Moving Toward an HIV Remission a Viable Approach Informed by Studies in Nhps and People That Might Work, at Least in Some People

Moving Toward an HIV Remission A viable approach informed by studies in NHPs and people that might work, at least in some people

Steven Deeks, MD Professor of Medicine University of California, San Francisco 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

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 In absence of a complete cure (which is unprovable) some sustained (life-long) immune response targeting HIV will be needed HIV Cure versus Remission: Remission

• Remission: Durable control of a persistent residual reservoir • Achieved with “elite” and post-treatment control • Is a remission an improvement over ART? Elite versus post-treatment control

The very curious differences between these two clinical phenotypes and the search for an ideal model “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

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

Inhibitory activity (ex vivo Perforin and granzyme killing autologous CD4+ T cells)

Low PD-1, Vulnerable Low CD38 TCR diversity CTLA-4, TIGIT epitopes

Polyfunctional Low T reg Public TCR Low IDO CD4+ T cells function Persistent inflammation during elite control is harmful Immunologic and clinical consequences have been described, leading to the recommendation that ART be considered Persistent inflammation during elite control is harmful Virologic progression among elite controllers is rare but does occur and is predicted by T cell activation, or low CD4/CD8 ratios • Exceptional, extraordinary and/or extreme elite controllers have been described – Low antibody levels, low reservoir and limited inflammation • Some are close to a “cure” 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 Post-treatment controllers and non-controllers have comparable levels of viremia during the acute (pre-ART) stage

Post-treatment control generally associated with lower post- interruption peak viral loads, suggesting ART fundamentally changed disease course Frequency of activated CD8+ T cells lower in PTCs than elite controllers

Reservoir level also likely lower (cause and effect unknown) • Elite control is achieved and maintained via a potent and sustained HIV-specific CD8+ T-cell population that is part of a highly activated and potentially harmful inflammatory immune response • Extraordinary control may prove to be a more viable model for HIV remission, but is poorly studied – Low reservoir, limited inflammation • Post-treatment control occurs provide proof that treatment can alter the natural course – Low reservoir, limited inflammation 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 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 Jacobson, JID 2006 VL 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 Pollard, Lancet HIV points 2014 ERAMUNE 02 DNA prime/MVA boost No effect (HIV DNA) Achenbach, Lancet HIV 2015 GeneCure Replication-defective HIV with Reduced VL set-point (compared to historical data) Tung, Vaccine 2016 VZV fusion protein (HIVAX) GeoVax DNA prime/MVA boost (virus-like No apparent effect during ATI (uncontrolled) Thompson, PLoS particles) ONE 16 ACTG 5281 Gag/Pol, Nef/Tat/Vif/Env and IL- Minimal CD4 effects, no CD8 effects, low dose IL-12 better than Jacobson, JAIDS 12 plasmids (Profectus) high dose IL-12 2016 BCN 02 ChAdV63.HIVconsv + 5/13 controlled (ATI) Mothe, CROI 17 MVA.HIVconsv 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 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 Therapeutic vaccine/bNAb program (UCSF/amfAR/DARE/ACTG) • 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) • Combination bNAbs/ATI: BMGF-funded, in development Immunotherapy and vaccine adjuvant program 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) Inflammation and HIV persistence (and cancer) • Many factors contribute to an inflammatory environment during treated HIV disease – Microbial translocation, CMV, obesity/life-style, others • Inflammation stimulates a potent and sustained immunosuppressive response – Immune checkpoint receptors – Myeloid-derived suppressor cells – T regulatory cells (TGF-β, IL-10) – IDO

Interventions that reduce inflammation or the counter- regulatory immunosuppression might be beneficial Immunotherapy to reduce inflammation Will anti-inflammatory drugs at the right time and dose enhance the capacity of the immune system to control HIV?

• Sirolimus (mTOR): Study completed (ACTG); data analysis pending • Everolimus (mTOR): Study completed (transplant population) • Canakinumab (IL-1β): Pilot safety study completed; RCT on hold • Ruxolitinib (JAK1/2 inhibitor): ACTG 5336 enrolled Will any of these probe studies be able to show any real benefit? Combination approaches 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 – Multiple combination studies using available agents that are safe and can be rationally done should be pursued Immune- modifying Agents Sanctuary Adjuvants Disruption

Therapeutic HIV Low Vaccine Remission 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 Combinatorial approaches towards and HIV remission Translating NHP success stories using available agents

• Stage 1: DNA prime (p24 conserved elements, p24CE) • Goal: induce responses to subdominant, conserved epitopes • Stage 2: DNA boost (p24CE and full-length p55) • Goal: boost CE responses and increase breadth • Stage 3: MVA boost (gag/pol/env) • Goal: boost CE response and increase breadth • Stage 4: bNAbs (10-1074 and VRC07-523LS) and TLR-9 agonist • Goal 1: expand T cell responses • Goal 2: include NK cells, reverse latency ( “shock and kill”, reservoir reduction) • Stage 5: ATI with bNAbs • Goal: induce T cell response (vaccinal effect) IND approval pending Study on track to open in early 2019 “Reduce and Control” Strategy • NK Plus • Tetramer CD8+

TRM/Tfh Reservoirs ATAC-Seq NK Plus Systems Biology CyTOF Tetramer CD8+ T-Cell VRCO1

Combination Vaccine Trial

Kansui Tideglusib NHP In Vitro Tideglusib CRISPRi Block and Lock