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Advances in Melanoma: Vaccines Doug Schwartzentruber, M.D., FACS System Medical Director for Cancer Indiana University H

Advances in Melanoma: Vaccines Doug Schwartzentruber, M.D., FACS System Medical Director for Cancer Indiana University Health Associate Director, IU Simon Cancer Center Indianapolis, IN. Disclosures. Medical Advisory Board: Prometheus Speaker: Zyopharm Oncology, Inc.

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Advances in Melanoma: Vaccines Doug Schwartzentruber, M.D., FACS System Medical Director for Cancer Indiana University H

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  1. Advances in Melanoma: Vaccines Doug Schwartzentruber, M.D., FACS System Medical Director for Cancer Indiana University Health Associate Director, IU Simon Cancer Center Indianapolis, IN

  2. Disclosures Medical Advisory Board: Prometheus Speaker: Zyopharm Oncology, Inc

  3. Incidence and Mortality of Cancer Jemal A. , et. al., CA Cancer J Clin 60:277-300,2010

  4. Rising Incidence of Melanoma

  5. Metastatic Melanoma Treated With IL-2 Courtesy of S. Rosenberg

  6. A Phase III Multi-institutional Randomized Study of Immunization with gp100:209-217(210M) Peptide Followed by High Dose IL-2 vs High Dose IL-2 Alone in Patients With Metastatic Melanoma

  7. BackgroundTreatment with IL-2 and gp100:209-217(210M) • Atkins M.B., et. al., J ClinOnc 17: 2105-2116, 1999. • Rosenberg S.A., et. al., Nature Medicine 4: 321-327, 1998. • Smith F.O., et. Al., Clin Cancer Res 14:5610-5618, 2008. IL-2 alone response rate (RR): 16%.1 gp100 209-217 (210M) + IL-2 every 3 weeks, RR 42% (13/31).2 Retrospective results NCI: IL-2 alone (n=305) RR 12.8 %; gp100 + IL-2 (n=49) RR 25.0 %.3

  8. Rationale:Gp 100 Vaccine + IL-2 Induces Tumor Destruction Tumors Vaccine Induces Anti-Tumor T-cells Vaccine T-cells IL-2 T-Cells Destroy Tumors IL-2 Induces T-Cell Proliferation

  9. Treatment Schema: 2-Arm Randomized Studyfor Patients with Metastatic Melanoma IL-2 Primary Endpoint:Clinical Response IL-2 Plus Vaccine

  10. Treatment: IL-2 Doses (mean) Patients 93 85 75 72 29 39 26 37

  11. More Clinical Responses were Seen inPatients Receiving IL-2 + Gp100 Vaccine 20.0% 9.7%

  12. Progression Free Survival is Enhancedwith Gp100 Vaccine Median Survival months (95% CI) IL-2 Alone: 1.6 (1.5-1.8) IL-2+gp100: 2.2 (1.7-3.9) p value: 0.008 Schwartzentruber D. J. et al., NEJM, 2011

  13. Trend for Increased Overall Survivalwith Gp100 Vaccine Median Survival months (95% CI) IL-2 Alone: 11.1 (8.7-16.3) IL-2+gp100: 17.8 (11.9-25.8) p value: 0.06 Schwartzentruber D. J. et al., NEJM, 2011

  14. Conclusions • gp100 209-217 (210M) in Montanide ISA 51 enhances the clinical activity of HD IL-2 in patients with metastatic melanoma. • Rational combinations of vaccines and immunomodulatory agents with IL-2 need to be further studied in the treatment of patients with metastatic melanoma.

  15. Future Peptide Vaccine Studies • Develop a more potent vaccine. • Perform a larger randomized trial to test the new vaccine.

  16. Thank you In-vitro Studies Lien Ngo, MS Steven Rosenberg, MD Nurses & Data Managers

  17. Immunotherapy of advanced melanoma by intra-tumoral injections of autologous, purified dendritic cells transducedwith gene construct of interleukin-12, with dose-dependent expression under the control of an oral activator ligand D.J. Schwartzentruber¹, J.M. Kirkwood², M. Guarino³, J. Richards⁴, O. Hamid⁵, S. O’Day⁵, J. Nemunaitis⁶; J. Talmadge⁷, S. Chada⁸, K. Menander⁹, K. Shafer-Weaver⁸, J. Senesac⁸, M. O. Thornton¹⁰, J. J. Lewis¹⁰, and R.B. Herberman⁸ ¹Indiana University Health Goshen Center for Cancer Care, Goshen, IN; ²University of Pittsburgh Cancer Institute, Pittsburgh, PA; ³Christiana Care Health Services, Inc, Newark, DE; ⁴Oncology Specialists, S.C., Park Ridge, IL; ⁵The Angeles Clinic & Research Institute, Los Angeles, CA; ⁶Mary Crowley Cancer Research Center, Dallas, TX; ⁷Univ. of Nebraska Med Ctr., Omaha, NE; ⁸Intrexon Corporation, Germantown, MD; ⁹Menander and Associates, Bellaire, TX; ¹⁰ZIOPHARM Oncology, Inc., Boston, MA

  18. RheoSwitch® + Activator Ligand Controls Timing and Level of Target Gene Expression RheoSwitch Protein 1 RheoSwitch Protein 2 Co-repressor protein RheoSwitch components Inducible Promoter Target Gene Ligand Basal Transcription Proteins RheoSwitch components Co-activator protein

  19. Ad-DC-RTS-IL-12 + Ligand Approach Enables Centralized Manufacturing Efficiencies Centralized MFR Clinical Location Oral dosing per protocol Ad-RTS-IL-12 Activator Ligand INXN-2001 INXN-1001 Transduction Stimulating elutriation Factors Monocytes Leukapheresis iDC’s DC-RTS-IL-12 INXN-3001 Thaw DC’s and inject target tumor Cryoprotectant Freeze and Ship

  20. Patient 001 CT Scan of Supraclavicular Mass Pretreatment: 4/17/09 1 month after 4th treatment 2/4/10

  21. Conclusions • The Rheoswitch control of gene expression has been utilized for the first time in patients • Therapy with DC-RTS-IL-12+AL has overall been well tolerated • One partial response was observed in 8 evaluable patients with metastatic melanoma who had prior progressive disease despite other treatments • This therapeutic approach has the potential advantage, relative to single epitope melanoma vaccine of triggering anti-tumor immunity via different antigens in each patient, without the need to restrict eligibility to patients with a particular HLA type

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