How Close are w e to a Cure? Douglas F. Nixon, MD, PhD Chair, Dept. of Microbiology, Immunology & Tropical Medicine, The George Washington University, Washington DC, USA October 25 th 2016 OHTN- Thank you! OHTN and NIH – Thank you! October 25, 2016, Toronto, Canada
Presenter Disclosure • Presenter: Douglas Nixon • No Conflicts of Interest
BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication NIH funded Martin Delaney Collaboratory OVERVIEW 1. Overview of Collaboratory Program 2. Expectations for the award 3. Community Engagement 4. “Believe” Science 5. What is a “Cure”? 6. “Precision Cure” approach
Martin Delaney 1946‐2009
Martin Delaney Collaboratories for HIV Cure Research I4C: Combined Immunologic Approaches to Cure HIV-1 Dan Barouch, John Mellors, Nelson Michael (Beth Israel Deaconess, Boston) defeatHIV: Cell and Gene Therapy BEAT-HIV: Delaney Collaboratory for HIV Cure to Cure HIV-1 Infection by Keith Jerome & Hans-Peter Kiem Combination Immunotherapy (FHCRC, Seattle) Luis Montaner & James Riley (Wistar Institute, Philadelphia) BELIEVE: Bench to Bed Enhanced Lymphoctye Infusions to Engineer Viral Eradication Douglas Nixon (GWU, Washington, DC) DARE: Delaney AIDS Research Enterprise to Cure HIV CARE: Collaboratory of AIDS Steven Deeks & Louis Picker Researchers for Eradication (UCSF, San Francisco) David Margolis (UNC, Chapel Hill)
Expectations for Collaboratories MDC program has a unique focus on partnerships, communication, collaboration Industry partners are expected to contribute intellectually and be fully engaged in research UM1 fosters dynamic changes in strategy and resource allocation, in partnership with NIH Exec. Comm. should establish a regular process for evaluating priorities and monitoring milestones
Community Engagement Community Engagement Coordinator (member of Collaboratory staff) Community Advisory Board (CAB) Consider diversity of CAB! Steering Committee representative (optional, can be non-voting, may want to rotate) 2 representatives (rotate?) & coordinator on “National” MDC CAB (NIAID coordinator: Zenovia Wright) Community outreach and education/research literacy UNAIDS/AVAC Good Participatory Practice (GPP) guidelines for clinical trials
Overview
HIV/AIDS in D.C. DC DOH HIV/AIDS Annual Epidemiology Report, 2013
HIV/AIDS in D.C. DC DOH HIV/AIDS Update, M h 2008
HIV/AIDS in D.C. DC DOH HIV/AIDS Annual Epidemiology Report, 2013
BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication Meet the BELIEVE Team
Investigator Locations Mario Ostrowski Mario Ostrowski, Mark Brockman Pamela Skinner Colin Kovacs Zabrina Brumme University of Minnesota, University of Toronto, Thomas Smithgall Simon Fraser University, St. Paul, Minnesota, USA Toronto, Canada Toronto, Canada University of Pittsburgh, Vancouver, Canada Pittsburgh, PA, USA James Whitney Harvard Medical School, Leslie Kean Cambridge, MA, USA Seattle Childrens Hospital Harris Goldstein Seatlle, WA, USA Albert Einstein College of Medicine, New York, USA Gregory Burton Una O’Doherty Brigham Young University, University of Pennsylvania, Deborah Persaud Provo, Utah, USA Philadelphia, PA, USA Johns Hopkins University, Baltimore, MD, USA Michael Bukrinsky Elizabeth Connick Amanda Castel University of Arizona, Catherine Bollard Alan Greenberg Tuscon, Arizona, USA Brad Jones Russell Cruz Children’s National Imtiaz Khan Medical Center, Fabio Leal Gustavo Reyes-Téran Washington DC, USA Rebecca Lynch CIENI, Mexico City, Mexico Manya Magnus Douglas Nixon Princy Kumar Georgetown University, Samuel Simmens Consultants: Washington DC, USA Gary Simon Edward Berger (MD, USA) The George Peter Kuebler (CA, USA) Esper Kallas Sergei Nekhai Washington University, University of São Paulo, Washington DC, USA Howard University, São Paulo, Brazil Washington DC, USA
Executive Committee Douglas F. Nixon, MD, PhD R. Brad Jones, PhD Catherine Bollard, MD Alan Greenberg, MD, MPH Program Director/Principal Principal Investigator Principal Investigator Co-Investigator Investigator Walter G. Ross Professor & Chair, Assistant Professor, Department of Professor of Pediatrics & Chief, Professor & Chair, Dep. of Microbiology, Immunology & Microbiology, Immunology & Tropical Division of Allergy and Immunology, Department of Epidemiology and Tropical Medicine, GWU Medicine, GWU Children’s National Health System Biostatistics, GWU
Corporate Partners Altor BioScience Corporation is a venture-backed, privately-held, clinical-stage biopharmaceutical company developing breakthrough immunotherapeutic products based on its multiple proprietary technology platforms for the treatment of cancer, viral infections, and autoimmune diseases. Altor’s technologies have been in development for more than twenty years. Altor currently has three products in clinical development: ALT-801, ALT- 836, and ALT-803. Torque Therapeutics, Inc. is focused on the specific modulation of immune cell subsets based on novel platform technologies. The goal is to develop a next generation of immunotherapies to address otherwise intractable cancers – particularly solid tumors.
