[PDF] - 12/8/18 Disclosures Moving Toward a Cure: Where are Research PDF Document

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12/8/18

Steven Deeks, MD

Professor of Medicine University of California, San Francisco

Moving Toward a Cure: Where are We Now? Disclosures

Research support: Gilead, Merck, ViiV
Consulting: Abbvie, Janssen
SAB: Enochian Biosciences, BryoLogix

HIV Cure versus Remission: Cure

Complete removal of all replication-competent

HIV

No residual stigma (key outcome in surveys)
Difficult to achieve and impossible to prove

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PrEP during very early HIV infection (“day 1”) followed by ART resulted in the lack of any detectable reservoir Reservoir size estimated to be ~ 100 replication-competent virions

There are now dozens of cases of very low reservoir states in which virus rebounded during an interruption, presumably due to lack of effective immunity

Durable and near-complete control of a persistent

residual reservoir –Undetectable viral load –No transmission risk

Achieved with “elite” and post-treatment control
Is a remission an improvement over ART?

–Inflammation persists in many controllers

HIV Cure versus Remission: Remission Elite versus post-treatment control The very curious differences between these two clinical phenotypes and the search for an ideal model

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Post-treatment control: Case

30 year old mixed race (African American/Native

American) man

2011: Presents with acute/recent infection and a viral

load of 10 million copies RNA/mL

–Elite control would be unlikely

2011-2014: Effective ART (TNF/FTC/RPV)
2014: No ART, continued virus control
Some (10% to 20%) of

people who start therapy early (but not too early) and remain on therapy for years exhibit control after ART is interrupted

Rare but reported in

chronic infectino

Mechanism unknown

In contrast to elite controllers, post-treatment controllers generally have high viral loads during acute infection Post-treatment control generally associated with low but detectable post-interruption peak viral loads, suggesting ART fundamentally changed disease course

ATI: monitored every 2 weeks; ART resumed for (1)sustained (≥4 weeks) viral load >50,000 copies RNA/ml, (2) confirmed >30% decline in CD4+ T cell count, an absolute CD4+ T cell count of <350 cells/mm3, or (3) acute retroviral syndrome

Placeb

Vaccin

e

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Frequency of activated CD8+ T cells lower in PTCs than elite controllers Reservoir level also likely lower (cause and effect unknown)

Exceptional, extraordinary and/or extreme elite

controllers have been described –Low antibody levels, low reservoir and limited inflammation

Some are close to a “cure”

Ideal models for an effective HIV remission/cure will likely prove to be post-treatment controllers and rare ”extraordinary” natural controllers Exceedingly rare clinical phenotypes, particularly in era of universal ART

All models of durable SIV/HIV remission suggest that durable control of established infection will require (1) low disease burden, (2) low inflammation and (3) sustained host responses that are primed, reside in tissues, and target susceptible epitopes These same attributes apply to cancer immunotherapy

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“Elite” control is most consistently associated with HIV-specific CD8+ T cell responses, although other pathways are likely involved

Protective Class I Alleles B*57, B*27, B*13, B*58 CD8+ T Cell Proliferation

Gag-specific degranulation, cytokines (polyfunctional CD8+ T cells)

Inhibitory activity (ex vivo autologous CD4+ T cells) Perforin and granzyme killing Low PD-1, CTLA-4, TIGIT Low CD38 Vulnerable epitopes TCR diversity Polyfunctional CD4+ T cells Public TCR Low T reg function Low IDO

Curing monkeys has proven to be relatively easy

HIV Immunotherapy: Decades of experimental research have largely failed to identify any promising interventions

Trial Regimen Comment Author/Paper ACTG 5068 ALVAC (vCP1452) Intermitting interruptions but not vaccine associated with reduced VL Jacobson, JID 2006 ACTG 5024 ALVAC (vCP1452) + IL-1 0.5 log VL reduction during ATI Kilby, JID 2006 ACTG 5097 Ad5 0.24 log10 Schooley, JID 2010 MANON-02 ALVAC-HIV No VL effect; activated CD4 cells may have induced early failure Papagno, AIDS 2011 Bionor p24 peptide mixture (Vacc-4x) ATI: no VL effect at primary endpoint, mild benefit at later time points Pollard, Lancet HIV 2014 ERAMUNE 02 DNA prime/MVA boost No effect (HIV DNA) Achenbach, Lancet HIV 2015 GeneCure Replication-defective HIV with VZV fusion protein (HIVAX) Reduced VL set-point (compared to historical data) Tung, Vaccine 2016 GeoVax DNA prime/MVA boost (virus-like particles) No apparent effect during ATI (uncontrolled) Thompson, PLoS ONE 16 ACTG 5281 Gag/Pol, Nef/Tat/Vif/Env and IL- 12 plasmids (Profectus) Minimal CD4 effects, no CD8 effects, low dose IL-12 better than high dose IL-12 Jacobson, JAIDS 2016 BCN 02 ChAdV63.HIVconsv + MVA.HIVconsv 5/13 controlled (ATI) Mothe, CROI 17

Immunotherapy for HIV infection

Two decades of largely failed approaches

Weak immunogenicity

–Pre-existing immuno-dominant responses –CTL escape

Inflammation and counter-regulatory

immunosuppression

High virus burden
Immune-privileged tissues sanctuaries

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Gene modification of stem cells (Berlin

Patient)

CAR-T cells
Broadly neutralizing antibodies (immune

complexes and the “vaccinal” effect)

