Curing HIV with Gene Therapy Moving from science fiction to reality - PDF document

12/14/19 Curing HIV with Gene Therapy Moving from science fiction to reality Steven Deeks, MD Professor of Medicine Division of HIV, Infectious Diseases, and Global Medicine Zuckerberg San Francisco General University of California, San Francisco 1 Disclosures • Research support: Gilead, Merck, ViiV • Consulting: AbbVie, Eli Lilly • Scientific advisory board: BryoLogyx, Enochian Biosciences 2 1

12/14/19 Why do we need a cure in an era of effective ART? • Individual perspective – Treatment toxicity – Polypharmacy – Stigma/discrimination • Public health perspective – 38 million currently living with HIV • ~ %50 on effective ART • 2 million new infections every year • Life-long treatment challenging for many now driving the epidemic – Total spent on HIV/AIDS: ~$50 billion per year • Shifting financing landscape 3 The ideal curative intervention will be readily scalable, safe, effective in those populations that are not currently doing well on ART (for any reason) and protective against re-infection 4 2

12/14/19 Viable pathways toward a durable remission or cure • Early ART: Not curative, PTC rare, unpredictable • Shock and kill: Reservoir reduction; not curative • Block and lock: Reservoir reduction; not curative • Immunotherapy: Most viable options require complex combinations (LRA/vaccine/bNAbs/adjuvants) • Gene and cell-based therapy 5 Should this work, multiple pathways are evolving that make in vivo gene editing scalable and effective (“one shot cures”) 6 3

12/14/19 Gene editing for an HIV Cure: Proof of Concept “It’s great that I finally have someone added to my family. It’s been too long” Timothy Brown, Science March 2019 7 Gene and Cell Therapy 8 4

12/14/19 Gene Therapy Deleting, repairing and/or inserting genes “Delete” “Copy and Paste” Paula Canon 9 Gene Therapy: Nine clinically approved products (2019) Galy, October 2019 10 5

12/14/19 Ex vivo cures achieved by gene modification of stem cells β -thalassemia: blunted production of β -globulin, leading to abnormal hemoglobin CD34+ stem cells are harvested from the bone marrow or from the mobilized peripheral blood and subjected to gene transfer with an integrating lentiviral vector encod- ing the β -globin complementary DNA 11 • Autologous HSCs gene-modified with lentiviral vector expressing an anti- sickling β -globin gene • Partial engraftment: approximately 50% of β -like–globin chains • All disease-related complications resolved 12 6

12/14/19 Gene editing clinical trials 13 Gene editing clinical trials 14 7

12/14/19 Gene Therapy and an HIV Cure Deleting, repairing and/or inserting genes “Delete” “Copy and Paste” CCR5 CAR-T HIV Provirus Antiviral genes Paula Canon 15 HIV Cure: Ex vivo approaches 16 8

12/14/19 • HIV-infected man with leukemia who received gene-modified (CRISPR) allogenic stem cell transplant • Safety acceptable (n=1), although gene therapy-associated cancers take several years to develop • No immunogenicity • No off-target effects detected with whole-genome sequencing • Chines regulatory environment allowed translation from discovery of CRISPR-Cas9 to phase I clinical trial in two years (NCT03164135). 17 Sangamo Trial ZFN editing of CCR5 • 902 Trial • Single dose • Nine enrolled in San Francisco • 1101 Trial • Cyclophosphamide to “make space” • Singe dose • Treatment interruption six weeks later • 5 individuals enrolled at multiple centers 18 9

12/14/19 902 Trial: Despite the observation that only ~5% of have evidence of CCR5 disruption, we found that a single administration of SB- 528-T was associated with durable decline in reservoir 19 Participant 01-060: Long-term post-treatment control CD4 nadir 12 cells/mm 3 • Advanced AIDS prior to 01-060 ART 100000 • Cyclophosphamide VL (copies/ml) 10000 conditioning; single infusion of SB-528-T 1000 Infusion ATI • ~8% of cells have bi- 100 allelic disruption of CCR5 10 N E 1 3 4 6 8 0 2 4 8 2 7 8 0 2 8 8 9 9 9 K K K K K 1 1 1 1 2 H H 1 1 1 1 1 1 1 E N K K K K K H H / / / / / E I E E E E E T T 3 2 9 8 6 • Durable post-ART L E E E E E T T R E E E E E N N / 1 / / / E 2 1 3 1 E E E E E N N / W W W W W O O C 1 2 1 S W W W W W O O S M M 1 A M M B control 20 10

12/14/19 NIH UO1: RCT of ex vivo CCR5-deletion Cleveland, Cincinnati, San Francisco • Intervention: Ex vivo disruption of CCR5 in T cells • Study Design: Randomized clinical trial of autologous cells either gene-modified (n=20) or not gene-modified (n=10) • Cyclophosphamide conditioning • Population: Treated HIV disease (chronic) • Outcomes: Safety, immune function, reservoir reduction • Status: Actively enrolling 21 HIV Cure: In vivo approaches 22 11

12/14/19 One-shot cure approaches Gene delivery of long-acting antiviral (bANb) or direct in vivo gene editing (HIV, CCR5) might eventually lead to durable cure for treated and even untreated people Aspirational, but theoretically possible 23 Sickle cell disease and HIV have similar disease distribution with the major burden being in Africa Gene therapy works in sickle cell disease and potentially promising for HIV The goal is to avoid development of expensive, complex strategies that require stem cell transplantation 24 12

12/14/19 Can we “repair” the immune system so it will more effectively target HIV? 25 CAR-T cells are now curing many leukemias and lymphomas June, NEJM 2018 26 13

12/14/19 CAR-T cells: Modified cells persist for decades, based on our experience with first generation of CAR-T ells in 1990s 27 • Intervention: Multi-specific autologous LVgp120 duoCAR-T cells • Study Design: Open-label dose-escalating • Cohort 1: No CTX; single dose of 3 x 10 5 cells/kg followed by ATI • Cohort 2: Non-ablative CTX conditioning; single dose of 3 x 10 5 cells/kg followed by ATI • Cohort 3: Non-ablative CTX conditioning; single dose of 1 x 10 6 cells/kg followed by ATI • Cohort 4: Non-ablative CTX conditioning; two doses of 1 x 10 5 cells/kg (day 0 and 14 of ATI) • Population: Treated HIV disease • Outcomes: Safety, reservoir reduction • Status: IND submission pending 28 14

12/14/19 Conclusions • A truly transformative cure will need to be administered to everyone regardless of treatment status, be fully effective, and prevent re-infection – Aspirational but a viable pathway exits • Most cure strategies involve combinations that reduce reservoir while enhance host-control mechanisms (“reduce and control”) – Field may shift toward true curative interventions, particularly those involving gene therapies 29 15