current clinical therapies for hiv...
TRANSCRIPT
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Current Clinical Therapies for HIV
Remission
David Margolis MDUNC HIV Cure Center
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Cohen J. Science 2014
Aiming for sustained remission off ART
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Luzuriaga et al. NEJM 372;8: 786
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Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia
following treatment interruption in individuals treated
during acute HIV infection (Fiebig III-IV)
Eugène Kroon, Jintanat Ananworanich, Keith Eubanks,
Jintana Intasan, Suteeraporn Pinyakorn, Nicolas Chomont,
Sharon R Lewin, Sarah Palmer, Lydie Trautmann, Hua Yang,
Nitiya Chomchey, Nittaya Phanuphak, Ken Cooper,
Praphan Phanuphak, Mark de Souza
on behalf of the SEARCH 019 study group
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HIV Rebound after ART Interruption
Median time to first VL detection: 22 days (range 14 to 77 days)
ART resume at VL > 1000 c/ml
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Stochastic
Reversal
of Latency
Chronically producing
cell
Host cell modification
KO: CCR5 (Sangamo)KI: sh5/C46 (Calimmune)
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• Challenges moving forward:– Is cytoreductive therapy needed?
Acceptable?
– Is there X4 escape?
– Scalability? Cost?
• CCR5-modified CD4 T cells at 1 week post infusion constituted 13.9% of
circulating CD4 T cells
• Modified cells had an estimated mean half-life of 48 weeks
• After ART interruption, decline in circulating CCR5-modified cells (−1.81 cells
per day) was significantly less than the decline in unmodified cells (−7.25 cells
per day) (P = 0.02)
• HIV RNA became undetectable in one of four patients who could be evaluated
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A first step to eliminate
latent HIV infection
Latency
Reversal
A second step to eliminate
latent HIV infection
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Latency Reversal and Clearance Candidates
• Latency Reversing Agents (LRAs)
– HDAC inhibitors• “lack potency and killing as single agents” (Mellors)
• “HDAC inhibitors do not kill non-transformed cells at clinical exposures” and “Appropriate serial dosing regimens of HDAC inhibitors have not yet been performed” (Margolis)
Apologies, too many references to cite!
Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt. 80
20
40
60
200
400
600
800
100
Baseline ART
VOR 400 mg
Re
lativ
e H
IV-1
ga
g R
NA
co
pie
s
2012!
Rasmussen Lancet ID 2014
Thrice weekly cycles of Panobinostat
**!**!
**!**!*!
Days!
Lewin CROI 2013!14 daily doses of vorinostat! Elliot&PLoS&Path&2014&
Sogaard IAS 2014
Total CD4 cell-associated unspliced HIV-1 RNA!
Weekly Romidepsin !
Sogaard&PLoS&Path&2015&
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Latency Reversal and Clearance Candidates
• Latency Reversing Agents (LRAs)
– HDAC inhibitors• “lack potency and killing as single agents” (Mellors)
• “HDAC inhibitors do not kill non-transformed cells at clinical exposures” and “Appropriate serial dosing regimens of HDAC inhibitors have not yet been performed” (Margolis)
Apologies, too many references to cite!
– PKC agonists• most potent activators but toxicity of concern
• Bryostatin clinical trial did not achieve effective drug exposures
– TLR agonists: • activate HIV expression and immune control in SIV/macaques
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TLR7 Agonists Induce Transient Plasma Viremia
Time after TLR7 agonist dose (Hours)
102
103
Pla
sm
a S
IV R
NA
co
pie
s/m
l
Pla
sm
a S
IV
(lo
g1
0R
NA
co
pie
s/m
L)
V1
V2 0
24
48
72
16
8 02
44
87
2
16
8 02
44
87
2
16
8 02
44
87
2
16
8 02
44
87
2
16
8 02
44
87
2
16
8 02
44
87
2
16
8 02
44
87
2
16
8 02
44
87
2
16
8 02
44
87
2
16
8
102
103
Vehicle
V1
V2 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168 0
24
48
72
168
Vehicle
Placebo GS-986 (0.1
mg/kg)
GS-9620 (0.05 mg/kg) GS-9620 (0.15
mg/kg)
• Reduced frequency of blips 38-75% (doses 3-10)
• No more blips from animals dosed after 3 month
pause (doses # 11-19)
Whitney et al., CROI 2016
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Phase I/II trial of GS-9620 in HIV-
infectionDesign:
• 3 escalating dose cohorts– 1 mg, 2 mg, 4 mg every 2 weeks for 6 doses
• Placebo-controlled, randomized, double-blinded (6 active, 2 placebo per cohort)
Study Population:
• HIV-infected adults (n=24)
• Virologically suppressed ≥12 months on ART
Study Monitoring:
• Close follow-up – VL 2-3x/w
• Repeat dosing only if VL <50 copies/mL
• Safety review prior to initiation of each cohort
Current status: Enrolling Cohort 3
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Latency Reversal and Clearance Candidates
• Latency Reversing Agents (LRAs)
– HDAC inhibitors• “lack potency and killing as single agents” (Mellors)
• “HDAC inhibitors do not kill non-transformed cells at clinical exposures” (Margolis)
– PKC agonists• most potent activators but toxicity of concern
• Bryostatin clinical trial did not achieve effective drug exposures
– TLR agonists: • activate HIV expression and immune control in SIV/macaques
Apologies, too many references to cite!