BELIEVE 1. Expand the knowledge base on HIV latency and persistence in HIV infected persons on HAART 2. Design and evaluate innovative cure strategies 3. Translate these findings to the clinical setting 4. Rapid Translation of basic research discoveries into clinical applications will be facilitated by partnerships among academia, government, the private sector and community stakeholders.
Project Narrative We hypothesize that enhancing patients’ autologous lymphocytes ex vivo and re‐ infusing them, along with latency reversing agents, and specific targeting to sites where latent virus resides, could lead to eradication of latently infected cells and potentially a cure for HIV infected patients
Major Scientific Objectives Overcome Nef immune evasion IRF 1 – Jones & Nixon Optimize targeting of Harnessing natural and persistent reservoirs by engineered CTLs to eradicate cellular immune HIV reservoirs responses IRF 2 – Goldstein Combining NK cells & bnAbs to target ADCC against the Use immunomodulation viral reservoir and cell engineering to enhance function of T cells & NK cells and reverse latency IRF 3 – Connick & Skinner Directing immune effectors to viral sanctuaries in lymphoid Directing CTLs against IRF 4 – Bollard & Simon tissues non-escaped epitopes Combining T cell therapy with an in viral reservoirs IL-15 superagonist to target HIV reservoirs in patients Deliver enhanced effector lymphocytes to lymphoid follicles
Community Engagement Three Domains of Concern I. Practical facets of recruitment of participants for provision of specimen and later Phase I testing II. Education, outreach, engagement locally and internationally to build foundation for eventual testing and scale up III. Examination of ethics to develop appropriate algorithms for sharing risks and benefits of eventual testing
Short Term Clinical Goals Leukopheresis Expansion HIV Peptides Viral Sequencing & HLA Typing Production of Reinfusion HIV‐specific T‐ of HST‐ cells with CETs conserved +/‐ LRA epitope targeting (HST‐ CET)
Cell Therapy Modifications Leukopheresis Expansion Viral Sequencing & HLA Typing T‐Cell Modification ADCC Modification 1. Bi‐Specific CD4 CAR 1. IL‐15SA and/or bnABs 2. TCR‐Redirected T‐Cells 2. NK‐CAR 3. Expanded HIV‐Specific HXTCs 3. NK cells producing bnABs +/‐ LRIA and/or Nef inhibitor 4. NK cells producing given systemically or via αCD3/αGP120‐BITES Measurement of Viral T‐Pharmacyte Suppression, Immune in vitro Restoration, Reservoir Characterization, & Toxicity Monitoring NHP Model CD4 ARV Treated CAT Mouse Model
“Cure ” • Origin Middle English (as a noun): from Old French curer (verb), cure (noun), both from Latin curare take care of, from cura care. The original noun senses were ‘care, concern, responsibility’, in particular spiritual care (hence cure). In late Middle English the senses ‘medical care’ and ‘successful medical treatment’ arose, and hence ‘remedy’.
“Cure ” The cure of individuals or the cure of the pandemic?
“Cure ” The cure of individuals or the cure of the pandemic? The cure of reliance on ARVs?
“Cure ” The cure of individuals or the cure of the pandemic? The cure of reliance on ARVs? The cure of complications associated with HIV infection?
“Cure ” The cure of individuals or the cure of the pandemic? The cure of reliance on ARVs? The cure of complications associated with HIV infection? The cure of stigma?
“Precision Cure ” Test, Treat and Cure Douglas F. Nixon, Gary L. Simon, and Rui André Saraiva Raposo J Acquir Immune Defic Syndr. 2015 Jan 1; 68(1): e9–10. PMCID: PMC4435739 Immunogenomic profiling can help identify “remission ready patients”.: “test” (immunogenomic profiling), “treat” (provide anti‐‐‐retroviral therapy), and “cure” (augmentative therapies designed for functional cures)
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