CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

for escape variants in most HIV-1 infected patients and therefore use of a combination of 2 or more bnAbs is desirable to maintain durable suppression of HIV-1 replication. Methods: We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: 1) the CD4 binding site, 2) the membrane proximal external region (MPER) and 3) the V1V2 glycan site. Prior studies demonstrated improved neutralization compared to parental bnAbs. These trispecific Abs have an intact IgG1 backbone and were assessed for Fc effector function and ability to suppress virus replication from activated HIV-1 infected donor T cells. One of the trispecific Abs was administered to viremic simian-human immunodeficiency virus (SHIV)- infected rhesus macaques to assess inhibition of viral replication. Results: Each of the three combining sites of the trispecific Abs were actively bound with high affinity binding to the HIV envelope glycoprotein. In addition, trispecific Abs retained binding to Fcγ receptors via their Fc region and mediated antibody dependent cellular cytotoxicity (ADCC). In cultures of activated CD4+ T cells from HIV-1 infected patients, trispecific Abs durably suppressed viral replication compared to individual parental bnAbs. In viremic SHIV-infected macaques, treatment with trispecific Abs reduced plasma viremia up to 1000- fold that was maintained until the plasma trispecific Ab levels dropped below a value that was greater than 5-fold its IC80 titer against the SHIV. Conclusion: Trispecific HIV antibodies demonstrate potent neutralization and ADCC in vitro, and mediate antiviral activity in vivo. Thus, trispecific Abs provide an attractive single immunotherapeutic protein for treatment of HIV-1 infection. 29LB SUSTAINED HIV-1 REMISSION FOLLOWING HOMOZYGOUS CCR5 DELTA32 ALLOGENIC HSCT Ravindra K. Gupta 1 , Sultan Abduljawad 1 , Laura McCoy 1 , H P. Mok 2 , Dimitra Peppa 1 , Helen Lee 2 , Eleni Nastouli 3 , Jonathan Lambert 3 , Matthew Pace 4 , John Frater 4 , Andrew Lever 2 , Simon Edwards 5 , Eduardo Olavarria 6 , Ian Gabriel 6 , for the CHERUB and ICISTEM Study Groups 1 University College London, London, UK, 2 Cambridge University, Cambridge, UK, 3 University College London Hospitals NHS Trust, London, UK, 4 University of Oxford, Oxford, UK, 5 Mortimer Market Centre, London, UK, 6 Imperial College Healthcare NHS Trust, London, UK Background: The “Berlin Patient” underwent 2 consecutive HSCTs with total body irradiation. It is unclear which aspects of treatment contributed to this only known case of HIV cure. We report an HIV-infected male diagnosed with Hodgkin’s Lymphoma (HL) who underwent allogenic HSCT using a homozygous CCR5d32 donor. Nadir CD4 was 290 cells/mm and baseline VL 180,000 copies/ml. ART (TDF/FTC/EFV) was started in 2012. During episodes of ART interruption viral rebound and selection of NRTI resistance was seen. HL was refractory to 1st line chemotherapy and multiple salvage regimens. An unrelated CCR5d32 homozygous donor was identified with one allelic mismatch at HLA-B. Conditioning was initiated with Lomustine, cyclophosphamide, Ara-C and etoposide followed by 3.6 million CD34+ cells/kg. In vivo T-cell depletion employed anti–CD52 and GvHD prophylaxis was cyclosporine and methotrexate. ART was continued throughout (Rilpivirine, 3TC, dolutegravir). The patient developed mild gut GvHD. Full donor chimerismwas maintained in blood. Six months post-HSCT complete remission was observed. Methods: Co-receptor tropismwas predicted with Geno2Pheno based on single genome sequencing (SGS). Post-HSCT PBMC were analysed by ddPCR and qPCR. Infectious virus was repeatedly analysed by qVOA. Isolated CD4 T cells were experimentally infected with X4 and R5 HIV. Results: SGS from pre-transplant PBMC identified multiple envelope clones all with predicted R5 tropism. ART was stopped 17 months post-HSCT and plasma HIV VL remained undetectable ( <1.4 copies/ml) at 33 months. ART drugs were not detectable in plasma by LC-MS. Total HIV DNA in CD4+ T-cells at 33 months showed 2 positive droplets in 1 out of 8 replicates (ddPCR HIV LTR, 10^6 cells tested) and no signal in qPCR (<0.69 HIV-gag and <0.65 HIV-LTR copies/million cells). At 16 months post transplant HIV-specific Western blot was positive while p24/p31 bands were absent. VITROS detuned and avidity analysis revealed low quantity and quality of HIV antibody titers. At three time points post-HSCT qVOA showed no reactivatable virus using a total of 24 million resting CD4+ T cells. Post-transplant CD4+ T cells did not express CCR5 and were susceptible in vitro to X4- but not R5-tropic virus. Conclusion: Absence of viral rebound was observed for 16 months following ART interruption at 17 months after single allogeneic CCR5-d32 HSCT using a no

