2019 Sc ie ntific Re tre a t F rida y, April 26, 2019 Disc o ve - PowerPoint PPT Presentation

2019 Sc ie ntific Re tre a t F rida y, April 26, 2019 Disc o ve ry Wo rld Pa vilio n ACT I VAT I NG ANT I -PANCRE AT I C CANCE R I MMUNI T Y Michael Dwinell, PhD Professor & Director Center for Immunology T o g e the r, T a king o n Ca nc e r’ s T o ug he st Cha lle ng e s mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r

DI SCL OSURE S • Cofounder and Vice President of Protein Foundry , a biotech startup that manufactures recombinant chemokines for biomedical research. • CXCL12 locked dimer technology and the use of CXCL12 as an anticancer agent have been patented and licensed to Watosa Bio, LLC. • Member, Scientific Advisory Board, Watosa Bio LLC

PANCRE AT I C CANCE R – A F AT AL DI SE ASE T o g e the r, T a king o n WI T H I NCRE ASI NG I NCI DE NCE Ca nc e r’ s T o ug he st Cha lle ng e s Projected Cancer Deaths Pancreas Cancer • Late diagnosis 2019 • Highly metastatic Sc ie ntific • Numerous genetic / epigenetic Re tre a t changes • Chemotherapy & Radiotherapy resistant • Unique tumor microenvironment • Pronounced immune suppression & evasion Pancreatic Cancer Action Network

GOAL : RE I GNI T E PANCRE AT I C T UMOR I MMUNE MI CROE NVI RONME NT Can STING agonist stimulate anti-pancreatic cancer immunity?

ST I MUL AT E S I NT E RF E RON GE NE S (ST I NG) cyclic dinucleotides (CDS)

APPROACH • KRas LSL-G12D /+;p53 LSL-R147A ;pdxCre (KPC) • Conditionally express overactive KRas and inactive p53 mutations • Isolated PDA cancer cells • Syngeneic graft pancreatic carcinoma cells to C57BL/6 mice – KPC1242 carcinoma cells – 1x10 6 cells engrafted to dorsal subQ or orthotopically to pancreas – Inject murine STING agonist (DMXAA DMXAA KPC C57Bl/6

ST I NG T RE AT ME NT I NCRE ASE S SURVI VAL AND DE CRE ASE S PDA T UMOR SI ZE Jing et al., Journal for ImmunoTherapy of Cancer , 2019

ST I NG AGONI ST I NCRE ASE S L E VE L S OF PANCRE AT I C CANCE R K I L L I NG T CE L L S Anti-tumor T cells Suppressor T cells T cell activation Jing et al., Journal for ImmunoTherapy of Cancer , 2019

ST I NG AGONI ST I NCRE ASE S I NF L AMMAT ORY ANT I -CANCE R T UMOR ASSOCI AT E D MACROPHAGE S B M2-like CD80 CD86 CD40 Class I PDL1 CD206 C DMXAA Vehicle Isotype Jing et al., Journal for ImmunoTherapy of Cancer , 2019

I NCRE ASE D I NF L AMMAT I ON I N ST I NG AGONI ST T RE AT E D PANCRE AT I C T UMORS * * * [ng/mL] * * * [ng/mL] DMXAA Vehicle Jing et al., Journal for ImmunoTherapy of Cancer , 2019

CHE MOK I NE PRODUCT I ON I N ST I NG AGONI ST T RE AT E D K PC T UMORS I N VI VO Macrophages T cells * * * [ng/mL] Jing et al., Journal for ImmunoTherapy of Cancer , 2019 * PMNs T cells * * [ng/mL] * * DMXAA Vehicle

ST I NG AGONI ST T RE AT ME NT : • Increases survival • Abrogates tumor growth and progression in an immune competent mouse model • Increases CTL infiltration and activation • Inflames pancreatic tumors • Reprograms suppressive M2-TAMs into inflammatory M1-TAMs • Increases cross-presenting dendritic cells • Activates proinflammatory signaling in pancreatic cancer

ST I NG AGONI ST PROMOT E S ANT I -T UMOR I MMUNI T Y I N PANCRE AT I C CANCE R

I f yo u wa nt to g o fa st, g o a lo ne . I f yo u wa nt to g o fa r, g o to g e the r. • Dwinell Laboratory • Dept of Medicine & MCWCC – Afric a n Pro ve rb Drug Development and • Donna McAllister Therapeutics Program • Nick Barnekow – Bryon Johnson, PhD • Laura McOlash – Weiqing Jing, PhD • Natasha Moussouras – Katie Palen • Emily Vonderhaar • Dept of Surgery & Surgical • Mahmoud Abu Eid Oncology Biorepository • Kathy Boyle, PhD – Douglas Evans, MD CANCE R – Susan Tsai, MD COL L ABORAT I VE mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r