Getting Past Go- Immune Based Therapies for HIV

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Getting Past Go-Immune Based Therapiesfor HIV

• Matt Sharp
• Project Inform
• ATAC

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Background

• HIV is a disease that targets the immune
  system-specifically CD4 CD8 cells, macrophages,
  dendritic cells, affects homeostasis
• (rarely stem cells and perhaps thymocytes)
• CD4 cells are key for controlling disease and are
  preferential for HIV replication
• This complication has made research into immune
  based therapies for HIV overarching and complex
  with many challenges and barriers

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More Background

• Also incomplete understanding of human immunology
• Immune reconstitution due to HAART led to delays
  in IBT research, but also opened doors
• Much of IBT research has been in the laboratory
• Most clinical trials to date have been early
  stage yet some are now moving into Phase II
• We need a comprehensive strategy that will
  include IBTs

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History

• Advancements
• HAART
• Co-receptor discovery
• Better understanding of CD8 killing
• Dendritic cell role
• Further understanding of immune activation and
  inflammation
• Senescence
• Leukemia cure patient
• IL-7?
• Gene therapy?

• Learning Moments
• IL-2
• G-CSF
• Immune suppressive therapies
• Thymus transplantation
• Baboon bone marrow transplantation
• Growth hormone?
• Treatment vaccines?

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Scientific Issues

• Many HIV pathogenesis and immunology
• discoveries still to be made
• Animal models have been complicated
• In many cases we are starting from scratch
• -many proof of concept studies required
• -little precedent for new concepts
• There is not an agreement on what are the
  appropriate correlates of immunity-endpoints?
• Human subject risks vs. benefits-safety concerns
  w/ perturbation of immune system
• Ethical IBT trial designs are a challenge in the
  HAART era
• Expense and resources

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Practical Issues

• Licensing, patent, regulatory and approval issues
• Laboratory and assay technology is cumbersome,
  time consuming and complex
• Competition
• Virology (ists) vs. immunology (ists)
• Institutions vs. smaller independent labs
• Pharmaceutical industrial complex
• Leadership and coordination
• Funding
• Advocacy

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Case Examples-IL-2

• First completed RCT for IBTs
• Took years to get results through large and
  expensive studies-SILCAAT ESPRIT
• Adverse side effects
• More clinical events in IL-2 arms-CD4
  functionality
• Licensing nightmare-Chiron/Novartis and NIH
• A surrogate marker for one type of therapy (CD4s
  ART) cannot not necessarily be applied to an
  IBT with a different mechanism (IL-2-induced CD4s
  not beneficial)
• Other studies ongoing
• Has led to studies of other cytokines including
  IL-7

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Case Examples-Thymus Transplantation

• Cumbersome and evasive
• Early results coincided with HAART discovery
  which slowed the research
• Larger studies incomplete
• Led to further understanding of
• the role of the thymus in healthy
• and immunocompromised HIV

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Ongoing and New

• Discordant responders/LTNP
• Elucidation of reservoirs
• Compare and contrast to SIV to HIV
• Lessons from leukemia cure patient including
• Gene therapy and delivery systems (stem cells)
• Stem cell research
• Anti-inflammatory agents
• Therapeutic vaccines
• Recombinant cytokine therapies-IL-7/IL-21/IL-15
• Growth hormone
• Combination approaches

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Advocacy Efforts

• Immune Restoration Think Tanks-Project Inform
  (92-08)
• Michael Palm Basic Science Blog-TAG
• IBT Strategy Workgroup-Project Inform TAG
• Advocacy and community education have been
  challenging due to the complexity of the issue
  and few successes, clinical trials and therefore
  few breakthroughs
• While many think IBTs are impossible, perhaps a
  waste in resources, research must continue in
  order to completely understand HIV and host
  responses, and improve upon current standard of
  care and perhaps a cure

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Thanks!

• Richard Jeffries
• Tim Horn
• HRCF

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