for HIV?

Research shows that CMV-HIV CAR T cells, when combined with a CMV vaccine, can expand in the blood and help control HIV levels in a mouse model. This suggests potential effectiveness in managing HIV in humans. ^{1 2 3 4 5}

Is CAR T cell therapy for HIV safe in humans?

The research does not provide specific safety data for CAR T cell therapy for HIV in humans, but it supports the clinical development of CMV-HIV CAR T cells in combination with a CMV vaccine for HIV-infected individuals. ^{4 6 7 8 9}

What makes the CMV/HIV-CAR T Cells treatment unique for HIV?

The CMV/HIV-CAR T Cells treatment is unique because it uses engineered T cells that target both HIV and CMV (a common virus) to enhance the immune response against HIV. This approach combines a CMV vaccine to boost the activity and persistence of these T cells, potentially improving control of HIV compared to traditional antiretroviral therapy alone. ^{1 3 4 10 11}

What is the purpose of this trial?

Human immunodeficiency virus type 1 (HIV-1) causes a persistent infection that ultimately leads to acquired immunodeficiency syndrome (AIDS). Treatment of HIV-1 infection with combination anti-retroviral therapy (ART) suppresses HIV-1 replication to undetectable viral levels and saves lives. Nevertheless, ART cannot eradicate latent cellular reservoirs of the virus, and HIV-1 infection remains a life-long battle. Adoptive cellular immunotherapy using chimeric antigen receptor (CAR) engineered T cells directed against HIV-1 envelope subunit protein gp120 (HIVCAR T cells) may provide a safe and effective way to eliminate HIV-infected cells. However, the number of HIV-infected cells is low in participants under ART, and CAR T cells disappear if they are not stimulated by their target antigens. Interestingly, about 95% of HIV-1-infected individuals are CMV-seropositive and CMV-specific T cells have been shown to persist. To overcome the CAR T cells low persistence issue, we propose to make HIV-CAR T cells using autologous cytomegalovirus (CMV)-specific T cells, which can be stimulated by endogenous CMV in vivo. The overall hypothesis of this first-in-human Phase 1, open-label, single-arm study is that endogenous immune signals to CMV-specific T cells can maintain the presence of autologous bispecific CMV/HIV-CAR T cells in healthy people living with HIV-1 (PLWH), and achieve long-term remission in the presence of ART.

Research Team

John Baird, M.D.

Principal Investigator

City of Hope Medical Center

David (Davey) Smith, MD

Principal Investigator

UCSD, San Diego Center for AIDS Research

Eligibility Criteria

This trial is for people living with HIV who are on anti-retroviral therapy (ART) but still have the virus in their bodies. Participants should be generally healthy and have a history of cytomegalovirus (CMV), which most HIV-positive individuals do.

Inclusion Criteria

My HIV is under control with ART and undetectable for over 48 weeks.

I am willing to pause my ART medication for 4 days before a cell collection procedure.

Documented HIV-1 infection anytime prior to study entry

Exclusion Criteria

Concurrent illness or comorbid condition

I have HIV that hasn't responded to at least two types of treatments.

I have previously received experimental HIV treatment or gene therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis and ART Interruption

Participants temporarily interrupt ART regimen for 4 days prior to leukapheresis to prevent residual cell drug levels that could inhibit lentiviral transduction of the T cells during CAR T cell manufacturing. ART is resumed immediately after leukapheresis.

1 week

1 visit (in-person)

Treatment

Participants receive a single intravenous infusion of autologous CMV/HIV-CAR T cells. Up to three doses may be explored.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including dose limiting toxicities and cytokine levels.

4 weeks

Multiple visits (in-person and virtual)

Treatment Details

Interventions

• CMV/HIV-CAR T Cells

Trial Overview The study is testing CMV/HIV-CAR T Cells, a type of immunotherapy designed to target and destroy HIV-infected cells using the body's own modified T cells that can also respond to CMV, potentially leading to long-term remission of HIV.

