HIV Gene Therapies Continue to Move Through the Pipeline With Promise

American Gene Technologies has begun withdrawing patients with HIV from antiretroviral treatment as part of its clinical trial (RePAIR; NCT04561258) for AGT103-T, a genetically modified cell product intended to repair the immune system and control HIV replication.¹

Between May 2021 and May 2022, 7 participants have been dosed with AGT103-T and no serious adverse events have occurred so far. Early data has indicated that the cells are properly engrafting and persisting without being infected. The analytic treatment interruption (ATI) was approved by the independent Institutional Review Board (IRB) overseeing the study in February 2022.

“This is a critical step in our mission to cure HIV using gene therapy,” Jeff Galvin, chief executive officer, American Gene Technologies, said in a statement.¹ “We’ll monitor participants carefully, and within the next few months we’ll begin to know how close we are to reaching our dream of curing HIV. If participants respond as we expect, they may no longer need to take their antiretroviral medications, and could remain immune to HIV for life without further treatment. If we obtain that result, we may have achieved the most exciting development in HIV research in decades. This milestone could lead to a reliable cure for HIV that returns infected individuals to a normal life without risk of ever developing AIDS or infecting another person.”

The phase 1 clinical trial is open to male and female participants aged 18 to 60 years who have been diagnosed with HIV for at least 3 years and have taken HIV antiretroviral medication for more than 2 years. Female patients of childbearing potential are required to have a negative pregnancy test, and all patients must be able to participate in 17 study visits over 10 months. Patients with active viral hepatitis B or C infections, liver disease, or a history of at least 1 AIDS-defining complication will be excluded from the study, as will patients that have received any previous gene transfer therapy and those who have allergies to dimethylsulfoxide (DMSO) or cyclophosphamide.

AGT103-T consists of autologous HIV-specific CD4 T-cells that have been enriched and genetically modified to fight infection. Patients in the low-dose arm will receive a single infusion of between 1x10⁸ and 1x10⁹ cells, while patients in the high-dose arm will receive a single infusion of between 1x10⁹ and 5x10⁹ cells. The primary end point is safety measured by the occurrence of adverse events related to treatment. Secondary end points include responses to treatment, such as any change in immune response to HIV. The ATI will also be used to determine efficacy. Results from the ATI are expected to be announced by the end of 2022.

Other recent major developments in the realm of HIV gene therapy include a $3.9 million NIH grant that has been awarded to scientists at Texas Biomedical Research Institute and Temple University in Philadelphia exploring a CRISPR/Cas9 gene therapy intended to target latent HIV in microglial cells.² Investigators Binhua “Julie” Ling, MD, PhD, of Texas Biomed, and Wenhui Hu, MD, PhD, of Temple University, intend to overcome the challenge of delivering the gene therapy across the blood-brain barrier with a new type of nonpathogenic adeno-associated virus (AAV) vector. “Our novel gene therapy approach will not only apply to neuro-HIV but also to other central nervous system diseases and injuries,” Hu said in a statement.² 

The investigators also intend to design the CRISPR tool to cut certain proteins to block HIV from entering cells and to reduce inflammation in the brain. “We want to take this very strategic, all-in-one approach so if any virus slips under the radar, we have a backup plan and can prevent the virus from entering new cells,” Ling added.² “We also want to try to limit any potential inflammation, which is especially important in the brain.”

REFERENCES

1. American Gene Technologies’ HIV cure clinical trial enters critical phase: withdrawing participants from antiretrovirals. News release. American Gene Technologies. July 28, 2022. https://www.americangene.com/news-releases/agt-hiv-trial-enters-phase-withdrawing-antiretrovirals/ 

2. Beyond the blood-brain barrier: HIV research at Texas Biomed gets NIH funding boost. News release. Texas Biomedical Research Institute. July 27, 2022. https://www.txbiomed.org/news-press/news/hiv-siv-brain/