Immune Based Therapies and HIV

advertisement
Getting Past GoImmune Based Therapies
for HIV
Matt Sharp
Project Inform
ATAC
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
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







IL-2
G-CSF
Immune suppressive
therapies
Thymus transplantation
Baboon bone marrow
transplantation
Growth hormone?
Treatment vaccines?

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?
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
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
Case Examples-IL-2
 First completed RCT for IBT’s

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
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…







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





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
Download