12/8/18 Disclosures Moving Toward a Cure: Where are Research - PDF document

12/8/18 Disclosures Moving Toward a Cure: Where are • Research support: Gilead, Merck, ViiV We Now? • Consulting: Abbvie, Janssen • SAB: Enochian Biosciences, BryoLogix Steven Deeks, MD Professor of Medicine University of California, San Francisco 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

12/8/18 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 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 HIV Cure versus Remission: Remission Elite versus post-treatment control • Durable and near-complete control of a persistent residual reservoir The very curious differences between – Undetectable viral load these two clinical phenotypes and the – No transmission risk search for an ideal model • Achieved with “elite” and post-treatment control • Is a remission an improvement over ART? – Inflammation persists in many controllers

12/8/18 Post-treatment control: Case • 30 year old mixed race (African American/Native American) man • Some (10% to 20%) of • 2011: Presents with acute/recent infection and a viral people who start therapy early (but not too early) load of 10 million copies RNA/mL and remain on therapy – Elite control would be unlikely for years exhibit control after ART is interrupted • 2011-2014: Effective ART (TNF/FTC/RPV) • Rare but reported in • 2014: No ART, continued virus control chronic infectino • Mechanism unknown Vaccin Placeb In contrast to elite controllers, e o 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/mm 3 , or (3) acute retroviral syndrome

12/8/18 Frequency of activated CD8+ T • Exceptional, extraordinary and/or extreme elit e cells lower in PTCs than elite controllers controllers have been described Reservoir level also likely lower – Low antibody levels, low reservoir and limit ed (cause and effect unknown) inflammation • Some are close to a “cure” All models of durable SIV/HIV remission suggest Ideal models for an effective HIV that durable control of established infection will remission/cure will likely prove to be require (1) low disease burden, (2) low post-treatment controllers and rare inflammation and (3) sustained host responses ”extraordinary” natural controllers that are primed, reside in tissues, and target susceptible epitopes Exceedingly rare clinical phenotypes, These same attributes apply to cancer particularly in era of universal ART immunotherapy 4

12/8/18 “Elite” control is most consistently associated with HIV-specific CD8+ T cell responses, although other pathways are likely involved Curing monkeys has proven to be relatively Protective Class I Alleles easy 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 HIV Immunotherapy: Decades of experimental research Immunotherapy for HIV infection have largely failed to identify any promising interventions Two decades of largely failed approaches Trial Regimen Comment Author/Paper • Weak immunogenicity 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 – Pre-existing immuno-dominant responses 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 – CTL escape Bionor p24 peptide mixture (Vacc-4x) ATI: no VL effect at primary endpoint, mild benefit at later time Pollard, Lancet HIV • Inflammation and counter-regulatory points 2014 ERAMUNE 02 DNA prime/MVA boost No effect (HIV DNA) Achenbach, Lancet HIV 2015 immunosuppression GeneCure Replication-defective HIV with Reduced VL set-point (compared to historical data) Tung, Vaccine 2016 VZV fusion protein (HIVAX) • High virus burden 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 • Immune-privileged tissues sanctuaries BCN 02 ChAdV63.HIVconsv + 5/13 controlled (ATI) Mothe, CROI 17 MVA.HIVconsv

12/8/18 T cell immunity: Therapeutic approaches • Gene modification of stem cells (Berlin Patient) Most likely to work • CAR-T cells Combination bNAbs after a treatment interruption • Broadly neutralizing antibodies (immune maintained virus suppression complexes and the “vaccinal” effect) Two of 9 individuals treated early maintained virus control • Therapeutic vaccination Most after bNAb levels waned, scalable consistent with a “vaccinal” – Proof-of-concept: herpes zoster vaccination, effect clearance of pre-cancerous lesions (HPV) HIV cure research has entered era of Vaccine (Ad26/MVA prime- experimental medicine boost) alone had minimal effect on reservoir Multiple “probe” studies ongoing Vaccine + TLR7 agonist reduces reservoir during ART and controls SIV post-ART V esatolimod now being tested in phase I/II clinical trials

12/8/18 Immune dysfunction – as quantified by measuring frequency of so- Therapeutic vaccine program (UCSF) “activated” T-cells or inflammation in lymph nodes - persists during long-term ART • 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 i n development; UO1 submitted • Conserved element DNA prime/MVA boost with combination bNAbs: Five-stage combination study recentl y approved (IND 18488) Hunt et al JID 2003, PLoS ONE 2011 and unpublished Hsue et al, JAMA Cardiology, 2017 Immunotherapy and vaccine adjuvant program (UCSF) Interventions that reduce inflammation or the counter-regulatory Pilot (“probe”) studies immunosuppression are reshaping the treatment of cancer and will likely me needed to achieve an HIV cure or remission • Nivolumab/pembrolizumab (anti-PD-1): Safety studies (cancer) ongoing; vaccine combination study in development • Nivolumab/vaccine: Will PD-1 blockade enhance vaccine • Immune checkpoint responsiveness (priming) and provide immediate response to receptors rebounding virus? RCT in development (Lewin/DARE) • Myeloid-derived • Vesatolimod (TLR7 agonist) : RCT in viremic controllers nearly suppressor cells completed (Gilead) • T regulatory cells (TGF- • IL-15: Follicular disruption pilot study in development β , IL-10) (Schacker/DARE) • IDO • Lefitolimod (TLR9 agonist): Five-stage combination study recently approved (IND 18488)

12/8/18 Immunotherapy and vaccine adjuvant program (UCSF) Reduce inflammation/proliferation • Sirolimus: Study completed (ACTG); data analysis pending Perspectives on the “state of the • Everolimus: Study completed (transplant population) • Canakinumab: Pilot safety study completed; RCT on hold art” in cure research and potential roadmaps for future success My own perspectives 1 My own perspectives 2 Cure versus remission It is all about the timing • A true cure will be difficult if not possible • Most immunotherapies need to be primed and • Even if one is cured, you can never be sure expanded and ready to pounce once the virus begins to replicate (proving a negative is impossible) • Timing of rebound unpredictable, but effector cells • Super-infection: if PrEP is needed, going from will likely need to in lymphoid tissues at or after three drugs to two drugs is not adding much week 2 of an interruption value • Sustained host response needed