CROI 2020 Abstract eBook
persistence of CD4ζ CAR-T cells 13-15 years post infusion in both PBMC and rectal tissues in all recipients. Rare HIV-RNA+ cells can be identified in the majority of rectal biopsies. Total PBMC HIV DNA at long-term follow up, and the change in total and integrated HIV DNA from pre- and post-treatment compared among the treatment arms was not statistically different. Conclusion: The CD4ζ transgene persisted for 13-15 years in CAR-T cell treated subjects. With the caveat of a trial with a small number of subjects, coupled with intersubject variability, our analysis suggests that there was no statistical difference in baseline to LTFU between arms and that HIV remains present in PBMC and rectal tissue. Furthermore, this is the most mature data set to date to indicate that CAR-T cells are safe for at least 15 years. 338 PHASE I STUDY OF GENE-MODIFIED CD4+ CELLS AND CD34+ CELLS W/ WO BUSULFAN IN HIV+ ADULT Ronald T. Mitsuyasu 1 , Jay Lalezari 2 , Bryan Burke 3 , Mollie Barrett 3 , Jeremy Casey 3 , Alison Knop 3 , Suparna Mishra 3 , Jeffrey Ahlers 3 , Louis Breton 3 , Orit Wolstein 3 , Jeffrey Bartlett 3 , W. David Hardy 4 , Louise Evans 3 , Geoffrey Symonds 3 1 University of California Los Angeles, Los Angeles, CA, USA, 2 Quest Clinical Research, San Francisco, CA, USA, 3 Calimmune, Inc, Pasadena, CA, USA, 4 Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: HIV gene therapy could reduce viral load, preserve immunity and mitigate ART toxicities. Safety and feasibility of an anti-HIV-1 dual-gene construct LVsh5/C46 (Cal-1) in modified, autologous CD4+ T-cells (Ttn) and HSC (HSCtn) was assessed. Methods: PLWH with CD4+ count > 500/mm 3 and voluntary ART suspension (drug toxicities, treatment fatigue or other reasons) underwent aphereses for CD4+ T-cells and CD34+ HSC following mobilization, then gene-modified cell infusion. Busulfan pre-conditioning was: none (Cohort 1), 4 mg/kg on Day -2 (Cohort 2) and 3mg/kg (Day -2) to a total AUC exposure of 8,000 μmolar/min at Day -4 (Cohort 3). Subjects were followed for 48 weeks with ART reinitiation if CD4+ count or viral RNA reached safety thresholds, or participant decision. BM aspirates and GALT biopsies were taken at 24 and 48 weeks. Results: 12 participants (4 per cohort) were treated. At 48 weeks, 4 remained off and 8 resumed ART. Only 1 unrelated SAE was reported. Procedure-related AEs included neutropenia, thrombocytopenia, fatigue, nausea, and back pain. One pt in Cohort 1 had Cal-1 marking in PB >1% at Wk 4 which was not sustained. All Cohort 2 pts had >1%marking at early time points which was not sustained. Cohort 3 had highest levels of Cal-1 marking at peak and longest persistence. While no association was seen between Cal-1 marking and Ttn dose, there was a correlation between HSCtn dose in Cohort 3. For all Cohorts, marking at wk 24 and 48 was not substantive in GALT and very low in BM. Higher busulfan AUC correlated with higher peak Cal-1 marking in PB. There was no effect on plasma HIV RNA. Absolute CD4+ counts were reduced following apheresis. Conclusion: Delivery of HSCtn and Ttn was feasible and well-tolerated. Low to moderatedose busulfan was safely administered in an all-outpatient settingThe impact of HSCtn and Ttn on control of HIV replication could not be fully assessed because of low level of marking in PB. Busulfan exposure correlated with higher levels of marking. Potential reasons for the lack of long-term survival of Cal-1 transduced cells include persistent HIV viremia and inflammation. Future research should focus on administering gene-modified stem cells in fully- suppressed individuals 339 HIV-SPECIFIC T-CELL RESPONSES IN AN HIV-POSITIVE COHORT POST ALLO-HSCT Johanna M. Eberhard 1 , Mathieu Angin 2 , Caroline P. Passaes 2 , Maria Salgado 3 , Valérie Monceaux 2 , Gero Hütter 4 , Pascual Balsalobre 5 , Mi Kwon 5 , Jose Luis Diez 5 , Monique Nijhuis 6 , Annemarie Wensing 6 , Javier Martinez-Picado 3 , Julian Schulze Zur Wiesch 1 , Asier Saez-Cirion 2 , for the IciStem Study Group 1 University Medical Center Hamburg–Eppendorf, Hamburg, Germany, 2 Institut Pasteur, Paris, France, 3 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 4 Cellex, Dresden, Germany, 5 University Hospital Gregorio Marañon, Madrid, Spain, 6 University Medical Center Utrecht, Utrecht, Netherlands Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only medical intervention which has led to HIV cure. While the size of the HIV reservoir sharply decreases after allo-HSCT, the dynamics of the T-cell reconstitution has not been comprehensively described. Methods: We analyzed the activation and differentiation of CD4+ and CD8+ T-cells, and the breadth and quality of HIV- and CMV-specific CD8+ T-cell
