There are seven updates in the July 2024 revision to TAG’s listing.
New Additions
Only one new cure-related clinical trial was identified in registries over the past month, which is a revised version of a protocol that was previously withdrawn. The study is sponsored by the US Military HIV Research Program (MHRP), and will assess a combination of broadly neutralizing antibodies and therapeutic vaccines in people with HIV in Bangkok, Thailand. The long-acting broadly neutralizing antibodies are VRC07-523LS and PGDM1400LS, while the therapeutic vaccine regimen involves two viral vectors — chimpanzee adenovirus (ChAd) and modified vaccinia Ankara strain (MVA) —and an HIV envelope protein with adjuvant. The version of the protocol that was initially registered and then withdrawn also included the IL-15 superagonist N-803, now nixed.
The trial plans to enroll people with HIV between 18 and 60 years old who were diagnosed during acute infection (soon after HIV acquisition) and have either been on antiretroviral therapy (ART) for at least 48 weeks or are willing to initiate ART as part of the protocol. After receipt of the interventions, participants will undergo an analytical treatment interruption (ATI) to evaluate any effects on the timing and magnitude of HIV viral load rebound.
Updates to Enrollment Status
Two recently added trials have now opened for enrollment:
- A novel gene therapy study at the City of Hope Medical Center in California. The protocol involves sampling T cells targeting the common virus CMV from participants living with HIV, and then genetically modifying them so that they can also recognize HIV (see blog post from February)
- A trial sponsored by Hookipa Biotech investigating replication-competent arenaviruses as therapeutic vaccine vectors (see last month’s blog post).
Completed Studies
A trial that closed to enrollment several months ago is now listed as completed: MacroGenics study of two dual-affinity re-targeting (DART) proteins (MGD020 and MGD014), which are designed to recognize and promote clearance of HIV-infected cells. Results from an evaluation of MGD014 were presented at the AIDS 2022 conference, demonstrating safety and favorable pharmacokinetics. To our knowledge, results from the study of MGD020 and MGD014 haven’t been publicly presented as yet.
New Links to Study Results
Preliminary results from an ongoing trial of an adoptive immunotherapy approach were presented in May at the 27th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). The protocol involves sampling T cells from participants (autologous T cells) via leukapheresis and then selecting and expanding cells that recognize parts of the HIV Gag, Pol and Nef proteins that are genetically conserved and represent more stable and potentially vulnerable targets for the immune response. The expanded T cells, which the researchers call HIV-Specific T Cells Targeting Non-Escaped Epitopes (HST-NEETs), are then reinfused back into the participants as a candidate immunotherapy. Details on the manufacturing process were published in October 2019.
The ASGCT abstract (#1908) is available online from the journal Molecular Therapy and describes results in six study participants after receipt of two infusions. No serious side effects were observed and the HST-NEETs showed evidence of expansion and persistence after administration in most recipients. Three of six participants experienced declines in the size of the intact HIV reservoir although the average magnitude of the reduction and statistical significance isn’t reported in the abstract. The authors write: “This promising therapeutic approach presents opportunities for combination therapies for HIV cure strategies.”
A link was also added to a previous abstract about the trial we’d missed, which was presented at the 64th American Society for Hematology Annual Meeting in 2022. This abstract reports individual data and notes decreases in the intact HIV reservoir in two participants whose samples had been analyzed at that stage.
Researchers led by Maria Reyes Jimenez-Leon from the research group of Ezequiel Ruiz-Mateos at the Institute of Biomedicine of Seville (IBiS) have published results from a clinical trial of vedolizumab, an antibody that blocks the α4β7 integrin receptor on cells. The rationale for the approach derives from studies in the SIV/macaque model showing reductions in the reservoir, although notably an initial report of SIV viral load control after ART interruption wasn’t reproducible in additional macaque experiments or in the first human trial in people with HIV.
The trial in Spain also included an ATI and was unable to document a substantial effect in delaying or reducing HIV viral load rebound. However, the researchers found that the blocking of the α4β7 integrin receptor by vedolizumab in the gut was incomplete and there was a correlation between the extent of the blocking and levels of HIV DNA in the ileum and caecum. Because vedolizumab administration has been shown to be safe in several studies in people with HIV, the researchers suggest that higher doses could be considered and conclude: “this clinical trial suggests that α4β7 is an important determinant of HIV-1 reservoir levels seeding in peripheral blood and specially in tissues in humans and therefore, supports further testing of vedolizumab in combination with other compounds, as a promising tool for HIV-1 cure strategies.”
The last added link is to an analysis of biomarkers associated with HIV viral rebound in a previously published trial of the toll-like receptor agonist vesatolimod. The study recruited people who displayed natural control of HIV viral load to low but detectable levels prior to starting ART (“viremic controllers”) and administered vesatolimod prior to initiating an ATI. Receipt of the intervention was associated with a slight delay in time to viral load rising over 200 copies/ml (about a week on average), and the new paper identifies a number of biomarkers associated with the speed of the rebound. Higher levels of several proinflammatory glycans, lipids, and metabolites were linked to more rapid reappearance of HIV viral load, but the authors note that the findings should be considered exploratory and require validaton.
Another trial in the listing had additional results presented at the ASGCT meeting in May, but the abstract doesn’t appear to be available for us to link to. The study has already received considerable publicity because it represents the first-in-human evaluation of a CRISPR gene editing approach to targeting the HIV reservoir. The candidate, EBT-101, is manufactured by Excision Biotherapeutics and emerged from extensive preclinical research conducted by Kamel Khalili and colleagues at Temple University in Philadelphia. EBT-101 uses an adeno-associated virus serotype 9 (AAV9) vector to deliver a CRISPR gene editing tool designed to target relatively conserved parts of HIV genetic’s code. The goal is to either remove the HIV genome from infected reservoir cells or render it non-functional.
Preliminary safety information was first presented at the Annual Congress of the European Society of Gene and Cell Therapy in Belgium in October 2023 (see abstract OR31 in the published abstracts). At the ASGCT meeting in May, principal investigator Rachel Presti debuted efficacy information, revealing that three recipients underwent an ATI but only one experienced a delay in HIV viral load rebound of 16 weeks, which appeared to be associated with a slight but statistically significant decline in the size of their intact HIV reservoir after EBT-101 administration. Excision Biotherapeutics issued a press release and details were reported by Liz Highleyman for AIDSmap. Rachel Presti is also presenting about the trial next Thursday, July 25, at the International AIDS Conference (AIDS 2024) In Munich.
Other candidates in TAG’s listing featured at AIDS 2024 include the ICVAX therapeutic vaccine (poster exhibition, Tuesday July 23) and GS-8588, a bispecific T-cell engager (poster exhibition, Wednesday July 24). For a full set of links to HIV cure-related research sessions and events at AIDS 2024, see previous blog post.
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