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Autologous Dendritic Cell Immunotherapeutic
(ArcelisTM for HIV) Tolerability and
Immunogenicity in HIV-1 Infected Subjects Treated
with ART Routy JP(1), Yassine-Diab B(2), Landry
C(3), Gagnon D(3), Yegorov O(2), Boulassel MR(1),
Caroline Benoît-Hébert(3), Antar R(1),
Tcherepanova I(4), Healey D(4), Jain RG(4), Finke
LH(4), Nicolette CA(4), Sekaly RP(2, 3) (1) Royal
Victoria Hospital, and McGill University,
Montréal, Québec, Canada (2) Centre de recherche
du Centre Hospitalier de lUniversité de
Montréal, Montréal, Québec, Canada (3) National
Immune Monitoring Laboratory (NIML) / Université
de Montréal, Montréal, Québec, Canada (4) Argos
Therapeutics, North Carolina, USA.
NATIONAL IMMUNE MONITORING LABORATORY (NIML)
CD4 Related Safety Results
Introduction

• Dendritic cells (DCs) Antigen-presenting cells
  that can stimulate cell-mediated immunity through
  effects on CD4 and CD8 T cells.
• Arcelis platform Manufacture of personalized
  medication using autologous DCs electroporated
  with autologous RNA. For HIV, use of 4
  autologous HIV antigens (Gag, Vpr, Rev, and Nef
  GVRN) obtained from HIV plasma along with
  synthetic CD40L to create Arcelis for HIV
  (AGS-004) (Fig 3)
• Hypothesis AGS-004 will surmount the genetic and
  antigenic variability of HIV by presenting a
  spectrum of autologous HIV epitopes (GVRN) to
  both memory and naive or resting T cells to
  induce an antigen-specific immune response
  optimal for each subject to achieve a level of
  virologic control sufficient to discontinue
  antiretroviral medications.
• Study design CAN-HIV-001 is a phase 1/ 2 pilot
  study to assess the tolerability, safety, and
  immunogenicity of AGS-004 in HIV-infected
  subjects who are virally suppressed on ART
• Primary endpoint Immunologic activity assessed
  by change from baseline in the proliferative
  capacity of HIV specific CD8 T cells in response
  to GVRN as measured by flow cytometry following
  4 doses of AGS-004 administered one intradermal
  dose per month.

Fig. 4

• Fig. 4 represent the change in absolute CD4 T
  cells/µL over the duration of study by subject
  and median values. The median remained stable
  around 400 cells/µL with no consistent trend
• The CD4/CD8 ratio remained constant throughout
  the study with minimal changes that were not
  considered clinically relevant

Primary Endpoint Immunologic Activity

• A positive response was prospectively defined as
  the CD8 T cell proliferation to HIV RNA
  expressing DC targets if gt3 SD above the response
  to the matched enhanced green fluorescent protein
  (eGFP) control, AND at least 2-fold increase over
  the pre-treatment response at baseline
• The null hypothesis was considered rejected if
  4 subjects met the criteria for a positive
  primary endpoint by the aforementioned criteria

CAN-HIV-001 Study
Fig. 5
Leukapheresis IM-blood draw
AGS-004 dose

• Results (Fig 5) CD8 T cell proliferative
  response to GVRN (the 4 gene target) has been
  noted in 4 out of the 9 subjects available for
  analysis (unable to grow one subjects DCs)
• As hypothesized, these responses were specific
  for the HIV antigens presented by the AGS-004
  product with the strongest responses
  characterized by a CD8CD28 effector memory
  phenotype
• It was also noted that the induced immunity
  preferentially targeted the CD8 rather than the
  CD4 compartment
• 7 of 9 subjects showed a gt2 fold increase in
  proliferative response to at least one antigen
  post-therapy
• At Visit 7, 4 of 9 subjects showed at gt2 X
  increase in the effector cell function as defined
  by IFN-? secretion post-therapy