– Other Epigenetic targets• Bromodomain inhibitors
• Histone methyltransferase inhibitors (eg. EZH2 inhibitors)
• Others in development
– High-throughput library screening efforts
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Merck HIV Latency HDAC Inhibitor
Synergy Screen
HIV LTR Induction
With 250nM SAHA2,900,000 Compounds
Confirmatory Assays, n=3HIV LTR Induction
With 250nM SAHA
Dose Response Assays, n=2
HIV LTR Induction
Without SAHA
HIV LTR Induction
With 250nM SAHA
NFkB BLA Reporter
Counter Screen
Toxicity @ 48 Hours
CTG
Data Analysis/
Hit Selection
Follow-up
Analysis~4,500 Compounds
Initial Screen, n=3
Objective: To identify compounds that potentially act synergistically
with HDACis to induce HIV transcription
Compounds with unknown mechanism
Known HDAC InhibitorsKnown Farnesyl-Transferase Inhibitors
66.5%16.1%
17.4%
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Testing interventions in vivo
ART *After
intervention
• Leukapheresis for QVOA and ca-HIV RNA
• SCA• Immune assays• Host cell assays & biomarkers• Novel assays, eg. Quanterix
Simoa
• Leukapheresis for QVOA and ca-HIV RNA
• SCA• Immune assays• Host cell assays & biomarkers• Novel assays, eg. Quanterix
Simoa
Baseline
LRAsImmunodulators
HIV vaccinesNovel approaches
Reduction in:• Resting CD4
cell infection• Low-level
viremia
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HIV RNAin cells or culture
HIV DNA, RNA, antigen & viruses
Ho, Cell 2013
Ericksson, PLoS Path 2013
HIV Antigen
(protein)
detector
The “Real”
Reservoir
HIV DNA
QVOAReplication-
competent
virus
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1 2 3 4 5 6 7Time on ART (years)
-
0.0001
0.001
0.01
0.1
1
10
100
0
Fre
quency
(per
10
6cells
)
0.00001
Margolis, Garcia, Hazuda, Haynes Science 2016
Time to eradication > 73.4 years
Persistent HIV infection despite ART
Residual
Replication
or Cell
Proliferation
Viral
Activation &
Clearance
or Cell Death
Crooks et al. JID 2015
• Given assay variance, a more than 6-fold RCI decrease would have likelihood 0.023 (2.3%)
• Therefore a measurable goal is therapy that can reduce the latent reservoir by half a log
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Challenges to clearing persistent infection after latency reversal
• Recent absence of antigen – low frequency of HIV-specific antiviral responses
• Immune dysfunction, deletion, or exhaustion• Archived viral diversity, including immune escape• Viral antigen is rare, dispersed,
compartmentalized, and may be transient• Latency Reversing Agents (LRAs) are host-
targeted, and alone or in combination may alter antiviral immune response
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Latency Reversal Agent Discovery
• New metric of viral antigen production or
presentation
- Antigen required to allow clearance
• Assessment of LRA effect on immune function as
part of development path
- Immune function required for clearance
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Quanterix Simoa™ Technology
Quanterix Simoa Platform• Ultrasensitive platform (sub-pg/mL sensitivity)
• Full automation (samples in – data out)
– Rapid readout (~1 hr), >500 data points per day
• Broad dynamic range (>4 logs)
• Commercial p24 assay applied to plasma and serum (Chang L, et al. J Virol Methods. 2013;188(1-2):153-160.)