1 Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 2 University of Melbourne, Melbourne, VIC, Australia, 3 Northwell Health, New York, NY, USA, 4 Université de Montréal, Montreal, QC, Canada, 5 Leidos Biomedical Research, Inc, Frederick, MD, USA, 6 National Cancer Institute, Bethesda, MD, USA, 7 National Cancer Institute, Frederick, MD, USA, 8 University of California San Francisco, San Francisco, CA, USA Background: Pembrolizumab is a monoclonal antibody against PD-1 approved for several cancers. In HIV-infected individuals on suppressive antiretroviral therapy (ART), HIV is enriched in CD4 T-cells that express PD-1. Within a Cancer Immunotherapy Trials Network (CITN) study, we prospectively evaluated markers of HIV persistence to test the hypothesis that pembrolizumab administration might increase HIV transcription and viral production consistent with latency reversal. Methods: CITN-12 is a prospective multicenter phase I study of pembrolizumab 200mg IV every 3 weeks in participants with HIV on ART and advanced cancer. Participants were enrolled in cohorts with CD4 counts of: 100-199 (C1), 200-350 (C2) and >350 cells/uL (C3). Specimens were collected at baseline, 2 hours, 1 day, 7 days (cycle 1 only) and before cycles 2 and 3. Plasma HIV RNA was measured using a single copy (sc) qRT-PCR for HIV gag. Intracellular unspliced (us) HIV RNA (RNA) and viral DNA (vDNA) were measured in CD4 T-cells. Pairwise correlation between assays was assessed by Pearson’s correlation coefficient. Kinetics of HIV plasma RNA, intracellular usRNA, usDNA, and usRNA/vDNA were evaluated by negative binomial regression. P<0.01 was considered statistically significant, p<0.05 a significant trend. Results: 29 participants (C1 N= 6, C2 N=12, C3 N=11) with a range of tumors were evaluated; median age 56 years (IQR 50-61); 28 men, 1 woman. Baseline sc HIV = 1.1 copies/mL (IQR 0.3-2.4). Median baseline CD4 272 cells/uL (IQR 210-568). After pembrolizumab, mean usRNA and usRNA/DNA ratio were significantly elevated at Day 7 compared to baseline (usRNA: 1.43 fold, 95% CI 1.12 – 1.82, P=0.004; usRNA/DNA 1.63 fold, 95%CI 1.17-2.27, P=0.004) but not at day 21 (P=0.15, P=0.87 respectively). vDNA was decreased at 24 hours (0.82, 95%CI 0.70-0.97, P=0.02) but not on Day 7 (P=0.2) (Figure). No significant changes in plasma scHIV RNA were observed over 2 cycles. scHIV RNA , usRNA, and vDNA were not correlated (p>0.05). Conclusion: Pembrolizumab leads to a transient increase in HIV transcription in CD4+ T-cells in vivo in individuals on ART consistent with latency reversal. It did not lead to increased plasma HIV RNA after administration of 2 doses. Evaluation of the long-term effects of pembrolizumab on HIV persistence and HIV specific immunity are ongoing. Further evaluation of monoclonal antibodies against PD-1 as a strategy for HIV cure is warranted.

Oral Abstracts

28LB POTENT ANTIVIRAL ACTIVITY OF TRISPECIFIC BROADLY NEUTRALIZING HIV ANTIBODIES Amarendra Pegu 1 , Ling Xu 2 , Megan Demouth 1 , Cassandra Almasri 1 , Eun S. Yang 1 , Jason M. Hataye 1 , Mangaiarkarasi Asokan 1 , Wanwisa Promsote 1 , Ronnie R. Wei 2 , Dana M. Lord 2 , Ercole Rao 2 , Jochen Beninga 2 , Zhi-yong Yang 2 , John R. Mascola 1 , Gary Nabel 2 1 Vaccine Research Center, NIAID, Bethesda, MD, USA, 2 Sanofi, Cambridge, MA, USA Background: Broadly neutralizing antibodies (bnAbs) against HIV-1 have been suggested as a complementary immunotherapy to current combination small molecule anti-retroviral therapies (cART) for treatment of HIV-1 infection. Due to their monospecific nature, use of single bnAbs leads to rapid selection


CROI 2019

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