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

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

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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

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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

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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

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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

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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

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Should this work, multiple pathways are evolving that make in vivo gene editing scalable and effective (“one shot cures”)

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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

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Gene and Cell Therapy

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Gene Therapy Deleting, repairing and/or inserting genes “Delete” “Copy and Paste”

Paula Canon

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Gene Therapy: Nine clinically approved products (2019)

Galy, October 2019

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Ex vivo cures achieved by gene modification of stem cells β-thalassemia: blunted production

  • f 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

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  • 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

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Gene editing clinical trials

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Gene editing clinical trials

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Gene Therapy and an HIV Cure Deleting, repairing and/or inserting genes “Delete”

CCR5 HIV Provirus

“Copy and Paste”

CAR-T Antiviral genes

Paula Canon

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HIV Cure: Ex vivo approaches

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  • 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).

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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

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902 Trial: Despite the observation that only ~5% of have evidence

  • f CCR5 disruption, we found that a single administration of SB-

528-T was associated with durable decline in reservoir

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Participant 01-060: Long-term post-treatment control CD4 nadir 12 cells/mm3

S C R E E N B A S E L I N E W E E K 1 W E E K 3 W E E K 4 W E E K 6 W E E K 8 W E E K 1 W E E K 1 2 W E E K 1 4 W E E K 1 8 W E E K 2 2 M O N T H 7 M O N T H 8 M O N T H 1 M O N T H 1 2 1 2 / 3 / 1 8 1 2 / 1 2 / 1 8 1 / 9 / 1 9 3 / 8 / 1 9 1 1 / 6 / 1 9 10 100 1000 10000 100000

VL (copies/ml)

01-060

ATI

Infusion

  • Advanced AIDS prior to

ART

  • Cyclophosphamide

conditioning; single infusion of SB-528-T

  • ~8% of cells have bi-

allelic disruption of CCR5

  • Durable post-ART

control

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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

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HIV Cure: In vivo approaches

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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

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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

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Can we “repair” the immune system so it will more effectively target HIV?

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June, NEJM 2018

CAR-T cells are now curing many leukemias and lymphomas

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CAR-T cells: Modified cells persist for decades, based on

  • ur experience with first generation of CAR-T ells in 1990s

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  • Intervention: Multi-specific autologous LVgp120 duoCAR-T cells
  • Study Design: Open-label dose-escalating
  • Cohort 1: No CTX; single dose of 3 x 105 cells/kg followed by ATI
  • Cohort 2: Non-ablative CTX conditioning; single dose of 3 x 105 cells/kg followed by ATI
  • Cohort 3: Non-ablative CTX conditioning; single dose of 1 x 106 cells/kg followed by ATI
  • Cohort 4: Non-ablative CTX conditioning; two doses of 1 x 105 cells/kg (day 0 and 14 of

ATI)

  • Population: Treated HIV disease
  • Outcomes: Safety, reservoir reduction
  • Status: IND submission pending

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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

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