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First two patients receive CAR T cell therapy for HIV
  Nature Medicine explores the latest translational and clinical research news, with a phase 1/2 trial of a dual CAR T cell therapy that targets gp120.
Thiago Carvalho
Two patients have received infusions of an investigational chimeric antigen receptor (CAR) T cell that targets the human immunodeficiency virus (HIV) envelope glycoprotein gp120 (LVgp120duoCAR-T cells). The open-label phase 1/2 dose-escalation study aims to recruit 18 participants and is expected to conclude by the end of 2025. To be included in the trial, patients must have been under effective anti-retroviral therapy for at least 12 continuous months before enrollment. The participants' anti-retroviral therapy is interrupted at the time of CAR T cell administration, and they are monitored for safety and viral rebound. Steven Deeks at the University of California, San Francisco, leads the trial, which also involves the University of California, Davis, and Case Western Reserve University hospitals.
According to the World Health Organization, 1.5 million people were newly infected with HIV in 2021, bringing the total number of people living with HIV to 38.4 million. Despite the availability of highly effective anti-retroviral therapy, coverage is incomplete, with only 75% of infected people receiving therapy and over 650,000 HIV-related deaths in 2021. Before the COVID-19 pandemic, HIV–AIDS was second only to tuberculosis as an infectious cause of death. People living with HIV who receive therapy and have high CD4+ T cell counts now have a lifespan similar to that of people without HIV, although there is evidence of increased chronic comorbidities.
The gp120 component of the HIV envelope glycoprotein initiates infection of host T cells by binding to the co-receptor CD4 on their surface. CAR T cell therapy 'trains' the patient's own T cells to target HIV-infected cells. LVgp120duoCAR-T cells target two separate gp120 epitopes, via two separate CARs: the first bears a minimized CD4 domain that binds to gp120, exposing the m36 epitope that is then recognized by the second CAR, thereby blocking interaction with the co-receptor CXCR5. Both chimeric gp120-binding sites are linked to the T cell antigen receptor invariant chain CD3; the first construct also incorporates signaling motifs from the co-stimulatory molecule 4-1BB to improve CAR T cell survival in vivo.
The dual CAR T cell trial is not the first attempt to target HIV gp120 with CAR T cells. The first CAR T cells ever tested in the clinic targeted HIV and made it as far as phase 2 clinical trials. Although those trials failed to show efficacy, they provided over a decade of encouraging data on the safety of CAR T cell therapy in people living with HIV. Earlier constructs were variations on fusion of the CD4 extracellular domain to CD3 and had an Achilles heel, in that the CAR T cells themselves could be infected by HIV.
In preclinical work, primary human T cells transduced with the dual CAR T construct were shown to be resistant to HIV infection (consistent with previous work, CAR T cells expressing only the minimized CD4 domain could be infected with HIV). The CAR T cells were efficient killers of HIV-infected cells in vitro and in a humanized mouse model of HIV infection (in which they were also shown to migrate to the sites of viral infection). 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 University of California, Davis, stating that "There were no adverse events observed that were related to the product and the participant is doing fine." The second patient was infused this spring. The trial has three cohorts: an initial group who will receive a low dose (3 x 105 CAR T cells per kilogram body weight), followed by two groups for whom the infusion dose will increase stepwise to up to a million CAR T cells per kilogram and whose patients will undergo conditioning with cyclophosphamide for transient depletion of host lymphocytes and potentially improvement of engraftment.
Eradicating HIV from a host is a monumentally difficult task. The virus establishes latent reservoirs that can rebound after years of hiding below the clinical detection limit in patients treated with anti-retroviral therapy. Dormant proviruses inserted into the host genome are not susceptible to existing therapy and are invisible even to artificially engineered T cells. In a variation on the 'shock and kill' theme, an anti-HIV CAR T cell phase 1 trial sponsored by Guangzhou 8th People's Hospital also suspends anti-retroviral therapy but administers CAR T cells only when the plasma HIV viral load reaches 1,000 copies per milliliter. Still, viral reactivation is a stochastic process, and people living with HIV may have to settle for a functional cure, rather than a sterilizing cure. The persistence of CAR T cells when HIV titers are low or undetectable is a key parameter to monitor in this context.
Global deaths from HIV–AIDS are concentrated in sub-Saharan Africa, and the highest growth in cases in the United States is among African Americans, who in 2020 accounted for 42% of all new infections. CAR T cell therapies approved for blood cancers are some of the most expensive treatments in medicine. This CAR T cell therapy trial is sponsored by a nonprofit organization, Caring Cross, and is funded by California's state stem-cell agency CIRM (California Institute for Regenerative Medicine). CAR T cell therapy was first shown to be safe in people living with HIV–AIDS. Perhaps this field be the first to show that it can also be affordable.
April 19, 2023

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