Transcript document

Randomized Therapeutic Vaccine Trial of Canarypox-HIV
(CP-HIV) + Dendritic Cells vs. CP-HIV Alone in HIVinfected Patients on Antiretroviral Therapy: ACTG A5130
• ALVAC-HIV (vCP1452): CP vector that contains HIV env
and gag genes and CTL epitopes from nef and pol.
• HIV+ subjects vaccinated with CP-HIV alone have small
and transient increases in HIV-specific immunity.
However, vaccination with CP-HIV in patients treated with
ART during acute or chronic HIV infection does not lead
to virologic control during treatment interruption Jacobson JID
194:623; Kinloch-de Loes JID 192:607; Autran AIDS 22:1313
• Dendritic cells infected with CP-HIV elicit HIV-specific
CD4 & CD8 immune responses in vitro Engelmayer. J Virol. 75:2142
• Hypothesis: Immunization of HIV+ patients on ART with
DCs plus CP-HIV will be more immunogenic and lead to
better control of viremia during a treatment interruption
than vaccination with CP-HIV alone
Study Schema
29 HIV+
Arm A
Subjects
DC+CP HIV
On ART
N=14
VL<50
Arm B
CD4 > 1:1
CP HIV
400
N=15
Wk 3 Wk 7
12-week ATI.
VL setpoint at
end of ATI
Wk 15
= vaccination with DCs + CP-HIV or CP-HIV alone.
At wks 3 and 7, subjects also received keyhole limpet
hemocyanin (KLH). KLH was a control to determine
whether priming of new immune responses occurred.
Primary Endpoints: 1) VL setpoint at the end of a 12week ATI; 2) Safety: ≥ grade 3 adverse event that is at
least possibly related to study treatment.
Inject CP-HIV-infected
DCs at wk 3, 7 & 15
Reinfuse
(1.5 toDC
6 million
+ agsDCs, SQ)
HIV+ pt on
antiretroviral
therapy
Add
agswith CPInfect
exHIV
vivo(ALVAC
vCP1452)
Isolate PBMC from
leukapheresis product
(1-3 billion PBMC)
Mature DCs using
cocktail of IL-1b, IL-6,
TNF-a, PGE2
remove
DCs
Expand
monocyte-derived
DCs using IL-4 and-GM CSF
(7 days in a cell processing lab at MGH)
Based on slide from Nina Bhardwaj, M.D., Ph.D.
Effect of Vaccination on LPA
• Subjects who received
KLH-pulsed DCs had a
significantly greater
increase in KLH LPA
response prior to ATI
than subjects who
received KLH alone
– Median SI fold change 5.7
in arm A vs. 1.8 in arm B,
p=0.007
• No change in LPA
response to tetanus,
candida or 5 pools of
HIV peptides
A: KLH-pulsed DCs. B: KLH alone
Fold-increase in ELISPOT Responses
During Vaccination
• 5/12 (42%)
subjects in arm A
and 5/12 (42%)
subjects in arm B
had a >3-fold
increase in
summed ELISPOT
response over
baseline at 1 or
more time points
after vaccination
and before ATI
Arm A (n=12)
DC+ CP-HIV
Arm B (n=12)
CP-HIV alone
Responder: 3-fold increase in ELISPOT
response that is also >30 SFC/million PBMC
Viral Load during ATI: Summary
• No difference in VL setpoint between subjects in Arm A and
B (medians 4.1 and 4.5 log10 c/mL)
• 4/13 (31%) in DC+CP-HIV arm had VL setpoint <5,000
compared with 0/13 (0%) in CP-HIV alone arm (p=0.096)
– Of the 4 subjects who achieved VL setpoint <5,000 at end of
ATI, 2 had increase in VL to >5,000 on follow-up (7 wks later)
Arm A (n=14) DC+CP-HIV
VL=5000
Setpoint VL <5000 c/mL
Arm B (n=15) CP-HIV alone
ELISPOT response and VL Setpoint
during ATI
• Summed ELISPOT level after vaccination negatively
but weakly correlated with VL setpoint (not sig.)
• Greater fold-increases in gag, nef or summed ELISPOT
response after vaccination are associated with lower VL
setpoint (all p-values <0.05)
Conclusions
• CP-HIV & DC+CP-HIV therapeutic vaccines are safe
and immunogenic in HIV-infected patients
• DCs effective as an adjuvant to prime responses to KLH,
but did not clearly enhance HIV-specific ELISPOT
responses
• Suggestion that subjects vaccinated with CP-HIV+DC
had a higher rate of VL setpoint <5,000 c/mL during ATI
than subjects immunized with CP-HIV alone; however,
control was transient
• Subjects who had higher fold-increases in HIV-specific
ELISPOT responses after vaccination had lower VL
setpoints
• Further studies of the correlates of antiviral immunity and
methods to more effectively boost antiviral immunity are
warranted
Acknowledgments
ACTG 5130 team
• Jeff Jacobson, protocol chair; Rajesh Gandhi and Nina
Bhardwaj, vice-chairs
• David O’Neill, Ellen Chan, Ron Bosch
• Pat Bucy, Mary Marovich, Lynn Baglyos, Reena Masih,
Barbara Schock, Lynette Purdue and the 5130 team
Massachusetts General Hospital
• Teri Flynn, Amy Sbrolla, Janet Shopis, Kathy Habeeb,
Nicole Burgett, Gil Roy, Daniel Kavanagh, Doug Kwon,
Bruce Walker
NYU Cancer Institute Vaccine Center
• Crystal M. Cruz, Angelica Angiulli and Francesca Angiulli
Burroughs Wellcome, Elizabeth Glaser, Doris Duke
Beth Israel, NY
• Ann Marshak, Gwen Constantini, Sondra Middleton,
Donald Garmon, Scott Barnett, Donna Mildvan
Study subjects at MGH and Beth Israel, NY