HIV and Cancer Curative Approaches Cross-disciplinary research

Steven Deeks, MD Professor of Medicine University of California, San Francisco Cancer immunotherapy is reshaping a fatal and progressive disease much as ART reshaped HIV

HIV and oncology immunotherapy: Synergistic and bi-directional research agendas In vivo relevance POC in cancer PD-1, HIV cure demonstrated and revolution CTLA-4 work now ex vivo and in modern discovered emerging animal models treatment (LCMV, HIV) Initial studies in POC in cancer CAR-T cells HIV cure HIV disease and revolution developed work now (NIH, in modern (animal) emerging UCSF/UCLA) treatment Curing cancer and chronic infections (HIV, HBV) Shared obstacles and therapeutic approaches • Defining success • Diagnostic challenges • Cellular targets: minimally altered host cell • Tissue environment abnormal (inflammation) • Immune evasion • Curative strategies – Immunotherapy: Reduce and control/eliminate – Gene therapy: CART-T cells, DARTs, other Defining success Cure versus remission

• Cure: Complete removal of all replication- competent HIV or cancer cells – May have happened in Berlin Patient but impossible to prove • Remission: Sustained virus control (HIV) or disease-free period in absence of treatment – Replication-competent virus persists at levels that does not cause harm or can be transmitted – Elite and post-treatment controllers PrEP during early (day 1) detectable infection followed by ART resulted in the lack of any detectable reservoir, using multiple highly sensitive methods

Robust and emerging research initiatives assessing imaging to detect rare cancer or HIV-infected cells • Cancer: Antigen production (chemotherapy) and presentation (APCs), leading to a sustained adaptive immune response enhanced by immunotherapy • HIV: At its core, this is the same as “shock and kill” Immunotherapy for HIV infection Two decades of largely failed approaches • High disease (virus) burden • T cells ineffective – Upregulation of PD-1 and other pathways – Target immunodominant (often escaped epitopes) • Inflammation and counter-regulatory immunosuppression

These same barriers explain how cancer evades immune response and why generations of immunotherapies failed Combination bNAbs after a treatment interruption maintained virus suppression

Two of 4 individuals treated early maintained virus control after bNAb levels waned, consistent with a “vaccinal” effect Immunotherapy works better against cancers that generate higher density of neo-antigens

Immunotherapy for HIV will need to target non-escaped, vulnerable regions Towards a more effective therapeutic vaccine: Inserts Targeting conserved regions to avoid CTL escape and shift immunodominance BCN01 Trial: ChAd.V63/MVA prime-boost with HIVconsv inserts among adults treated in early HIV infection • SHIV-162P3 • Day 7 ART • ART maintained for two years • Reservoir reduced or eliminated during ART • Mechanism not known: no blips observed with GS-9620 (although CD4+ T cell activation observed) • SHIV-162P3 • Day 7 ART • ART maintained for two years • Reservoir reduced or eliminated during ART • Mechanism not known: no blips observed with GS-9620 (although CD4+ T cell activation observed) PD-1 expression on tetramer-positive HIV- specific CD8+ T cells is high in acute and chronic untreated

100 infection and does not 2500 80 consistently change 2000 60 1500 during ART 40 1000 20 500

%PD1+ of tet+ 0 0 PD-1 levels are variable

ARTs PD-1 MFI (of PD-1+ tet+) ARTs but generally lower in viremic viremic controller controller controllers, as expected • Latent HIV is enriched in CD4+ T-cells that express PD1, TIM3 and TIGIT • CD8+ T cell dysfunction reversed in HIV-infected individuals on ART ex vivo with inhibitors of PD- 1, CTLA-4 and TIGIT Careful assessment of safety and efficacy of immunotherapies in HIV/cancer will provide pathway for developing curative interventions

• CITN 12: Phase I Study of pembrolizumab (anti-PD-1) in patients with HIV and relapsed/refractory or disseminated malignant neoplasm • AMC 095: Phase I study of ipilimumab (anti-PD-1) and nivolumab (anti-CTLA-4) in advanced HIV-associated tumors (including anal CA and KS) Towards an HIV Cure

• The path toward a cure will take many years, involve multiple failures (which are important learning experiences) and likely require discoveries yet to be made, but there are reasons for optimism – Experiments of nature: elite control and perhaps post- treatment control – Advances in cancer immunotherapy – Advances in HIV vaccinology