• In-house Merck assay optimized to reduce nonspecific binding and enhance sensitivity, thus enabling p24 quantitation in cell lysates
1. Single-protein molecules are captured and labeled on individual beads using standard ELISA reagents
2. Beads + substrate are loaded in individual femtoliter wells. Oil added to seal well
3. Digital or analog fluorescence readout of individual beads
http://www.quanterix.com/Howell et al. submitted
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CD8+
LatencyReversing
Agent
PBMCs
No Effectors
or or
AddEffectors
LimitingDilution
Co-culture
Measure HIV
Productionat 2 weeks
CD8+ by negative selection
CultureResting CD4+cells
Resting CD4+ cells bynegativeselection
RemoveEffectors
CD8+,HXTCs
,or
DARTs
Latency Clearance Assay
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Patient
425Patient
532Patient
250
0
20
40
60
80
100
120
% V
ira
l re
cover
y
Patient
423
Patient
250
Patient
231
Patient
492
Patient
532
Patient
425
0
1
2
3
4
5
6
7
8N
um
ber
of
posi
tive w
ells
(ou
t of
12
tota
l)
No Effectors
CD8HXTC
††
††
†
Patient 425
PHA
VOR
†p<0.05 compared to No Effector
††p<0.05 compared to BOTH
HXTCs Reduce Recovery of Virus from autologous
resting CD4+ T cells stimulated with:
††
††
†
†
Sung et al. JID 2015
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Latency Reversal and Clearance Candidates• Natural and Engineered Antibodies
– Broadly-neutralizing monoclonal antibodies (bnMAbs)• Can delay rebound and promote cell clearance in humans (3BNC117)
• Resistance can rapidly develop (VRC01, 3BNC117)
• Effect in individuals on ART? (VRC01)
– Engineered bnMAb• Can prolong half-life and enhance Fc effector functions (e.g. PGT-151)
– Bispecific Ab (anti-HIV/anti-host, e.g. CD3 or CD16)• Enhance effector function ex vivo and in animal models
Apologies, too many references to cite!
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A5342/VRC01 Study• Double-blind, randomized, placebo-controlled, Phase I study
• 40 participants (20 per arm)
• VRC01 40 mg/kg IV at Day 0 & 21 (Arm A) or Day 42 & 63 (Arm B)
Trial Completed and Analyses Underway!
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• SIV-infected monkeys were treated with a 90-day course of ART initiated 5 weeks post infection
• 9 weeks post infection infused with primatizedmonoclonal antibody against the α4β7 integrin every 3 weeks until week 32
• All animals subsequently maintained low to undetectable viral loads and normal CD4+ T cell counts for more than 9 months, after all treatment was withdrawn.
• Human trial underway at NIH
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Dual Affinity ReTargeting (DARTs) Molecules for HIV
• Do not require pre-existing HIV specificity• Not impacted by archived CTL escape variants
• Anti-Env arm based on well characterized mAbs that have: • Are broad neutralizing antibodies -- bind virions and infected cells: DH542 (V3
glycan bnAb), CH557 (CD4bs bnAb), DH511-K3 (gp41 MPER bnAb)• Are ADCC mediating antibodies -- bind only infected cells: (7B2, gp41
immunodominant), A32 (C1)
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Dual Affinity Re-Targeting proteins direct T cell –mediated cytolysis of latently HIV-infected cells.Sung, JA, Pickeral, J, Liu, L, Stanfield-Oakley, SA, Lam, CY, Garrido, C, Pollara, J, LaBranche C. Bonsignori, M. Moody, MA, …..Haynes, BF, Nordstrom JL, Margolis, DM, Ferrari, G. JCI 2015
Sung et al.:• Screened ADCC, non-neutralizing
Abs that bound HIV-infected CD4 T cells for optimal ADCC
• Constructed DARTs with non-Neutralizing mAbs A32XCD3 and 7B2XCD3
• Showed DARTs + CD8 CTL eliminated HIV-infected CD4 T cells in vitro by CD8 T cell-mediated cytolysis.
Sloan et al.:• Constructed bnAb PGT145 (V1V2),
PGT121 (V3 glycan), VRC01 (CD4 bs), and 10E8 (distal MPER)---compared to A32 and 7B2 non-neutralizing DARTs
• Best were PGT121, A32 and 7B2 DARTs
Targeting HIV Reservoir in Infected CD4 T cells by DARTs that bind Envelope and Recruit CTLs. Sloan DD et al. PLoS Pathogens, 2015
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HIVxCD3 DART-mediated virus clearance in 4 of 4 patients (longer time needed for Pt 795)
V O R -E x p o s e d L a te n tly In fe c te d C e lls
6 7 4 4 0 8 4 0 7 7 9 5 7 9 5
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
P a tie n t
2 4 h r c u ltu re w ith D A R T s 9 6 h r
%v
ira
l re
co
ve
ry
(no
rm
ali
ze
d t
o n
o E
ffe
cto
rs
co
ntr
ol)
N o E ffe c to rs
C D 8 o n ly
C D 3 x4 4 2 0
C o m b o D A R T s
00
Sung, et al. JCI 2015
HIVxCD3 DART Mediated Clearance of Resting
Patient CD4 Cells Exposed to Vorinostat
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• Immune Checkpoint Blocking Antibodies– Major advance in cancer immunotherapy
– Reverse immune exhaustion
– Examples: Anti-PD-1/PD-L1, LAG-3, 2B4, CD160, TIM-3, others
• Cellular therapies– CD8+T-cells with chimeric antigen receptors
– Ex-vivo Effector cell expansion/re-infusion
– Activated NK cells
• Therapeutic Vaccines– Multiple approaches
– Chimp Adeno vector, CMV vector, VSV vector, Ad26/MVA vectors, Dendritic cells
– Can induce broad CTL responses
Covering immune escape variants is critical!
