Immune Based Therapies and HIV

Getting Past GoImmune Based Therapies for HIV Matt Sharp Project Inform ATAC

Background  HIV is a disease that targets the immune system-

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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

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 IBT’s

History 

Learning Moments   

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

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Advancements     

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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?

Scientific Issues 

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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

Practical Issues 

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Licensing, patent, regulatory and approval issues Laboratory and assay technology is cumbersome, time consuming and complex Competition   

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Virology (ists) vs. immunology (ists) Institutions vs. smaller independent labs Pharmaceutical industrial complex

Leadership and coordination Funding Advocacy

Case Examples-IL-2  First completed RCT for IBT’s 

Took years to get results through large and expensive studies-SILCAAT & ESPRIT  

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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

Case ExamplesThymus 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+

Ongoing and New    

Discordant responders/LTNP Elucidation of reservoirs Compare and contrast to SIV to HIV Lessons from leukemia “cure” patient including… 

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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

Advocacy Efforts 

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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 IBT’s 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

Thanks!

Richard Jeffries Tim Horn HRCF