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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 l’Université 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)

                                   Introduction                                                                                  CD4+ Related Safety Results
• Dendritic cells (DCs): Antigen-presenting cells that can                                              Fig. 4
                                                                                                                                       CAN-HIV-001 Absolute CD4 Counts
  stimulate cell-mediated immunity through effects on CD4+                                                  1200                                                               Median

  and CD8+ T cells.                                                                                                                                                            Sub #002

• Arcelis™ platform: Manufacture of personalized medication                                                 1000
                                                                                                                                                                               Sub #003
                                                                                                                                                                               Sub #004
  using autologous DCs electroporated with autologous RNA.

                                                                                                 CD4 [cells/mL]
                                                                                                                                                                               Sub #005
  For HIV, use of 4 autologous HIV antigens (Gag, Vpr, Rev,                                                       800                                                          Sub #006

  and Nef [GVRN]) obtained from HIV plasma along with                                                                                                                          Sub #007

  synthetic CD40L to create “Arcelis™ for HIV” (AGS-004) (Fig                                                     600
                                                                                                                                                                               Sub #008

                                                                                                                                                                               Sub #009
  3)                                                                                                                                                                           Sub #010
• Hypothesis: AGS-004 will surmount the genetic and antigenic                                                     400                                                          Sub #013

  variability of HIV by presenting a spectrum of autologous HIV
  epitopes (GVRN) to both memory and naive or resting T cells                                                     200
                                                                                                                        Screen     0           4          8       12     18
  to induce an antigen-specific immune response optimal for
  each subject to achieve a level of virologic control sufficient
  to discontinue antiretroviral medications.                                                     • Fig. 4 represent the change in absolute CD4+ T cells/µL over the
• Study design: CAN-HIV-001 is a phase 1/ 2 pilot study to                                         duration of study by subject and median values. The median remained
  assess the tolerability, safety, and immunogenicity of AGS-                                      stable around 400 cells/µL with no consistent trend
  004 in HIV-infected subjects who are virally suppressed on                                     • The CD4/CD8 ratio remained constant throughout the study with
  ART                                                                                              minimal changes that were not considered clinically relevant
• Primary endpoint: Immunologic activity assessed by change                                                             Primary Endpoint: Immunologic Activity
  from baseline in the proliferative capacity of HIV specific
                                                                                                 •A positive response was prospectively defined as the CD8+ T cell
  CD8+ T cells in response to GVRN as measured by flow
                                                                                                 proliferation to HIV RNA expressing DC targets if >3 SD above the
  cytometry following 4 doses of AGS-004 administered one
                                                                                                 response to the matched enhanced green fluorescent protein (eGFP)
  intradermal dose per month.
                                                                                                 control, AND at least 2-fold increase over the pre-treatment response at
                              CAN-HIV-001 Study                                                  baseline
                                                                                                 •The null hypothesis was considered rejected if ≥ 4 subjects met the
 Fig. 1                                                                                          criteria for a positive primary endpoint by the aforementioned criteria
                      Dose 1        Dose 2         Dose 3       Dose 4
                                                                                                         Fig. 5
           Screen        Week 0          Week 4     Week 8       Week 12       Week 14

                                                                                  IM assay
  VISIT # 2               3               4           5             6                  7

           Arcelis™ for HIV

      Leukapheresis =                    IM-blood draw =          AGS-004 dose=

 • For the generation of each subject’s personalized AGS-004 (Fig. 3)                              • Results (Fig 5): CD8+ T cell proliferative response to GVRN (the 4 gene
    – Availability of a frozen 2.5 mL pre-ART plasma (HIV RNA source)                                target) has been noted in 4 out of the 9 subjects available for analysis
    – PBMCs obtained via leukapheresis (DC source)                                                   (unable to grow one subjects DCs)
 • Doses were stored in cryostorage and shipped in cryoshippers to                                 • As hypothesized, these responses were specific for the HIV antigens
   the clinical sites immediately prior to each dosing visit                                         presented by the AGS-004 product with the strongest responses
 • The patient dose is 0.6 mL, which is administered as three 0.2 mL                                 characterized by a CD8+CD28+ effector memory phenotype
   intradermal (id) injections in the lateral aspect of the chest wall                             • It was also noted that the induced immunity preferentially targeted the
   between the anterior and midaxillary line, targeted to a single lymph                             CD8+ rather than the CD4+ compartment
   node in the axilla                                                                              • 7 of 9 subjects showed a >2 fold increase in proliferative response to at
 • Immune monitoring samples and safety labs were collected                                          least one antigen post-therapy
   at every dosing visit (Fig. 1)                                                                  • At Visit 7, 4 of 9 subjects showed at >2 X increase in the effector cell
                                                                                                     function as defined by IFN-γ secretion post-therapy
  Fig. 2
                                                    41.5 year (median) males
                                                    CD4+ T-cells at screening:
     12 subjects signed ICF and                        490/mL (median)                       Fig. 6
     pre-ART HIV RNA amplified

                                                  1 unable to amplify
                                                  1 only 3 genes amplified
     10 subjects received
     “Arcelis TM for HIV” (AGS-004)
  • Subjects had viral suppression and were on their initial
    ART regimen.
  • The CD4 nadir was ≥ 200 cells/µL at the time of pre-ART                                              • Figure 6 depicts responses to simultaneous presentation of all
    sampling                                                                                             4 antigens (GVRN) or to individual antigens (Gag, Vpr. Rev, and Nef).
  • No co-infections or co-morbidities were permitted                                                    Numbers in the boxes are the percent CFSElow CD4+ T cells.
                                                                                                         •Data presented in Fig 6 show that AGS-004 rarely induced CD4+
                    CAN-HIV-001 Safety Results
        AGS-004 Related Adverse Event                 (Observed in 6 of 10 subjects)                                                            Conclusions
  Local and Systemic Reactions                                                                                    • The CAN-HIV-001 study met its predefined endpoint of
             Axillary pain                                          1
             Injection site erythema                                3                                               demonstrating polyvalent multifunctional CD8+ T cells response in
             Injection site induration                              2                                               4 of 9 subjects
             Injection site pain                                    3
             Influenza-like illness                                 2                                             • Arcelis™ for HIV rarely induced a CD4+ response which is
             Fatigue                                                5                                               consistent with the proposed mechanism of action of this product
                                                                                                                    utilizing CD40L to bypass the need for canonical T cell help to
              Diarrhea                                              1
              Headache                                              1                                               ensure CD8+ T cell maturation
                                                                                                                  • No untoward effects on viral load and absolute CD4+ T cells were
  • There were no deaths
  • 2 SAEs occurred; unrelated to AGS-004: cholecystitis &                                                          observed over study duration
    appendicitis                                                                                                  • Treatment emergent adverse events were mild local and mild
  • All study drug (AGS-004) related adverse events were mild                                                       systemic grades
    (grade 1) and none caused a subject to discontinue from the                                                   • No lab changes indicative of the induction of autoimmunity or
                                                                                                                    clinical autoimmune breakthrough events were observed
  • No viral blips were observed during the study duration
  • No clinically relevant changes were observed in the safety labs                                               • Providing personalized Arcelis™ cell therapy to HIV-infected
     – One subject experienced detectable rheumatoid factor at two                                                  patients from one central, well controlled point of manufacture is
       time points, which resolved without treatment and was not                                                    feasible
       associated with other clinical or laboratory signs of                                                      • The Arcelis™ approach can support multi-center studies in a
                                                                                                                    broad geographical area with minimal burden on the clinical site,
  • Minor changes in the vital signs were not considered clinically
    relevant                                                                                                        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

                                                                    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 (CTN:219),
   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
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

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