Transcript lecture-4_theraeutic_vaccine_immune-based

Therapeutic Vaccines and
Immune-Based Therapies
Curtesy Jeffrey, Drexel University
Table of Contents
Therapeutic Vaccines
Passive immunization
Adoptive immunotherapy
Immune-based therapies (IBTs)
Future directions and challenges
Therapeutic vaccination
• Rationale: strengthen or create new and more effective immune
responses to HIV in HIV-positive individuals
• Challenging because CD4 T cells normally play a central role in
coordinating the immune response to infection
• CD4 T cells are the primary target of HIV and are disrupted and killed by the
virus
• CD4 T cells targeting HIV (HIV-specific CD4 T cells) are preferentially infected
Types of immune response
• Innate immunity
• Consists of non-specific responses to pathogens based on shared features
• Transient activity
• Adaptive immunity
• Specifically recognizes pathogen fragments (antigens)
• CD4 T cells, CD8 T cells, B cells (produce antibodies), natural killer cells
(possibly)
• Responses persist as “memory” cells
Therapeutic vaccination
• Generate long-lived adaptive immune responses targeting HIV
antigens
• Induction of innate immunity can help generate adaptive immune
responses (e.g. via vaccine adjuvants)
• Focus has been on CD4 T cell and CD8 T cell responses (cellular
immunity)
• Increasing interest in B cells due to potential to produce antibodies
that can flag virus-infected cells for destruction
Therapeutic vaccines
• Use various methods to deliver non-infectious HIV antigens into the
body (most often injection into muscle tissue)
• Antigens are picked up and processed by immune system sentinels
called antigen-presenting cells (dendritic cells and macrophages)
• Antigens then presented to CD4 T cells, CD8 T cells and B cells,
inducing immune responses
Types of therapeutic vaccines
• DNA and RNA vaccines
• Consist simply of genetic code for HIV antigens
• Viral vector vaccines
• Genetic code for HIV antigens inserted into modified non-pathogenic virus
e.g. canarypox (ALVAC), modified Vaccinia Ankara strain (MVA), adenoviruses,
lentiviruses
• Protein or peptide vaccines
• Mimics of HIV proteins or protein fragments (peptides)
• Dendritic cell vaccines
• Extract antigen-presenting dendritic cells, mix with HIV antigens outside the
body (sometimes HIV antigens derived from individual’s virus), then injected
as vaccine
Therapeutic vaccine studies
• So far, mostly studied in people on antiretroviral therapy (ART) (some
exceptions) with impact on viral load measured after ART
interruption
• A few studies have reported significant reductions in viral load
associated with therapeutic vaccination, albeit typically transient
Therapeutic vaccines in cure research
• Goal for therapeutic vaccination has largely shifted to elimination of
latent HIV reservoir
• Therapeutic vaccines are being combined with latency-reversing
agents (LRAs)
• The rationale:
• LRA triggers latent HIV to produce viral proteins
• HIV antigens are expressed by infected cell
• Immune responses induced by therapeutic vaccine recognize HIV antigens
and kill infected cell (T cells) or flag for destruction (antibodies)
Therapeutic vaccine trials
2015
ChAdV63.HIVcons
+ MVA.HIVconsv
2016
AGS-004
Vac-3s
2017
2018
GTU-MultiHIV
+ LIPO-5
GTU®-MultiHIV
B Clade Vaccine
Vac-3s
Tat-Oyi
RIVER:
ChAdV63.HIVconsv +
MVA.HIVconsv
vaccines, vorinostat
Vacc-4x +
romidepsin
THV01
HIVAX
IHIVARNA-01
MAG-pDNA + rVSVIN
HIV-1 Gag
http://www.treatmentactiongroup.org/cure/trials
Therapeutic vaccines in cure research
• Ongoing trial in Denmark is combining the LRA romidepsin (an HDAC
inhibitor) with the therapeutic vaccine Vacc-4x (consisting of HIV
peptides)
• Planned UK trial named RIVER aims to combine an LRA with two viral
vector-based therapeutic HIV vaccines (chimpanzee adenovirus &
MVA)
• Planned US CARE collaboratory trial will combine an LRA with a
dendritic cell-based therapeutic HIV vaccine (AGS-004)
Unconventional therapeutic vaccines
• VAC-3S aims to prevent CD4 T cell depletion by inducing antibodies to