responses in 16 HIV-infected patients who underwent allo-HSCT (including 4 individuals who received cells from CCR5D32/D32 donors) to treat their underlying hematological malignancy and remained under antiretroviral therapy (ART). Results: We found that reconstitution of the CD4+ and CD8+ T-cell compartment was slow and heterogeneous with an initial expansion of activated CD4+ T-cells that preceded the expansion of CD8+ T-cells. Transplanted patients did not achieve full immune reconstitution after allo- HSCT. While HIV-specific CD8+ T-cells disappeared immediately after allo-HSCT, weak ex vivo HIV-specific CD8+ T-cell responses were detectable several weeks after allo-HSCT, and could still be detected at the time of full T-cell chimerism, indicating that de novo priming, and hence antigen exposure, occurred during the time of T-cell expansion. These HIV-specific T-cells had limited functionality compared to CMV-specific CD8+ T-cells, and persisted years after allo-HSCT. Conclusion: In conclusion, immune reconstitution was slow, heterogeneous and incomplete and coincided with de novo detection of weak HIV-specific T-cell responses. The initial short phase of high T-cell activation, in which HIV antigens were present, may constitute a window of vulnerability for the reseeding of viral reservoirs, emphasizing the importance of maintaining ART directly after allo-HSCT. 340 MYCOPHENOLATE MOFETIL FOR DEPLETION OF THE HIV RESERVOIR Joshua T. Schiffer 1 , Claire Levy 2 , Sean Hughes 2 , Mel Padullo 2 , Katrina Puckett 2 , Eric Helgeson 2 , Robert D. Harrington 2 , Florian Hladik 2 1 Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 2 University of Washington, Seattle, WA, USA Background: Recent data suggests that proliferation of latently infected memory CD4+ T cells is essential to the maintenance of the HIV reservoir in individuals who are taking suppressive antiretroviral therapy (ART). Mathematical model projections suggest that curtailing lymphocyte proliferation may accelerate the rate of reservoir clearance. We conducted a clinical trial to test this hypothesis. Methods: We performed a small (n=4), open-label, non-randomized Phase II clinical trial (NCT03262441) to assess the safety and tolerability of 22 months of low-dose mycophenolate mofetil (MMF) in chronically HIV-infected men on suppressive ART. The in vivo anti-proliferative effect of MMF was assessed using a “total antiproliferation test” (TAPT) assay, in which anti-CD3/CD28-stimulated participant T cells are exposed to serum from participants after MMF dosing. The TAPT is reported as percent reduction in proliferation compared to serum/ cells taken before the start of the trial. We escalated the MMF dose in those individuals with <80% anti-proliferative effect at peak drug levels (one-hour after dosing). We measured the effect of MMF on levels of total (“total”) and potentially intact (“intact”) HIV proviral DNA at 3-month intervals. HIV proviral DNA was measured with a multiplexed digital droplet PCR assay simultaneously targeting HIV-1gag, env and pol genes. Results: All participants maintained stable CD4 T cell counts and subset composition, remained suppressed on ART and tolerated MMF. One participant required dose escalation fromMMF 500 to 750 mg twice daily to achieve >80% anti-proliferative effect at drug peak. Proliferation inhibition at drug trough pre-dosing was highly variable. No participant met the pre-specified criteria for study continuation at 12 months (0.25 log reduction in total HIV DNA) and MMF was therefore stopped for all participants. Intact HIV DNA levels were undetectable in one participant and remained stable in the remaining participants over one year of MMF (Table). Conclusion: One year of low-dose MMF was safe and well-tolerated in ART suppressed men but did not lower total or intact HIV proviral DNA levels. The anti-proliferative effect waned during the dosing interval, suggesting that higher doses, or more frequent or extended-release dosing may be necessary to lower the HIV reservoir.
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