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

mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r

ACT I VAT I NG ANT I

• PANCRE

AT I C CANCE R I MMUNI T Y

T

• g e the r, T

a king o n Ca nc e r’ s T

• ug he st Cha lle ng e s

Michael Dwinell, PhD Professor & Director Center for Immunology

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 WI T H I NCRE ASI NG I NCI DE NCE

Projected Cancer Deaths

• Late diagnosis
• Highly metastatic
• Numerous genetic / epigenetic

changes

• Chemotherapy & Radiotherapy

resistant

• Unique tumor

microenvironment

• Pronounced immune

suppression & evasion

Pancreas Cancer

T

• g e the r,

T a king o n Ca nc e r’ s T

• ug he st

Cha lle ng e s 2019 Sc ie ntific Re tre a t

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

• KRasLSL-G12D/+;p53LSL-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 – 1x106 cells engrafted to dorsal subQ or orthotopically to pancreas – Inject murine STING agonist (DMXAA

KPC C57Bl/6 DMXAA

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

T cell activation Anti-tumor T cells Suppressor T cells

Jing et al., Journal for ImmunoTherapy of Cancer, 2019

B CD80 C CD86 CD40 Class I PDL1 CD206

DMXAA Vehicle Isotype

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

M2-like Jing et al., Journal for ImmunoTherapy of Cancer, 2019

* [ng/mL] * * * * * [ng/mL]

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

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

* * * * * * * * T cells T cells Macrophages PMNs [ng/mL] [ng/mL]

Jing et al., Journal for ImmunoTherapy of Cancer, 2019

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

• Dwinell Laboratory
• Donna McAllister
• Nick Barnekow
• Laura McOlash
• Natasha Moussouras
• Emily Vonderhaar
• Mahmoud Abu Eid
• Kathy Boyle, PhD
• Dept of Medicine & MCWCC

Drug Development and Therapeutics Program

– Bryon Johnson, PhD – Weiqing Jing, PhD – Katie Palen

• Dept of Surgery & Surgical

Oncology Biorepository

– Douglas Evans, MD – Susan Tsai, MD

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.

– Afric a n Pro ve rb

CANCE R 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