block a mechanism believed to be involved in triggering immune
activation and CD4 T cell death (as opposed to targeting HIV directly)
• Ongoing trials
• Vacc-C5 also aims to induce antibodies that may block immune
activation
• Trial completed, results pending
• A vaccine that suppresses immune responses to SIV has been
reported to protect macaques from infection and suggested to have
therapeutic potential
• Clinical trial planned, possible launch toward end of 2015 or so
Passive immunization
• The most effective type of antibody response is called a broadly
neutralizing antibody (bNAb) response
• bNAbs can potently inhibit a broad array of different HIV isolates
from multiple clades
• Unfortunately, no vaccine can induce the production of bNAbs (as
yet)
• bNAbs have been isolated from the B cells of some HIV-positive
individuals (not present at sufficient levels to benefit the individual)
• These isolated bNAbs are being manufactured and can be
administered via infusion or subcutaneous injection (passive
immunization)
Single 3BNC117 infusion – Antiviral activity
106
HIV RNA (copies ml-1)
HIV RNA (copies ml-1)
30 mg/kg
105
104
103
102
101
-7
0
7
14 21 28
Days after infusion
42
56
1
0
2D1
2C1
2D3
2E1
2E2
2E3
2E4
2E5
-1
-2
0
7
14
21
28
42
56
Days after infusion
Dr. Sarah Schlesinger, Rockefeller University, AVAC webinar: New Frontiers in HIV Prevention, Treatment and
Cure, Tuesday April 21, 2015: http://www.avac.org/blog/new-frontiers-hiv-prevention-treatment-and-cure
Passive immunization in cure research
• Some antibodies have the capacity to flag infected cells expressing
HIV antigens for destruction by antibody-mediated cellular
cytotoxicity (ADCC) and antibody-mediated cellular phagocytosis
(ADCP)
• Destruction performed by natural killer (NK) cells and monocytes
• As with therapeutic vaccines, interest in combining passive
immunization with LRAs (promising results in humanized mice)
Ariel Halper-Stromberg et al. Broadly Neutralizing Antibodies and Viral Inducers Decrease Rebound from HIV-1 Latent
Reservoirs in Humanized Mice, Cell , Volume 158, Issue 5, p989–999, 28 August 2014
Passive immunization in cure research
• Ongoing studies of bNAbs in HIV-positive individuals
• VRC01
• 3BNC117
• Additional studies planned
• VRC01 + ART in acute HIV infection
• 3BNC117 effect on HIV reservoir, effect on viral load rebound after ART
interruption
• PGT121
• VRC07
• 3BNC117 + 10-1074
• bNAbs + LRAs
Antibody gene transfer
• An alternative approach to bNAb delivery also being studied
• Employs adeno-associated virus (AAV) vector to deliver gene for
making bNAb(s) into muscle tissue
• AAV persists and produces supply of bNAb
• Method used with some success to deliver factor IX to hemophiliacs
• Ongoing Phase I trial of AAV encoding bNAb PG9 in HIV- individuals in
UK
• AAV also being considered to deliver potent antibody-like protein
inhibitor of HIV (eCD4-Ig) based on promising macaque results
Adoptive immunotherapy
• Instead of infusing bNAbs, adoptive immunotherapy infuses HIVspecific T cells
• T cells are extracted from an individual, cultured with HIV antigens
and expanded in the laboratory, then reinfused into the individual
• Goal of promoting elimination of HIV-infected cells (similar to
therapeutic vaccination)
• Clinical trials ongoing
• HXTC (US CARE collaboratory)
• Autologous HIV-specific CD8 T cells (China)
Immune-based therapies (IBTs)
•Broad category of therapies including:
•Substances produced by the immune
system (e.g. cytokines)
•Approaches that aim to work via
modulation of the immune system
Cytokines
• Interleukin-7 (IL-7) studied as a latency-reversing agent but did not
work (promoted proliferation of latently infected cells)
• IL-15 being studied as a potential latency-reversing agent & promoter
of natural killer cell activity
• Clinical trial of ALT-803 (recombinant human super agonist interleukin-15
complex) due to start soon
Cytokines
• IL-21 has been reported to limit the viral reservoir in Simian
immunodeficiency viruses (SIV)-infected macaques, researchers plan