Participant Groups

Group I: Dose Level -1 Experimental Treatment 1 Intervention

EGFR+ T Cell Dose (Day 0) 5 x 10\^6 cells

Group II: Dose Level +2 Experimental Treatment 1 Intervention

EGFR+ T Cell Dose (Day 0) 50 x 10\^6 cells

Group III: Dose Level +1 Experimental Treatment 1 Intervention

EGFR+ T Cell Dose (Day 0) 25 x 10\^6 cells

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

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]

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]

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]

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 of 23 AIDS patients with cytomegalovirus (CMV) infection, common symptoms included fever, cough, and retinitis, with a significant decrease in CD4+ T cell counts compared to non-CMV patients, indicating a severe immune compromise.

Routine screening for CMV infection using pp65 antigen and specific anti-CMV IgM is recommended for AIDS patients with CD4+ T cell counts of 100 cells/µL or less, especially when they present with symptoms like fever and blurred vision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Twenty-three cases of cytomegalovirus infection in acquired immunodeficiency syndrome]. Tao, MM., Ye, JJ., Kuang, JQ.[2014]

Adoptive cellular therapies targeting CMV-specific T cells show promise as a non-toxic alternative to traditional antiviral treatments for patients undergoing allogeneic hematopoietic stem cell transplantation, with preliminary results indicating low risk of graft-versus-host disease.

Recent advancements in generating CMV-specific T cells, particularly targeting the pp65 antigen, suggest that these therapies can effectively restore anti-CMV immunity, demonstrating antiviral activity after infusion in early clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trials with CMV-specific T cells. Peggs, KS., Mackinnon, S.[2018]

In a study involving 16 patients, treatment with polyclonal CMV-specific T-cell lines led to significant in-vivo expansion of these immune cells, effectively reconstituting viral immunity against CMV infection after transplantation.

The use of these T-cell lines was shown to be effective, as eight patients did not require antiviral drugs, and only two experienced subsequent reactivation of the virus, highlighting the potential of this therapy in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Peggs, KS., Verfuerth, S., Pizzey, A., et al.[2023]

A novel method using synthetic CpG oligodeoxynucleotides and modified vaccinia Ankara (MVA) to expand CMV-specific CD4(+) and CD8(+) T cells resulted in a 30-fold increase in T cell populations within 10 days, demonstrating high efficacy for potential therapeutic use.

The expanded T cells showed minimal alloreactivity and strong cytotoxic activity against CMV, making this approach promising for managing CMV viremia in patients undergoing hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro expansion of polyclonal T-cell subsets for adoptive immunotherapy by recombinant modified vaccinia Ankara. La Rosa, C., Wang, Z., Lacey, SF., et al.[2008]

Anti-CD3 activated T cells (ATCs) armed with a bispecific antibody targeting CMV (CMVBi) demonstrated significant cytotoxicity against CMV-infected cells, achieving up to 82% specific killing at certain effector-to-target ratios, compared to less than 20% for unarmed ATCs.

This innovative approach, which does not rely on major histocompatibility complex (MHC) restrictions, shows promise for preventing or treating CMV infections in patients undergoing allogeneic stem cell or organ transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting cytomegalovirus-infected cells using T cells armed with anti-CD3 × anti-CMV bispecific antibody. Lum, LG., Ramesh, M., Thakur, A., et al.[2021]

Cellular responses from CD8 and CD4 lymphocytes are effective against CMV infections but ineffective against HIV, highlighting the need for different therapeutic approaches for these viruses.

Monitoring and characterizing specific T-cell responses can aid in assessing immune status and developing targeted therapies or vaccines, as well as providing a quantitative measure of the immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro selection of HIV and CMV specific T-lymphocytes. Li Pira, G., Bottone, L., Ivaldi, F., et al.[2006]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

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

3. 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]

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. China pubmed.ncbi.nlm.nih.gov

[Twenty-three cases of cytomegalovirus infection in acquired immunodeficiency syndrome]. [2014]

6. England pubmed.ncbi.nlm.nih.gov

Clinical trials with CMV-specific T cells. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

In vitro expansion of polyclonal T-cell subsets for adoptive immunotherapy by recombinant modified vaccinia Ankara. [2008]

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

Targeting cytomegalovirus-infected cells using T cells armed with anti-CD3 × anti-CMV bispecific antibody. [2021]

10. Italy pubmed.ncbi.nlm.nih.gov

In vitro selection of HIV and CMV specific T-lymphocytes. [2006]

11. 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]