poster template - Argos Therapeutics

Autologous Dendritic Cell Therapy AGS-003, Induces Strong Durable Immune Responses In Patients With Advanced Renal Cell Carcinoma
M. DeBenedette, W. Lewis, E. Wansley, A. Gamble, J. Horvatinovich, I.Y. Tcherepanova, C.A. Nicolette
Argos Therapeutics Inc, Durham, NC, USA
Abstract #1024
Abstract
AGS-003-006 Mechanism of Action
AGS-003-006 Study Design
AGS-003, an autologous dendritic cell (DC) immunotherapy has recently been evaluated in
combination with sunitinib in AGS-003-006, an open label phase 2 trial for treatment of patients with
newly diagnosed, unfavorable-risk, metastatic renal cell carcinoma (mRCC). The mechanism of action
(MOA) of AGS-003 is predicated on the expansion of antigen reactive CTL having a broad multifunctional response. Multi-color flow cytometry was used to identify tumor-reactive central memory
CTL subsets expanded after treatment with AGS-003. Multi-functionality of CTL responses to AGS-003
was identified by partitioning CTL subsets into discreet combinatorial expression patterns of Markers
of Immune Function (MIFs) defined by cytokine (IFN-g, TNF-a, IL-2) expression, cytolytic marker (Grb,
CD107) expression and proliferation in response to autologous RNA tumor encoded antigens
presented by the stimulating DCs. Expansion of central/memory CTL displaying a broad MIF profile
are shown to have a statistically significant correlate with overall survival in patients treated with AGS003 (see Poster #1031). Data presented herein show the durability of the AGS-003 induced response.
The AGS-003 induced immune response was profiled in a patient treated long term with AGS-003.
The CTL displaying the signature phenotype of CD28+/CCR7+/CD45RA- and maintaining a broad MIFs
profile could be recalled from the peripheral blood with autologous DC stimulation. These CTL were
present after quarterly booster dosing with AGS-003 outwards to 3 years post initial treatment
resulting in patient survival in excess of 30 months. Furthermore, decreases in the numbers of T
regulatory cells and MDSC could be seen in this long term surviving patient. Therefore, one of the
consequences of DC immunotherapy is to remodel the immune system resulting in durable antitumor immunity in conjunction with alterations in known suppressor mechanisms.
Change in Available CTL Pool
Multi-Functionality of A Durable CTL Response
Suppressor Cell Modulation
Immune Monitoring Methods
Results of AGS-003 Immunotherapy in Combination with Sunitinib
Multi-color flow cytometry was used to identify CTL subsets present in longitudinal blood draws collected pre-dosing (0D) after the 5th dose
(5D), at the 2nd booster phase dosing (BP2) and at the 4th booster phase dosing (BP4) from patient #16 (see Poster #1034). Pie charts
indicate the functional composition of all combinations of CTL subsets at each time point. The colored arcs represent the expression of
each individual phenotype marker within each pie section. Bar diagram indicating all possible combinations of CTL subsets defined by
expression of CD28, CCR7, CD27, and CD45RA are shown on the x-axis versus the absolute number of CTL present in each subset for the
four time points assessed. Bar chart legend; Group 0D , Group 5D , Group BP2 , and Group BP4 . Results showing statistically
significant changes in CTL numbers are highlighted in red in the table. The durability of the multi-functional response in this patient is
represented by the pie charts depicting the composition of expression of all combinations of the functional markers Brdu , CD107a ,
Grb ,IFN-g , IL-2 , and TNF-a  for CTL subset CD28+/CCR7+/CD27+/CD45RA- across the four time points analyzed. The colored arcs
represent the expression of each individual functional marker within each pie section. Multi-functional subsets having statistical significant
increases post treatment with AGS-003 are highlighted in red in the table. Multi-color flow data was analyzed with FlowJo version 9.31
(Tree Star, Ashland, OR), and combinatorial analysis performed using PESTLE and SPICE software, (version 5.3)1.
1 Roederer M, Nozzi JL, Nason MC. Cytometry A. 2011 Feb;79(2):167-74.
 AGS-003 induces long lived central/memory CTL
 Statistically significant increases in CD28 expressing CTL can be detected during booster treatment with AGS-003
 CTL within the CD28+ central/memory subset maintain broad multi-functionality
 AGS-003 immunotherapy in combination with sunitinib results in long term decreases in both MDSC and T
regulatory cells
 AGS-003 immunotherapy results in remodeling of the immune system to favor robust anti-tumor activity
 Correlates of CTL multi-functionality and clinical benefit can be determined in patients receiving AGS-003
immunotherapy (see Poster #1034)
 AGS-003 induces durable changes in the composition of peripheral blood CTL thus providing a biomarker to monitor
DC immunotherapy efficacy
 Future Immune monitoring analysis will be undertaken in the ADAPT Phase 3 study (see poster #1031)
Keystone Symposia –Understanding Dendritic Cell Biology to Advance Disease Therapies (C2) March 3-8, 2013 Keystone, Colorado