Therapeutic vaccination

–Proof-of-concept: herpes zoster vaccination, clearance of pre-cancerous lesions (HPV)

T cell immunity: Therapeutic approaches

Most likely to work Most scalable

Combination bNAbs after a treatment interruption maintained virus suppression Two of 9 individuals treated early maintained virus control after bNAb levels waned, consistent with a “vaccinal” effect

Vaccine (Ad26/MVA prime- boost) alone had minimal effect

n reservoir

Vaccine + TLR7 agonist reduces reservoir during ART and controls SIV post-ART Vesatolimod now being tested in phase I/II clinical trials

HIV cure research has entered era of experimental medicine Multiple “probe” studies ongoing

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Therapeutic vaccine program (UCSF)

HIV DNA (Inovio): RCT enrolling
CMV/HIV vaccine: Funding secured; waiting for GMP product

and phase I data in HIV uninfected population

RNA vaccine (CureVac): Dose-escalation study in

development; UO1 submitted

Conserved element DNA prime/MVA boost with

combination bNAbs: Five-stage combination study recently approved (IND 18488)

Hunt et al JID 2003, PLoS ONE 2011 and unpublished Hsue et al, JAMA Cardiology, 2017

Immune dysfunction – as quantified by measuring frequency of so- “activated” T-cells or inflammation in lymph nodes - persists during long-term ART Interventions that reduce inflammation or the counter-regulatory immunosuppression are reshaping the treatment of cancer and will likely me needed to achieve an HIV cure or remission

Immune checkpoint

receptors

Myeloid-derived

suppressor cells

T regulatory cells (TGF-

β, IL-10)

IDO

Immunotherapy and vaccine adjuvant program (UCSF) Pilot (“probe”) studies

Nivolumab/pembrolizumab (anti-PD-1): Safety studies (cancer)
ngoing; vaccine combination study in development
Nivolumab/vaccine: Will PD-1 blockade enhance vaccine

responsiveness (priming) and provide immediate response to rebounding virus? RCT in development (Lewin/DARE)

Vesatolimod (TLR7 agonist): RCT in viremic controllers nearly

completed (Gilead)

IL-15: Follicular disruption pilot study in development

(Schacker/DARE)

Lefitolimod (TLR9 agonist): Five-stage combination study recently

approved (IND 18488)

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Immunotherapy and vaccine adjuvant program (UCSF)

Reduce inflammation/proliferation

Sirolimus: Study completed (ACTG); data analysis pending
Everolimus: Study completed (transplant population)
Canakinumab: Pilot safety study completed; RCT on hold

Perspectives on the “state of the art” in cure research and potential roadmaps for future success

My own perspectives 1 Cure versus remission

A true cure will be difficult if not possible
Even if one is cured, you can never be sure

(proving a negative is impossible)

Super-infection: if PrEP is needed, going from

three drugs to two drugs is not adding much value

Sustained host response needed

My own perspectives 2 It is all about the timing

Most immunotherapies need to be primed and

expanded and ready to pounce once the virus begins to replicate

Timing of rebound unpredictable, but effector cells

will likely need to in lymphoid tissues at or after week 2 of an interruption

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My own perspectives 3

Reservoir size is too large

Natural controllers and post-treatment controllers: reservoir

at least 2 logs lower than in typical infection

Early ART, gene modification strategies, “shock and kill”

and/or “block and lock” approaches might reduce reservoir and all are in the clinic –Long-term ART may also be sufficient

My own perspectives 4

In absence of a biomarker, only an ATI is interpretable

Scientific and community engagement and support
Legitimate informed consent
Avoid coercement
Mitigate against risk
Exclude those with low nadir, history of cancer/CAD
High baseline CD4+ T cell count
Age limits
Partner engagement (PrEP)
Strick restart criteria for sustained viremia

My own perspectives 5

Product profile

The preferred product profile needs to be defined now
This requires a precise discussion on why a cure is

needed

– What will be the unmet need in 15 to 20 years? – Should the cure be designed to have a global impact, in which case a remission strategy will be helpful, or do we need to improve upon ART, in which case only a real cure may be needed?

Scalability will be needed for a full impact

My own perspectives 6

You learn by doing

Deep investment exists in basic discovery and pre-clinical

models, particularly animal models

Most animal models designed to show an effect of

intervention; parameters set are rarely relevant to typical HIV-infected person

Single therapies may not show anything yet still ultimately

be of value

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My own perspectives 7 Combination approaches

Given multiple known barriers, combination

approaches will almost certainly be needed

–Escape, immunodominance, dysfunctional T cells, chronic inflammation, low antigen exposure on target cells, sanctuaries HIV Remission

Therapeutic Vaccine

Adjuvants Immune- modifying Agents Sanctuary Disruption Low Reservoir

Combinatorial therapy with a therapeutic conserved element DNA/MVA vaccine strategy, a TLR9 agonist and broadly neutralizing antibodies: A pilot study aimed at inducing an HIV remission

HIV Remission Therapeutic vaccine (CE DNA)

Vaccine boost (MVA) Vaccine adjuvant (TLR9 agonist) Reservoir reduction (bNABs/TLR9) Enhanced CTL (ATI/bNAbs)

Combinatorial therapy with a therapeutic conserved element DNA/MVA vaccine strategy, a TLR9 agonist and broadly neutralizing antibodies: A pilot study aimed at inducing an HIV remission (IND 18488)

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