HIV and Cancer Curative Approaches Cross-disciplinary research. Steven Deeks, MD Professor of Medicine University of California, San Francisco

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1 HIV and Cancer Curative Approaches Cross-disciplinary research Steven Deeks, MD Professor of Medicine University of California, San Francisco

2 Cancer immunotherapy is reshaping a fatal and progressive disease much as ART reshaped HIV HIV and oncology immunotherapy: Synergistic and bi-directional research agendas

3 PD-1, CTLA-4 discovered In vivo relevance demonstrated ex vivo and animal models (LCMV, HIV) POC in cancer and revolution in modern treatment HIV cure work now emerging

4 CAR-T cells developed (animal) Initial studies in HIV disease (NIH, UCSF/UCLA) POC in cancer and revolution in modern treatment HIV cure work now emerging

5 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

6 Defining success Cure versus remission Cure: Complete removal of all replicationcompetent 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

7 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

8 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

9 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

10 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

11 Immunotherapy works better against cancers that generate higher density of neo-antigens Immunotherapy for HIV will need to target non-escaped, vulnerable regions

12 Towards a more effective therapeutic vaccine: Inserts Targeting conserved regions to avoid CTL escape and shift immunodominance

13 BCN01 Trial: ChAd.V63/MVA prime-boost with HIVconsv inserts among adults treated in early HIV infection

14 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)

15 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)

16 %PD1+ of tet viremic ARTs controller PD-1 MFI (of PD-1+ tet+) viremic ARTs controller PD-1 expression on tetramer-positive HIVspecific CD8+ T cells is high in acute and chronic untreated infection and does not consistently change during ART PD-1 levels are variable but generally lower in controllers, as expected

17 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

18 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)

19 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 posttreatment control Advances in cancer immunotherapy Advances in HIV vaccinology