Opening new routes into the brain for treatment of Glioblastoma
VEGFC Delivery can:● Recruit more immune cells to brain● Allow for increased neuroimmune responses● Potentiate cancer immunotherapies to eradicate tumors
Immunaxis
Akiko Iwasaki PhDWaldemar Von Zedtwitz Professor of Immunobiology; Molecular Cellular and Developmental Biology; DermatologyInvestigator, Howard Hughes Medical [email protected]
Eric SongMD/PhD [email protected]
Role of VEGF-A in tumors
Role of VEGF-A in tumors
• Angiogenic
• Primary signaling through VEGFR2
• Bevacizumab(approved therapy for GBM) target
Role of VEGF-A and VEGF-C in tumors
• Angiogenic
• Primary signaling through VEGFR2
• Bevacizumab(approved therapy for GBM) target
• Lymphangiogenic
• Primary signaling through VEGFR3
• Not a target of Bevacizumab therapy
GBM has…
A very poor prognosis
Limited immune cell infiltrationLack of response after PD1 treatment
Increase immune cell infiltration
Increase antigen drainage
Potentiate current immunotherapy
VEGFC treatment can…GBM has…
A very poor prognosis
Limited immune cell infiltrationLack of response after PD1 treatment
LYVE1VEGFC results in increased brain-associated lymphatic vasculature
VEGFC treatedMock treated
• Delivered as protein, AAV virus vector or mRNA
• Protein expression kinetics can be effectively and sensitively measured
• Delivery can be localized to brain through Intrathecal injections
• Non-toxic; amenable to various delivery methods, high manufacturability and scalability
Peak expression
Controlled expression kinetics
Multiple doses
High expression
Protein Quick 0h Yes Yes No
AAV Delayed 4wks No No Yes
mRNA Quick 6-24 h Yes Yes Yes
CTRL-AAV VEGFC-AAV0
1
2
3
Rel
ativ
e Ar
ea
Confluence of Sinuses
*** P = 0.0007
Using VEGFC potentiates immunotherapy to eradicate GBM
VEGFC-mRNA treatment after tumor establishment potentiates anti-PD1 therapy to eliminate tumors
T cells are more polyfunctional (producing more cytokines) after VEGF-C treatment
0 50 1000
50
100
Time (d)
Per
cent
sur
viva
l
VEGFC only
Control
PD1 only
VEGFC + PD1
7 9 11 13 15105
106
Days C
D3+
Cel
l num
ber
Brainwtvegfc-mrna
T cell numbers increase in the brain tumor after VEGF-C administration
01
23
4# of cytokinesproduced
Control VEGF-C
Penetration to brain Administration Broad
Scope
Possible immune memory against
tumor
Animal model efficacy
(monotherapy)
Patient clinical benefit
ChemotherapyGLIADEL Yes Local No No - minimal
ChemotherapyTemozolomide minimal Systemic No No minimal minimal
Avastin Yes Systemic Yes No minimal minimal
Checkpoint inhibitor (PD-1) Yes Systemic Yes Yes minimal
Not completed//
minimalVEGFC
+Checkpoint
inhibitor
Yes Intra-thecal Yes Yes Significant survival benefit -
Approved therapies
Current Trial
Our Proposal
VEGFC overcomes current treatment limitations
Confidential
Penetration to brain Administration Broad
Scope
Possible immune memory against
tumor
Animal model efficacy
(monotherapy)
Patient clinical benefit
ChemotherapyGLIADEL Yes Local No No - minimal
ChemotherapyTemozolomide minimal Systemic No No minimal minimal
Avastin Yes Systemic Yes No minimal minimal
Checkpoint inhibitor (PD-1) Yes Systemic Yes Yes minimal
Not completed//
minimalVEGFC
+Checkpoint
inhibitor
Yes Intra-thecal Yes Yes Significant survival benefit -
Approved therapies
Current Trial
Our Proposal
VEGFC overcomes current treatment limitations
Confidential
Penetration to brain Administration Broad
Scope
Possible immune memory against
tumor
Animal model efficacy
(monotherapy)
Patient clinical benefit
ChemotherapyGLIADEL Yes Local No No - minimal
ChemotherapyTemozolomide minimal Systemic No No minimal minimal
Avastin Yes Systemic Yes No minimal minimal
Checkpoint inhibitor (PD-1) Yes Systemic Yes Yes minimal
Not completed//
minimalVEGFC
+Checkpoint
inhibitor
Yes Intra-thecal Yes Yes Significant survival benefit ???
Approved therapies
Current Trial
Our Proposal
Memory response against tumor even 100 days post initial rejection
VEGFC overcomes current treatment limitations
Completed2017 Q2 – 2018 Q3Evaluation of VEGFC therapy in murine GBMMechanistic studiesOptimization of deliveryTherapeutic benefit confirmedInvention disclosure submittedCompleted provisional patent filing
In progress2018 Q4 – 2019 Q4Effects of different administration routesDose escalation and toxicity studiesPK studies in mice and rats
Future directions2020 – futureProduce GMP quality materialStart phase I trialDevelop higher potency VEGF-C
2017 2018 2019
Timeline and Milestones with Future Funding
Opening new routes into the brain for treatment of GlioblastomaImmunaxis