Apologies, too many references to cite!
Latency Reversal and Clearance Candidates
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Tools to Test Latency Reversal and
Clearance
Autologous DC vaccineMinimal effect of VOR on immune function
Clutton
Sci Rep 2016
Baseline Multidose
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
p < 0 .0 0 0 1
HIV
-1
ga
g R
NA
co
pie
s p
er
we
llArchin
Keystone Symposium on
HIV Persistence 2016
Persistent LRA activity of multiple VOR doses
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Combination Latency Reversal and
Clearance Trial I
Step4
AGSEOS
Term~Week15-
Week24
~Week73-
Week89
Visit8 27
AGSManufacturing EOS
visits-nodosing Leukapheresis&rc-RNA IMandProviral Viralinhibitionandlatencyclearanceassays
visits-Vorinistatdoses Safetylabs SCA Acetylation
visits-AGS-004injections PKSamples ExploratoryImmunology
rc-RNAmeasurementdeterminesprogress
SingleDose
Step7
AGSDosing
Step8
MultipleVORDosing
Step1
Screen
Step2
Enrollment
Step3
Interval
Step5
AGSDosing
Step6
MultipleVORDosing
~Week39-Week54
Visits14-17 Visits18-22
~Week52-Week73
Visits23-26
~Week64-Week81
PairedDoses
Approximately
Weeks0-8
InjectionsX4
IntervaldosingX10doses
InjectionsX4
IntervaldosingX10doses
~Week27-Week46
Visit9-13
BASELINE
~Week6-Week13
Visits1&2 Visit3&4
~Week10-Week
18
Vists5-7
Vaccine Vaccine
LRA x 10
Vaccine = Argos dendritic cell therapy
LRA = vorinostat
LRA x 1 LRA x 2LRA x 10
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Combination Latency Reversal and
Clearance Trial II
ART
STEP1PretreatmentPhaseExhibit Ex-vivoresponsetoVOR
STEP2:SingleVOR400mgdose
STEP3:HXTCsproduced
STEP4:FirstCombinationtreatmentVORevery72hoursx10dosesand2HXTCInfusions
RESTPERIOD
STEP5:FirstCombinationtreatmentVORevery72hoursand2HXTCInfusions
STEP 6:ImmuneResponsemonitoring
~4weeks ~8weeks
~6-8weeks
4weeks 2-4weeks
4weeks ~45weeks
Visits12 33.1 45 6789101112 13141516171819 20 2122232425
ImmuneResponseAssays HXTCInfusion LeukapheresisSingleCopyAssayOtherResearchAssays
VORevery72hoursx10doses
VORevery72hoursx10doses
cART
STEP1PretreatmentPhaseExhibit Ex-vivoresponsetoVOR
STEP2:SingleVOR400mgdose
STEP3:HXTCsproduced
STEP4:FirstCombinationtreatmentVORevery72hoursx10dosesand2HXTCInfusions
RESTPERIOD
STEP5:FirstCombinationtreatmentVORevery72hoursand2HXTCInfusions
STEP 6:ImmuneResponsemonitoring
~4weeks ~8weeks
~6-8weeks
4weeks 2-4weeks
4weeks ~45weeks
Visits12 33.1 45 6789101112 13141516171819 20 2122232425
ImmuneResponseAssays HXTCInfusion LeukapheresisSingleCopyAssayOtherResearchAssays
VORevery72hoursx10doses
VORevery72hoursx10doses
cART
HX
TC
HX
TC
HX
TC
HX
TC
HX
TC
Cath Bollard
Clio Rooney
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Steps to eliminate
HIV infection
Latency
Reversal
Finally: the addition of durable vaccine protection if rebound or reexposure occurs