Slide 1: Phase I clinical results of an APC-targeted hCGβ vaccine (CDX-1307) with TLR agonists
Phase I clinical results of an APC-targeted hCGβ vaccine (CDX-1307) with TLR agonists. Michael Morse1, Robert Chapman2, John Powderly3, Kimberly Blackwell1, Ding Wang2, Tibor Keler4, Lizhen He4, Venky Ramakrishna4, Laura Vitale4, Timothy Clay1, Jennifer Green4, Thomas Davis4 1. Duke University Medic
Slide 2: Disclosure Slide
Disclosure Slide Michael Morse No disclosures related to this presentation
Slide 3: Challenges in Immunotherapy
Challenges in Immunotherapy Choosing target antigens to which tolerance may be broken Efficient delivery of antigen to APCs Presentation to CD8+ and CD4 + T cells Providing “danger signals” to APCs that lead to enhanced activation of T cells
Slide 4: Targeting Ag to APC with Mannose Receptor-Binding Ab
Tumor antigen delivered to dendritic cells and macrophages Efficient uptake Presentation of multiple epitopes (MHC-I and –II) Antibody and T cell immune responses Allows potential access to a larger APC population compared to standard protein vaccination strategies Targeting Ag to APC with Mannose R
Slide 5: CDX-1307: APC-targeted hCGβ vaccine
CDX-1307: APC-targeted hCGβ vaccine hCGb (tumor antigen) B11 (fully human antibody to mannose receptor on APCs)
Slide 6: Rationale for targeting hCG in cancer immunotherapy
overexpressed by common cancers; few normal tissues1 Implicated in survival and growth of cancer cells Elevated expression associated with poor prognosis Anti-hCGb Ab response associated with improved survival2 Tolerance to hCGb may be broken specific cytotoxic T cells can be generated from PBL of h
Slide 7: In vitro targeting of B11-hCGβ (CDX-1307) to human dendritic cells
In vitro targeting of B11-hCGβ (CDX-1307) to human dendritic cells 0 min 60 min 120 min hCGβ-FITC 0.5 M B11-hCGβ-FITC 0.25 M 0 min 10 min 60 min 120 min hCGb B11 mAb hCGb
Slide 8: Adjuvants provide additional signals for APC activation
Adjuvants provide additional signals for APC activation GM-CSF Local recruitment and maturation of DCs Up-regulation of mannose receptors TLR agonists Trigger maturation and activation of APCs enhance co-stimulatory signals and release of cytokines Poly-ICLC (Hiltonol: Oncovir, Inc.): ds RNA with po
Slide 9: Combination with TLR-Agonists Generates Anti-Tumor Immunity
Combination with TLR-Agonists Generates Anti-Tumor Immunity 0 20 40 60 80 100 120 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Days post tumor inoculation Average Tumor area (mm 2) Saline CDX-1307 CDX-1307 & Poly-ICLC
Slide 10: CDX-1307: Clinical Studies
CDX-1307: Clinical Studies Two Phase I studies: Intravenous vs. intradermal delivery Advanced breast, colorectal, pancreatic, ovarian or bladder cancer Objectives: Safety and tolerability; Immune responses Clinical activity (ORR, TTP)
Slide 11: Clinical Study Cohorts
Clinical Study Cohorts Intradermal/Intracutaneous Study Intravenous Study CDX-1307 (no adjuvants) 0.3 mg (n=6) 1.0 mg (n=6) 2.5 mg (n=6) 2.5 mg + GM-CSF (n=7) CDX-1307 + GM-CSF 2.5 mg + GM-CSF + Hiltonol (n=6) 2.5 mg + GM-CSF + Resiquimod (n=7) 2.5 mg + GM-CSF + Poly-ICLC + Resiquimod (n=8+) CDX-130
Slide 12: Treatment Regimen
Treatment Regimen CDX-1307 Vaccine (Day 1, 14, 28, and 42) GM-CSF (100 mcg s.c.) 2 wks 2 wks 2 wks Poly-ICLC (2 mg s.c.) Resiquimod (2 mg, topical 2% gel) 5 days 5 days 5 days 5 days
Slide 13: Baseline Characteristics
