HIV-1
Conditions
Keywords
HIV-1, PLWH (Healthy People Living with HIV-1) autologus, CMV-specific T cells, anti-retroviral therapy (ART), Immunotherapy
Brief summary
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.
Detailed description
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 (HIV-CAR T cells) may provide a safe and effective way to eliminate HIV-infected cells. However, HIV-infected cells in participants under ART, and CAR T cells disappear if they are not stimulated by their target antigens. Interestingly, about 95% of individuals with HIV-1 are CMV-seropositive and CMV-specific T cells have been shown to persist at high frequency due to CMV antigen stimulation. 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, open-label, single-arm, pilot 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). Based on the results of this safety study, CMV vaccine and analytic treatment interruption will be evaluated with the CMV/HIV-CAR T cell investigational product in a subsequent protocol. The trial is a first-in-human, pilot study to evaluate the feasibility and safety and determine the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D) of CMV/HIV-CAR T cells in PLWH. Eligible participants will temporarily interrupt their 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. Participants will resume their ART regimen immediately after leukapheresis. If the manufacturing is not successful, a second apheresis may be scheduled no sooner than 3 weeks later with temporary interruption of ART regimen for 4 days prior to leukapheresis. Participants will resume their ART regimen immediately after leukapheresis. Once the final cell product is released, participants will receive a single intravenous (IV) infusion of autologous CMV/HIV-CAR T cells (defined as Day 0). Up to three doses of CMV/HIV-CAR T cells may be explored.
Interventions
BIOLOGICALCMV/HIV-CAR T Cells
Eligible participants will temporarily interrupt their 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 cewll manufacturing. Participants will resume their ART regimen immediately after leukapheresis. Once the final cell product is released, participants will receive a single intravenous (IV)infusion of autologous CMV/HIV-CAT T cells (defined as Day 0). Up to three doses of CMV/HIV-CAR T cewlls may be explored.
Sponsors
City of Hope Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Participant must be ≥ 18 years of age at the time of screening; * Karnofsky Performance Status (KPS) ≥ 70; * Documented HIV-1 infection anytime prior to study entry.; * On stable ART with undetectable HIV-1 RNA (i.e \< 20 copies /mL) for at least 48 weeks prior to screening (2 plasma HIV-1 RNA blips 25-200 copies/mL are allowable); * CD4+ cell count ≥ 450 cells/μL; * Adequate organ function; * Willingness to interrupt ART regimen for 4 days prior to leukapheresis; * Not pregnant or breastfeeding.
Exclusion criteria
* Concurrent illness or comorbid condition; * History of resistance to two or more classes of antiretroviral drugs; * History of prior receipt of an experimental HIV-1, immunotherapeutic agent, or gene therapy product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicities (DLT) | Up to 28 days after the infusion | Toxicity will be graded per CTCAE v5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Criteria on CRS/Neurotoxicity: DLT. |
| Toxicity profile | Up to 28 days after the infusion | Toxicity will be graded per CTCAE v5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Criteria on CRS/Neurotoxicity: all other toxicities to define the toxicity profile. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EGFR+ CD3+ T cells | Up to 28 days after the infusion | Number, percentage and persistence of EGFR+ CD3+ T cells in the peripheral blood and EGFR- CD3+ T cells in peripheral blood |
| Cytokine levels | Up to 28 days after the infusion | Cytokine levels in the peripheral blood post CAR T cell infusion. |
| CD4+ T cell count and HIV RNA levels | Up to 28 days after the infusion | CD4+ T cell count and HIV RNA levels in the peripheral blood; |
| Number of CMV/HIV-CAR T cells | Up to 28 days after the infusion | Number of CMV/HIV-CAR T cells: measured by qPCR in peripheral blood); and Using two in-depth interviews (1) shortly following screening (within 2 weeks), and 2) within 1 month of initiating Step 4, we will assess perceptions of the CMV/HIV-CAR T cell intervention and overall trial experiences in participants |
Countries
United States
Contacts
CONTACTMarvin Hanashiro
CONTACTSteven Hendrickx
PRINCIPAL_INVESTIGATORJohn H. Baird, MD
City of Hope Medical Center
PRINCIPAL_INVESTIGATORDavid (Davey) Smith, MD
UCSD, San Diego Center for AIDS Research
Outcome results
None listed