to study in HIV-positive individuals (already in trials for cancer)
• Alpha interferon is approved for the treatment of hepatitis C, several
trials are studying impact on the HIV reservoir
• Small study reported reductions in levels of integrated HIV DNA
Toll-like receptor (TLR) agonists
• Class of compounds that interact with immune cell receptors involved
in non-specific recognition of pathogens (toll-like receptors or TLRs)
• Several TLR agonists being studied as potential latency-reversing
agents & promoters of innate immunity
• MGN1703 (TLR-9 agonist)
• Poly-ICLC (TLR-3 agonist)
• GS-9620 (TLR-7 agonist)
James Whitney et al. Treatment With a TLR7 Agonist Induces Transient Viremia in SIV-Infected ART-Suppressed Monkeys, Abstract 108, CROI
2015, Seattle, Washington, February 23-26, 2015
Immune checkpoint blockers
• Certain immune cell receptors known as immune checkpoints (or
negative regulators) are involved in dampening immune responses
• Expression of these receptors can impair HIV-specific T cell responses
• Also appear involved in maintaining latently infected CD4 T cells in
quiescent state
• Examples include PD-1, CTLA-4, LAG3, TIGIT
Immune checkpoint blockers
• Antibodies that block these receptors (or the ligands they interact
with) may both enhance HIV-specific T cell responses and reverse HIV
latency
• Ongoing study of an antibody to PD-L1 in HIV-positive individuals on
ART
• Plans to study an antibodies to PD-1, CTLA-4
• Several of these antibodies are now licensed treatments for cancers
• Can have significant side effects, including autoimmunity
Immune checkpoint blockers
Stephen Mason, Bristol-Myers Squibb, The potential role of PD-1/PD-L1 blockade in HIV Remission & Cure, Community Cure
Workshop, February 22, 2015 Seattle, WA
Ethical considerations for therapeutic
vaccines
• Therapeutic vaccine trials often (although not
always) include ART interruptions to assess if
vaccine-induced immune responses can exert an
anti-HIV effect in the absence of ART
• There is a possible risk that a therapeutic vaccine
could increase rather than decrease HIV replication
by creating additional CD4 T cell targets for the virus
Ethical considerations for therapeutic
vaccines
• Participation in a clinical trial of a therapeutic
vaccine candidate may preclude participation in
future trials of other therapeutic vaccine candidates
• The multiplicity of factors that can influence
adaptive immunity (genetics, sex, age) makes
diversity of trial participants particularly key
• The words “therapeutic vaccines” may be
misleading and lead to therapeutic (or curative)
misconception
Future directions & challenges
• Likely need for more combination studies
• May need cooperation of different corporate & academic partners
• Raises complex regulatory (FDA) issues e.g. assessing safety and activity of
each component
• Better understanding of effective immune responses needed
(correlates of immunity, biomarkers of efficacy)
• Immunologic mechanisms can be complex and unpredictable,
relevance of animal models not always clear
Future directions & challenges
• Incentives for industry limited by lack of precedents (no approved
IBTs for HIV although recent significant progress in cancer)
• History of immune-based approaches being perceived as off-the-wall
compared to antiretroviral therapy
• Research funding environment
Future directions & challenges
• Defining success
• If a cure is not achieved (as defined by an absence of any detectable HIV),
what degree of immune control of HIV might be considered “remission”?
• Challenge of proving even strict immune control of HIV is clinically equivalent
to ART (e.g. elite controllers may face elevated risk of inflammation-related
disease vs. individuals on ART)
Town Hall
Meetings
Concept
CROI 2014
PowerPoint
Teaching Sets
US AIDS Care
Conference,
October 4, 2014
Participatory
Activities &
Events
Visual/
Graphic
updates
(Phase 2
Launch)
NIH Martin Delaney
Collaboratories meeting
October 14, 2014
Pre- and
Post-Test
Assessments
Webinar
Recordings
CROI
February 2015
Launch