Douglas F. Nixon, MD, PhD Chair, Dept. of Microbiology, Immunology - - PowerPoint PPT Presentation

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

BELIEVE: Bench to Bed Enhanced Lymphoctye Infusions to Engineer Viral Eradication Douglas Nixon (GWU, Washington, DC) DARE: Delaney AIDS Research Enterprise to Cure HIV Steven Deeks & Louis Picker (UCSF, San Francisco) defeatHIV: Cell and Gene Therapy for HIV Cure Keith Jerome & Hans-Peter Kiem (FHCRC, Seattle) CARE: Collaboratory of AIDS Researchers for Eradication David Margolis (UNC, Chapel Hill) BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy Luis Montaner & James Riley (Wistar Institute, Philadelphia) I4C: Combined Immunologic Approaches to Cure HIV-1 Dan Barouch, John Mellors, Nelson Michael (Beth Israel Deaconess, Boston)

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

Michael Bukrinsky Amanda Castel Alan Greenberg Brad Jones Imtiaz Khan Fabio Leal Rebecca Lynch Manya Magnus Douglas Nixon Samuel Simmens Gary Simon The George Washington University, Washington DC, USA Catherine Bollard Russell Cruz Children’s National Medical Center, Washington DC, USA Princy Kumar Georgetown University, Washington DC, USA Sergei Nekhai Howard University, Washington DC, USA

Investigator Locations

James Whitney Harvard Medical School, Cambridge, MA, USA Pamela Skinner University of Minnesota,

• St. Paul, Minnesota, USA

Mark Brockman Zabrina Brumme Simon Fraser University, Vancouver, Canada Leslie Kean Seattle Childrens Hospital Seatlle, WA, USA Elizabeth Connick University of Arizona, Tuscon, Arizona, USA Mario Ostrowski Toronto, Canada Mario Ostrowski, Colin Kovacs University of Toronto, Toronto, Canada Esper Kallas University of São Paulo, São Paulo, Brazil Gregory Burton Brigham Young University, Provo, Utah, USA Gustavo Reyes-Téran CIENI, Mexico City, Mexico Thomas Smithgall University of Pittsburgh, Pittsburgh, PA, USA Consultants: Edward Berger (MD, USA) Peter Kuebler (CA, USA) Harris Goldstein Albert Einstein College of Medicine, New York, USA Una O’Doherty University of Pennsylvania, Philadelphia, PA, USA Deborah Persaud Johns Hopkins University, Baltimore, MD, USA

Executive Committee

Program Director/Principal Investigator Walter G. Ross Professor & Chair,

• Dep. of Microbiology, Immunology &

Tropical Medicine, GWU Douglas F. Nixon, MD, PhD

• R. Brad Jones, PhD

Catherine Bollard, MD Alan Greenberg, MD, MPH Principal Investigator Assistant Professor, Department of Microbiology, Immunology & Tropical Medicine, GWU Principal Investigator Professor of Pediatrics & Chief, Division of Allergy and Immunology, Children’s National Health System Co-Investigator Professor & Chair, Department of Epidemiology and Biostatistics, GWU

Corporate Partners

Altor BioScience Corporation is a venture-backed, privately-held, clinical-stage biopharmaceutical company developing breakthrough immunotherapeutic products based

• n 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

IRF 4 – Bollard & Simon Combining T cell therapy with an IL-15 superagonist to target HIV reservoirs in patients IRF 1 – Jones & Nixon Harnessing natural and engineered CTLs to eradicate HIV reservoirs IRF 2 – Goldstein Combining NK cells & bnAbs to target ADCC against the viral reservoir IRF 3 – Connick & Skinner Directing immune effectors to viral sanctuaries in lymphoid tissues Use immunomodulation and cell engineering to enhance function of T cells & NK cells and reverse latency Overcome Nef immune evasion Directing CTLs against non-escaped epitopes in viral reservoirs Deliver enhanced effector lymphocytes to lymphoid follicles Optimize targeting of persistent reservoirs by cellular immune responses

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

Community Engagement

Leukopheresis Viral Sequencing & HLA Typing HIV Peptides Expansion Production of HIV‐specific T‐ cells with conserved epitope targeting (HST‐ CET) Reinfusion

• f HST‐

CETs +/‐ LRA

Short Term Clinical Goals

Leukopheresis Viral Sequencing & HLA Typing Expansion

Cell Therapy Modifications

T‐Cell Modification 1. Bi‐Specific CD4 CAR 2. TCR‐Redirected T‐Cells 3. Expanded HIV‐Specific HXTCs +/‐ LRIA and/or Nef inhibitor given systemically or via T‐Pharmacyte ADCC Modification 1. IL‐15SA and/or bnABs 2. NK‐CAR 3. NK cells producing bnABs 4. NK cells producing αCD3/αGP120‐BITES CD4 ARV Treated CATMouse Model NHP Model in vitro

Measurement of Viral Suppression, Immune Restoration, Reservoir Characterization, & Toxicity Monitoring

“Cure”

• Origin

Middle English (as a noun): from Old French curer (verb), cure (noun), both from Latin curare take care

• f, 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)