Multiple Treatment Interruptions and Protecting HIV-Specific CD4 T-Cells Enables Durable CTL Response and Viral Control

BACKGROUND The cell and gene therapy product AGT103-T was evaluated ([NCT04561258][1]) for safety, immunogenicity, and persistence for up to 180 days post infusion. We sought to investigate the impact following analytical treatment interruptions (ATIs). METHODS Six patients suspended their antiretroviral therapy (ART) until their viral load reached 100,000 copies/mL in two successive visits, or their CD4 count fell below 300 cells/μL. We measured the magnitude of viral rebound, the persistence of AGT103-T transduced CD4+ T-cells and the impact on HIV-specific immune responses. RESULTS During the ATI, all patients experienced logarithmic viral rebound followed by a 2-5-fold increase in total CD8 counts, that coincided with a rise in HIV-specific CD8 T-cells. This was attributed to the increase in antigen availability and memory recall. Thus, to determine if the immune response generated during this “auto-vaccination” event can contribute to viral suppression upon subsequent exposures, a second ATI was initiated. During the second ATI, the Gag-specific CD8 T cells were either maintained or rose and the peak viremia was substantially decreased with viral set-points ranging from 7,000-25,000 copies/mL. Upon ART resumption, faster viral control was demonstrated without any serious adverse events (SAEs) or drug resistance. CONCLUSION AGT103-T gene therapy and multiple ATIs were not associated with SAEs and allowed subjects to establish a low viral set-point with relatively stable CD4 T cell counts. Additionally, multiple ATIs are beneficial for the study design when induction of CD8 T cells is required to establish viral control. REGISTRATION [ClinicalTrials.gov][2] [NCT05540964][3] FUNDING American Gene Technologies International Inc. ### Competing Interest Statement Conflict of Interest: Authors AJ, GEC, ML, ELF, AIC, LX, IM, JAG, MAC and JSB are shareholders and current employees of American Gene Technologies International, Inc. Authors PNK and JB received funding for the costs of the clinical trial from American Gene Technologies International, Inc. ### Clinical Trial NCT05540964 ### Funding Statement The authors declare that the study received funding from American Gene Technologies International, Inc. the funder was involved in study design, data analysis and submission of this manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study Approval This clinical trial was approved by the central institutional review board (IRB) of Advarra, Inc. and the IRB of Georgetown University Medical School. Written informed consent was obtained from all the participants prior to their enrollment on the clinical trial. The clinical trial is registered at [Clinicaltrials.gov][4] ([NCT05540964][3]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04561258&atom=%2Fmedrxiv%2Fearly%2F2023%2F10%2F25%2F2023.10.24.23297421.atom [2]: http://ClinicalTrials.gov [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05540964&atom=%2Fmedrxiv%2Fearly%2F2023%2F10%2F25%2F2023.10.24.23297421.atom [4]: http://Clinicaltrials.gov