• For the generation of each subjects personalized
  AGS-004 (Fig. 3)
• Availability of a frozen 2.5 mL pre-ART plasma
  (HIV RNA source)
• PBMCs obtained via leukapheresis (DC source)
• Doses were stored in cryostorage and shipped in
  cryoshippers to the clinical sites immediately
  prior to each dosing visit
• The patient dose is 0.6 mL, which is administered
  as three 0.2 mL intradermal (id) injections in
  the lateral aspect of the chest wall between the
  anterior and midaxillary line, targeted to a
  single lymph node in the axilla
• Immune monitoring samples and safety labs were
  collected
• at every dosing visit (Fig. 1)

Fig. 2
41.5 year (median) males CD4 T-cells at
screening 490/mL (median)
Fig. 6

• Subjects had viral suppression and were on their
  initial ART regimen.
• The CD4 nadir was 200 cells/µL at the time of
  pre-ART sampling
• No co-infections or co-morbidities were permitted

• Figure 6 depicts responses to simultaneous
  presentation of all
• 4 antigens (GVRN) or to individual antigens (Gag,
  Vpr. Rev, and Nef).
• Numbers in the boxes are the percent CFSElow CD4
  T cells.
• Data presented in Fig 6 show that AGS-004 rarely
  induced CD4 responses

CAN-HIV-001 Safety Results
Conclusions

• The CAN-HIV-001 study met its predefined endpoint
  of demonstrating polyvalent multifunctional CD8
  T cells response in 4 of 9 subjects
• Arcelis for HIV rarely induced a CD4 response
  which is consistent with the proposed mechanism
  of action of this product utilizing CD40L to
  bypass the need for canonical T cell help to
  ensure CD8 T cell maturation
• No untoward effects on viral load and absolute
  CD4 T cells were observed over study duration
• Treatment emergent adverse events were mild local
  and mild systemic grades
• No lab changes indicative of the induction of
  autoimmunity or clinical autoimmune breakthrough
  events were observed
• Providing personalized Arcelis cell therapy to
  HIV-infected patients from one central, well
  controlled point of manufacture is feasible
• The Arcelis approach can support multi-center
  studies in a broad geographical area with minimal
  burden on the clinical site, applicable to
  practice settings
• These data support a multi-center phase 2 study
  presently ongoing in Canadian centers (Protocol
  AGS-004-001), that will investigate the ability
  of AGS-004 to control viral load when
  interrupting ART

• There were no deaths
• 2 SAEs occurred unrelated to AGS-004
  cholecystitis appendicitis
• All study drug (AGS-004) related adverse events
  were mild (grade 1) and none caused a subject to
  discontinue from the study
• No viral blips were observed during the study
  duration
• No clinically relevant changes were observed in
  the safety labs
• One subject experienced detectable rheumatoid
  factor at two time points, which resolved without
  treatment and was not associated with other
  clinical or laboratory signs of autoimmunity
• Minor changes in the vital signs were not
  considered clinically relevant

Arcelis Platform and Process
Fig. 3
This project has been funded in whole or in part
with Federal funds from the National Institute of
Allergy and Infectious Diseases, National
Institute of Health, department of Health and
Human Services, under Contract No.
NO1-AI-60019.This study (CAN-HIV-001) has been
supported by the McGill Research Center, Canadian
Clinical Trials Network (CTN219), Canadian
Institutes for Health Research, CAN-VAC, National
Institutes of Health (USA), DC Bio, Inc., and
Argos Therapeutics, Inc.CAN-HIV-001 is subject
to a CTA with Health Canada, a full NOL has been
issued prior to start of accrual received REB
approval, all participants granted informed
consent was registered at ClinicalTrials.gov
Identifier NCT00381212
Abbreviations DC- dendritic cells ART-
antiretroviral therapy PBMC- peripheral blood
mononuclear cell eGFP- enhanced green
fluorescent protein CD- cluster of
differentiation GVRN- Gag, Vpr, Rev, Nef HIV
antigens SD- standard deviation mRNA- messenger
ribonucleic acid ICF- informed consent IM
immune monitoring SAE- serious adverse event