CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

the final CMDR was given after termination. No vaccine related AE prompted discontinuation of investigational product. All participants are expected to complete the study by mid-October 2023. Conclusion: This study represents the first combined therapeutic HIV vaccine study in pediatrics. While all participants reported local and/or systemic reactions to vaccination, most events were self-limiting and no dose limiting AEs were reported.

remained detectable, and 11 of the boosted responses remained ≥2 fold above BL magnitude (Fig. 1B). Conclusion: HIV DNA therapeutic vaccination both boosted pre-existing T cell responses and also elicited responses against new epitopes. The higher magnitude of boosted responses by IFNγ ELISpot post-vaccination yet similar proliferative responses suggest their per-cell proliferative capacity is lower than that of new responses. Eliciting new T cell responses may be required in order for HIV therapeutic vaccines to enhance T cell function.

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WITHDRAWN

Linking TCR αβ Chains to Costimulatory Signaling Domains Enhances HIV-Specific CD8 T-Cell Function

Marta Santos Bravo , Harris Goldstein Albert Einstein College of Medicine, Bronx, NY, USA

Background: The addition of costimulatory signalling domains to the CAR construct has dramatically increased the functional capacity of CAR-T cells to kill cancer cells. We hypothesized that we could augment the functional anti-HIV activity and persistence of cytotoxic CD8 T cells (CTLs) engineered to express HIV-specific TCRs used as an adoptive therapy to provide a functional HIV cure by incorporating the intracellular activation domain of costimulatory signalling domains into the TCR construct, termed TCR-costim. Methods: As a proof-of-concept, we constructed a lentiviral vector (LV) encoding chimeric α and β TCR chains containing the well described HIV-1 Gag epitope SL9 human variable TCR region fused to the murine constant region, to prevent TCR mispairing with the endogenous TCR. We added the signal transduction domain of either the CD28 or 41BB to the α and/or β TCR chains. Jurkat/MA-NFAT-luciferase reporter (Jurma) cells were transduced with the LV to evaluate SL9-TCR activation by quantification of the luciferase reporter. SL9- TCR expression in CTLs from seronegative donors was determined by tetramer staining; and their cytotoxic activity, activation, and IFNγ and TNFα production by flow cytometry. Results: In Jurma cells transduced with the different SL9-TCR LV constructs, TCR was highly expressed (95- 99%). Jurkat/Ma transduced with the SL9-CD28 LV displayed 1.47 or 2.2-fold greater TCR activation than SL9- TCR or SL9-41BB, respectively, after coculturing with SL9-loaded T2 cells. Donor CD8 T cells were effectively transduced (15-30%) with all LV contructs and SL9-TCR expression reached 80% of the transduced cells. SL9 reactivity was demonstrated by increased LAG3 and CD25 expression in SL9-TCR, SL9-CD28 and SL9-41BB CTLs incubated with SL9-loaded T2 cells but not with T2 cells alone. Of great interest was the increased cytotoxic activity (figure 1A) and IFNγ and TNFα production of SL9-CD28 and SL9-41BB CTLs as compared with SL9-TCR CTLs (figure 1B). Conclusion: Incorporating costimulatory signalling domains with the TCR construct (TCR-costim) provides an increased downstream activation of the TCR and an improved functional activity of CTLs. Because TCRs require recognition of far fewer HIV peptides than CARs to activate their effector functions, adoptive therapy with TCR-costim CTLs may overcome CAR-T cell limitations in recognizing and killing latent HIV infected cells which produce low levels of HIV proteins, and provide the sustained CTLs response required for a functional HIV cure.

Poster Abstracts

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Safety of Therapeutic HIV-1 Vaccine for Adolescents with Early Treated Perinatal HIV Infection Shaun L. Barnabas 1 , Mark F. Cotton 1 , Nicola Cotugno 2 , Britta Wahren 3 , Pontus Blomberg 3 , Ellen Turk 4 , Mark S. de Souza 5 , Els Dobbels 1 , Yasmeen Akhalwaya 1 , Samantha Fry 1 , Hans Spiegel 6 , Patrick Jean- Philippe 7 , Paolo Palma 2 , Merlin L. Robb 6 , for the Hvrricane Study Team 1 Stellenbosch University, Cape Town, South Africa, 2 Bambino Gesu Children's Hospital, Rome, Italy, 3 Karolinska Institute, Stockholm, Sweden, 4 Henry M Jackson Foundation, Rockville, MD, USA, 5 Institute for HIV Research, Essen, Germany, 6 Henry M Jackson Foundation, Bethesda, MD, USA, 7 National Institute of Allergy and Infectious Diseases, Rockville, MD, USA Background: HVRRICANE is a phase I, proof of concept, open-label, randomized clinical trial to evaluate safety, immunogenicity and efficacy in HIV reservoir reduction of a prime-boost strategy with a multigene, multi-subtype A, B, C HIV-DNA vaccine (HIVIS DNA) and modified vaccinia Ankara Chiang Mai Double Recombinant (MVA-CMDR) vaccine ± co-administration of Toll-like Receptor 4 agonist (within Cervarix® human papilloma vaccine) in adolescents and youth living with perinatally acquired HIV-1. Methods: Twenty-five South African adolescents living with perinatal HIV, 14 to 16 years of age were enrolled. All started antiretroviral therapy prior to 6 months of age, with continuous viral suppression through enrollment, and randomized to HIV vaccines only (n=10, Arm 1), HIV vaccines and Cervarix® (n=10, Arm 2) or Cervarix® only (n=5, Arm 3). The HIV DNA vaccines were administered through a needle free device (PharmaJet Stratis®) at weeks 0 and 4 ± Cervarix® and the MVA-CMDR at 24 (± Cervarix®) and 36 weeks (MVA-CMDR only). Local and systemic reactions were captured 30 minutes after vaccination and on diary cards for seven days. Pregnancy was screened at each visit. Results: Two participants missed week 24 immunization (due to TB and pregnancy). There were no loss to follow up, no deaths and 15 participants have completed their week 60 visits. Local and systemic reactogenicity reported as mild or moderate in all 25 participants: 24 (96%) had local and 21 (84%) systemic reactions. Five participants with severe reactogenicity all reduced to moderate, mild or resolved within 2 days. There was one serious adverse event (SAE) and 2 adverse events (AEs) above Grade 2, all in Arm 2. The SAE (acute appendicitis) was unrelated to study participation. One Grade 3 AE (reduced estimated glomerular filtration rate) was considered tenofovir- and not vaccine related. The other Grade 3 AE was headache for 10 days that was severe on days 1 and 2. A pregnancy during the study was noted (Arm 2) and was electively terminated. The first MVA-CMDR vaccine was omitted due to the pregnancy, but

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CROI 2024