03 deeks cure update - ucsf cme · art” in cure research and potential roadmaps for future...
TRANSCRIPT
12/8/18
Steven Deeks, MDProfessor o f Medic ineUnivers i ty o f Cal i forn ia , San Franc isco
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-competentHIV• 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 persistentresidual 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: RemissionElite 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/NativeAmerican) 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
Placebo
Vaccine
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4
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 elitecontrollers 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 AllelesB*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 infectionTwo decades of largely failed approaches
• Weak immunogenicity–Pre-existing immuno-dominant responses–CTL escape
• Inflammation and counter-regulatoryimmunosuppression• High virus burden• Immune-privileged tissues sanctuaries
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• Gene modification of stem cells (BerlinPatient)• 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 on 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 recentlyapproved (IND 18488)
Hunt et al JID 2003, PLoS ONE 2011 and unpublishedHsue et al, JAM A 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)
ongoing; 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 1Cure 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 muchvalue• Sustained host response needed
My own perspectives 2It is all about the timing
• Most immunotherapies need to be primed andexpanded and ready to pounce once the virusbegins to replicate• Timing of rebound unpredictable, but effector cells
will likely need to in lymphoid tissues at or afterweek 2 of an interruption
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My own perspectives 3Reservoir size is too large
• Natural controllers and post-treatment controllers: reservoirat least 2 logs lower than in typical infection
• Early ART, gene modification strategies, “shock and kill”and/or “block and lock” approaches might reduce reservoirand all are in the clinic–Long-term ART may also be sufficient
My own perspectives 4In 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 5Product 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 6You learn by doing
• Deep investment exists in basic discovery and pre-clinicalmodels, particularly animal models
• Most animal models designed to show an effect ofintervention; parameters set are rarely relevant to typicalHIV-infected person
• Single therapies may not show anything yet still ultimatelybe of value
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My own perspectives 7Combination approaches
• Given multiple known barriers, combinationapproaches will almost certainly be needed–Escape, immunodominance, dysfunctional T cells,
chronic inflammation, low antigen exposure on targetcells, sanctuaries HIV
RemissionTherapeutic
Vaccine
Adjuvants
Immune-modifying
AgentsSanctuary 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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IND approval pendingStudy on track to open in early 2019 SCOPTIONS-CIL-LCV-ASB Platform