CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

538

Phase I Clinical Trial AMC097 Evaluating Engraftment and HIV Resistance of Gene Modified Blood Cells Timothy J. Henrich 1 , Julie Beegle 2 , Deborah Stewart 2 , Christina Dyer 2 , Amanda M. Buck 1 , Joanna Donatelli 1 , Gunjun Shah 3 , David Asmuth 2 , Richard B. Pollard 2 , Joseph Anderson 2 , Ariela Noy 3 , Mehrdad Abedi 2 1 University of California San Francisco, San Francisco, CA, USA, 2 University of California Davis Medical Center, Davis, CA, USA, 3 Memorial Sloan Kettering Cancer Center, New York, NY, USA Background: For HIV patients, there is currently no effective cure. Approaches involving stem cell and gene therapies aimed at mimicking the results of the Berlin Patient and others have been developed including ongoing human clinical trials. There is an urgent need for strategies that expand gene therapy beyond CCR5 modification to target multiple stages of HIV replication. Methods: Thus, we completed a Phase I clinical trial, on behalf of the AIDS Malignancy Consortium (grant UM1CA121947), enrolling HIV-related lymphoma patients requiring an autologous transplant. Following BEAM conditioning, participants received autologous peripheral blood CD34+ cells transduced with a lentiviral vector containing three HIV-resistance genes, a CCR5 shRNA, a chimeric TRIM5alpha gene, and a TAR decoy. A fourth gene was included and used as a selectable marker to purify the gene modified cells prior to transplant. Three cohorts of participants (total N=11) each receiving the gene modified cells in a dose dependent ratio along with unmodified cells: 1:1, 2:1, 1:0 were enrolled. Results: Safety of the vector transduced cells was determined by (1) predetermined engraftment timelines and (2) by average vector copy number in the peripheral blood post-transplant by quantitative PCR. Flow cytometry of immune cell reconstitution in the peripheral blood was also evaluated. In all participants, successful and steady engraftment was observed over the course of one to two years. One participant underwent an optional analytical treatment interruption (ATI) 42 months post-transplant. Criteria for ATI included CD4 >300 and undetectable plasma viral load. Upon analysis of vector copy number in the peripheral blood, an 8-fold increase in gene marking was observed at seven weeks post-ATI. An in-house single-cell droplet PCR method to evaluate HIV infection in this patient’s cells during the ATI estimated that approximately 75% of the gene modified cells were protected from de novo infection compared to cells without detectable lentiviral vector DNA. This protection of infection was similar at both early and late ATI timepoints. ATI was suspended on week 8, after the CD4 and plasma viral load safety thresholds were met. CD4 rose to >300 one week post-treatment resumption and viral load became undetectable by week 8. Conclusions: Our results highlight both the safety and efficacy of our approach and warrants further assessment.

537

HIV-1 Reservoir Reduction in PWH Receiving ART and Dasatinib Mario Manzanares 1 , Guiomar Casado Fernández 1 , Alicia Simón Rueda 1 , Montserrat Torres 1 , Elena Mateos 1 , Christoph Wyen 2 , Kerstin Lammersmann 2 , Adam M. Spivak 3 , Vicente Planelles 3 , Christian Hoffmann 4 , Mayte Coiras 1 1 Instituto de Salud Carlos III, Madrid, Spain, 2 Cologne University Hospital, Cologne, Germany, 3 University of Utah School of Medicine, Salt Lake City, UT, USA, 4 ICH Study Center, Hamburg, Germany Background: Long-term ART cannot change the reservoir landscape. We analyzed the reservoir composition and competency in two PWH on ART over 4 years of treatment with dasatinib. Methods: Blood samples were collected periodically since 2019 from two PWH on ART and dasatinib to treat chronic myeloid leukemia (CML). Proviral composition was analyzed by ddPCR and IPDA in PBMCs. Proviral reactivation was assessed in CD4+ T cells by mini QVOA. Results: First participant: 1) 50 year-old male on ART for 17 years and imatinib for 9 years that changed to dasatinib. He discontinued dasatinib after 3 years 4 months but was reintroduced after 4.3 months. 2) Median HIV-1 DNA copies per 10 6 PBMCs was 1724.0 on imatinib; it decreased to 219.3 after 3.5 months on dasatinib and 2.24 (IQR 0.45-25.12) from 9.5 months of treatment onwards. During discontinuation, proviral DNA was 0.63 (IQR 0.5-3.16). 3) Median intact proviruses was 158.0 after 3.5 months on dasatinib and undetectable from 9.5 months onwards. Median 3´-defective proviruses was 31.01 (IQR 13.53-48.49) after 9.5 months on dasatinib, and 8.52 (IQR 1.48-48.49) from 1 year 4 months onwards. Median 5´-defective proviruses was 8.41 (IQR 3.67-13.15) after 9.5 months on dasatinib and decreased to 6.76 copies (IQR 0.49-29.19) from this moment onwards. 4) Proviral reactivation was 2.49% (IQR 0.82-4.46) p24-gag in CD4+ T cells. Second participant: 1) 62 year-old male on ART for 25 years and dasatinib for 4 years. 2) HIV-1 DNA copies per 10 6 PBMCs was 20.95 after 5 months on dasatinib and 7.59 (IQR 2.0-10.0) from 1 year 4 months onwards. 3) Median intact proviruses was 43.33 on ART and undetectable from 1year 4months on dasatinib onwards. Median 3´-defective proviruses was 128.3 (IQR 18.0-310.0) when only on ART, and 31.42 (IQR 4.88-164.17) on dasatinib for 4years and 4months. Median 5´-defective provirus was 124.35 (IQR 50.0-232.3) on ART and 8.22 (IQR 3.88-29.19) on dasatinib for 4 years and 4 months. 4) Proviral reactivation was 4.29% (IQR 0.85-7.69) p24-gag in CD4+ T cells. Conclusions: Dasatinib treatment changed the reservoir landscape towards a more favourable scenario in which there was a reduction in intact and defective proviruses. Detectable p24-gag during proviral reactivation may proceed from defective proviruses.

Poster Abstracts

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