Preclinical research showed the therapy was able to reduce cellular HIV infection by up to 99% in an in vitro model and more than 97% in a mouse model.
The first patient has been dosed in a phase 1/2a clinical trial (NCT04648046) of Caring Cross’s Anti-HIV DuoCAR-T cell therapy (LVgp120duoCAR-T), an investigational chimeric antigen receptor T-cell (CAR-T) therapy intended to target HIV cells for elimination.1
Preclinical research published in Science Translational Medicine showed that the Anti-HIV DuoCAR-T therapy was able to reduce cellular HIV infection by up to 99% in an in vitro model and more than 97% in a mouse model.2 The therapy uses a lentiviral vector to confer a 2-molecule CAR architecture (duoCAR) to T-cells, which targets sites on the HIV-1 envelope glycoprotein. The preclinical research further showed that these transduced T-cells are themselves resistant to diverse HIV-1 strains. In a humanized NSG mouse model of intrasplenic HIV infection, the therapy demonstrated an ability to control infection long-term. A separate pre-clinical study, results from which have been accepted for publication in The Journal of Clinical Investigation (JCI) Insight, demonstrated that the anti-HIV DuoCAR T-cells are capable of traveling to the spleen and durably suppressing HIV replication in a humanized mouse model.1
The current clinical trial is being conducted in collaboration with University of California, San Francisco, University of California, Davis, and the California Institute for Regenerative Medicine (CIRM). The first patient was dosed in August 2022 and no adverse events (AEs) related to the cell product have been reported.
“We have reached an important milestone with the dosing of the first participant in the Phase 1/2a clinical trial evaluating a potentially groundbreaking anti-HIV duoCAR-T cell therapy,” Steven Deeks, MD, the University of California, San Francisco, said in a statement.1 “Our primary goal for this clinical trial is to establish the safety of this promising therapeutic approach. We are happy to be collaborating with UC Davis, Caring Cross, Case Western Reserve University Hospitals and CIRM on this clinical trial.”
The open-label, dose escalation trial will enroll approximately 18 patients aged 18 to 65 years who have HIV-1 infection. Participants are required to have been on a continuous and stable antiretroviral therapy (ART) regimen for at least a year without interruption greater than 14 days. Participants must additionally have plasma HIV RNA levels below the limit of quantification on all available determinations in the past year and a screening CD4+ T-cell count of at least 500 cells/mm3. Patients whose ART regimen includes a non-nucleoside reverse transcriptase inhibitor or a long-acting ART drug that may remain active for 1 year after ART interruption will be excluded from the study, as will patients whose ART regimen includes protease inhibitor(s) and/or azidothymidine (AZT). Additional exclusion criteria relate to patient health status and history.
Participants will be divided into 3 experimental arms and receive a single dose of the Anti-HIV DuoCAR-T cells, immediately after which their ART regimen will be interrupted. Patients in the first low-dose cohort will receive 3x105 cells/kg, while patients in the second low-dose cohort will receive the same amount of cells along with non-ablative conditioning with cyclophosphamide. Patients in the high-dose cohort will receive 1x106 cells/kg along with non-ablative conditioning with cyclophosphamide. The study’s primary end points are the number of participants reporting a new grade 3 AE within 1-year post-administration that is definitely, probably, or possibly related to study treatment and the number of participants who achieve control within 36 weeks. Secondary end points include measures of the persistence of CAR T-cells in the blood and in tissue samples, and changes from baseline in quantitative virologic measures of the HIV reservoir.
“We are delighted to have dosed the first participant in this first-in-human clinical trial using CAR-T cells that kill HIV-infected cells and simultaneously protect CD4 T-cells from HIV infection,” Boro Dropulić, PhD, co-founder and executive director, Caring Cross, added to the statement.1 “We look forward to continuing the trial with the goal of establishing the safety and efficacy of this therapeutic approach. We are honored to be collaborating with UC San Francisco, UC Davis and Case Western Reserve University Hospitals on this clinical trial and we are grateful to the California Institute for Regenerative Medicine for their support.”