A first-in-human HIV duoCAR-T shows encouraging safety in data presented at ASCGT, with early evidence of viral suppression for up to 2 years after stopping ART.
Early clinical data from a first-in-human phase 1/2a trial of a novel chimeric antigen receptor T-cell (CAR-T) therapy targeting HIV suggest that a single infusion may enable durable viral control without ongoing antiretroviral therapy (ART) in a subset of participants, according to findings presented at the American Society of Gene and Cell Therapy Annual Meeting in Boston, Massachusetts.1
The data were presented by principal investigator Steven Deeks, MD, a professor of medicine in residence at the University of California, San Francisco (UCSF), and a faculty member in the Division of HIV, Infectious Diseases, and Global Medicine at Zuckerberg San Francisco General Hospital. Although the data are from only a small population, the signals represent the first human results from Caring Cross's duoCAR-T cell platform applied to HIV infection.
"Although the primary focus of the study was safety, a few participants experienced better-than-expected outcomes following interruption of antiretroviral therapy. We are particularly interested in 2 individuals who have maintained
The study’s (NCT04648046) primary safety outcome was the number of participants reporting a new grade 3 or greater adverse event (AE) definitely, probably, or possibly related to study treatment within 1 year of product administration. The primary efficacy outcome was the proportion of participants achieving posttreatment control within 36 weeks of product administration, defined as either no consistent viral rebound above 400 copies of RNA/mL between weeks 12 and 36, or a rebound followed by 24 consecutive weeks of viral control.2 The study enrolled participants across 3 cohorts distinguished by the use of lymphodepleting conditioning prior to cell infusion and by infusion dose.
No serious AEs were attributed to the LVgp120duoCAR-T cell product itself across all 9 participants. One participant experienced a reduction in blood counts related to the bone marrow conditioning regimen, consistent with the known hematologic effects of cyclophosphamide-based lymphodepletion.1 No dose-limiting toxicities were reported that would have triggered the protocol-specified stopping rules under the 3+3 design.2 Caring Cross noted that the absence of product-related serious AEs events across all treated participants supports continued development and dose exploration.
The trial is a limited-center, open-label, dose-escalating study evaluating the safety and preliminary antiviral activity of LVgp120duoCAR-T cells—autologous CD4+ and CD8+ T cells transduced with a lentiviral vector encoding bispecific anti-gp120 CAR molecules—in individuals with ART-suppressed HIV-1 infection.1,2 Thus far, 9 participants have received treatment across 3 sequentially enrolled dose cohorts following a 3+3 design.2
In cohort 1, participants received no conditioning and a single low dose of 3 × 105 cells/kg LVgp120duoCAR-T cells, with ART interrupted immediately after infusion.2 CAR-T cells were undetectable in peripheral blood in all 3 participants following infusion, and viral rebound was rapid after ART interruption, indicating that engraftment was insufficient without prior lymphodepletion.1
In cohorts 2 and 3, participants received nonmyeloablative conditioning with cyclophosphamide administered 3 days before infusion.2 Cohort 2 received the same low dose of 3 × 105 cells/kg; cohort 3 received a higher dose of 1 × 106 cells/kg.2 Among the 6 conditioned participants, 2 maintained undetectable to very low viral loads following ART interruption—one for nearly 1 year and another for nearly 2 years. A third participant demonstrated transient viral control for approximately 3 months before viral rebound.1 Several additional participants who did not achieve sustained control showed delayed viral rebound relative to typical kinetics, which investigators interpreted as evidence of partial immune-mediated suppression even without full viral control.
All 3 participants who achieved any degree of sustained or transient viral control had initiated antiretroviral therapy early in the course of their HIV infection, a characteristic associated with a smaller and less diverse viral reservoir. Investigators noted that early ART initiation may be a meaningful predictor of response, given its role in limiting the size and distribution of latently infected cell populations.1
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Mehrdad Abedi, MD, a professor of medicine and director of the Alpha Stem Cell Clinic at the University of California, Davis, who served as clinical coinvestigator underscored the significance of the conditioned-arm results. "While this level of viral control can rarely occur in the absence of intervention, the depth of viral suppression observed after our clinical trial in 2 consecutive patients in the conditioning arm is especially compelling," he said.1
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Caring Cross's duoCAR technology engineers a participant's own T cells with bispecific chimeric antigen receptors designed to recognize and eliminate HIV-1 gp120-expressing cells—both productively infected cells displaying surface antigen and cells harboring reactivated latent virus.2 The approach aims to reconstitute functional immune surveillance against the virus, an objective that ART, which suppresses viral replication without eliminating the latent reservoir, cannot achieve. Secondary outcome measures in the trial include longitudinal assessment of CAR-T cell persistence in blood and tissue by quantitative PCR, as well as changes in quantitative virologic measures of the HIV reservoir from baseline through week 36, using methods including the intact proviral DNA assay (IPDA).2
The vector used in this trial reflects a first-generation design. Caring Cross has indicated that next-generation constructs are already in development, with the goal of improving the potency and durability of the antiviral immune response.
"This work represents the culmination of years of scientific and clinical effort to develop a therapy that harnesses the body's own immune cells to fight HIV. While the clinical data are encouraging, the vector used to generate the anti-HIV duoCAR-T cells reflects a first-generation design—an important step toward a definitive therapeutic solution,” Boro Dropulic, PhD, founder and executive director of Caring Cross, said in a statement.1 "We have already advanced next-generation versions that we expect will further enhance the potency and durability of the anti-HIV response, bringing us closer to a lasting, potentially one-time treatment."
The trial is ongoing, and investigators noted that future directions will include evaluation of whether modifications to the treatment protocol—such as adjusting the timing of ART interruption relative to infusion or administering multiple sequential infusions—could improve the proportion of participants achieving durable viral control.1
HIV remains among the most significant
The concept of a functional cure has long been a central objective of HIV research. Only a small number of individuals, known as elite controllers and posttreatment controllers, achieve spontaneous or therapy-associated remission through immune mechanisms that remain incompletely understood. The LVgp120duoCAR-T approach aims to replicate or augment that immune-mediated control in a broader population through a single intervention.