Baseline Characteristics 4.5 Number of prior chemotherapy regimens (Mean) 42% Elevated Serum hCG-b 59% Received prior radiotherapy 13% 46% 37% 4% Primary Cancer Pancreatic Colorectal Breast Other 49% 50% 1% ECOG Performance Status 0 1 2 40% Male 60 (35-81) Median age (years [range]) All Patients (n=
Slide 14: Serum hCGb Measurements
Serum hCGb Measurements Elevated hCGb found commonly in cancer patients 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% All Breast Colorectal Pancreatic Other Female Male Primary Cancer Gender % of Patients with Elevated hCG b Elevated prior to study entry Elevated at any time
Slide 15: CDX-1307 Tolerability & PK
CDX-1307 Tolerability & PK No DLTs or treatment discontinuation due to toxicity 4 patients treated with 2nd cycle Treatment-related AEs: G1-2 administration site reactions (23%) CDX-1307 locally (17%); addition of adjuvants (55%) G1-3 fatigue (21%), G1 flu-like illness (10%), G1 diarrhea (6%), G1 my
Slide 16: hCGb accumulation in dermal dendritic cells at injection site
Skin punch-biopsies taken from injection site and opposite limb 48 hrs post CDX-1307 (1 mg, i.d.) IHC - rabbit anti-hCGb Injection site Control arm Accumulation of hCGb in dermal dendritic cells and macrophages CDX-1307 Injection Site
Slide 17: Humoral Immune Responses
Humoral Immune Responses % Patients that developed anti-hCGb IgG CDX-1307 alone intradermal intravenous all patients CDX-1307 + GM CDX-1307 + GM + Poly ICLC CDX-1307 + GM + Resiquimod 2/17 3/7 3/5 3/6 4/15 3/6 3/6 6/32 6/13 6/11 Similar outcome with i.d. and i.v. administration 0 10 20 30 40 50 60 7
Slide 18: Correlates of Anti-hCG-β Immune Response
Correlates of Anti-hCG-β Immune Response Highest titers in GM + TLR combination Titers ranged to > 1/200,000 Similar response in males (44%) and females (52%) Anti-hCGb response despite elevated serum hCGb Anti-hCGb response in 3 of 4 patients receiving retreatment In adjuvant groups 75 % (9/12) of
Slide 19: Cellular Immune Responses
Cellular Immune Responses Analysis not complete Monitored from 90ml blood samples In vitro re-stimulation to expand T cells Analysis by ELISPOT with hCGb peptide pool Enhanced T cell responses observed in some patients Examples of hCGb –specific T cell response 3016 0313 0 100 200 300 400 500 600 70
Slide 20: Emerging data: CDX-1307 plus combined TLR agonists
Emerging data: CDX-1307 plus combined TLR agonists Enhanced local response with combined TLR agonists d1 d3 d4 3 of 3 with + humoral immune response
Slide 21: Clinical Outcomes
Clinical Outcomes Tumor response: 1 mixed response seen in Pancreatic Cancer 7 patients with SD for 2.2+ to 6.5+ months (5 breast cancer, 1 colorectal, 1 pancreatic) Tumor markers Robust humoral response in 1 colon cancer patient - coinciding with decrease in CEA Second patient (testicular cancer) w
Slide 22: Summary/Conclusions
Summary/Conclusions CDX-1307 is designed for delivery of hCG-β to APCs Administration of CDX-1307 is well tolerated hCG-β localization in APCs demonstrated Anti-hCGβ immune responses observed in combination with adjuvants No clear differentiation between systemic and local administration 1 mixed res
Slide 23: Acknowledgements
Duke University: Amy Hobeika, PhD Takuya Osada, MD Delila Serra Amanda Summers Karrie Comatas Herbert Lyerly, MD Liz Anderson, RN, BSN, OCN Henry Ford Health System Tiffany Pearce Nikki Adams, RN Tomasz Stankiewics Carolina BioOncology Institute: Bryan Greene, PhD Sonja Carabello Lori Lipocky Paola