Development of New Treatment Modalities Oncolytic Viruses and Nano

By

Professor Kjell Öberg, M.D., Ph.D.

Dept. of Endocrine Oncology , University Hospital , Uppsala, Sweden

Nashville Oct. 2011

Development of

New Treatment

Modalities –

Oncolytic Viruses

and Nano-

technique

Hallmarks of GEP-NETs

Initially diffuse symptoms (Doctors and

patient delay of 3-4 years!)

More than 60% present metastatic

disease at diagnosis

Variable growth rate

Expression of specific receptors

(SSTR, DA, GF)

Highly vascular

Therapeutic Options NETs

Surgery

– Curative (rarely), Ablative (very often)

Debulking

– Radiofrequency ablation (RFA)

– Embolization/chemoembolization/radioembolization

(Spherex®)

Medical therapy

– Chemotherapy

– Biological treatment:

• Somatostatin analogs

• α-interferon

• m-TOR inhibitors

• VEGF R inhibitors

• Other TKI’s

Irradiation

– External (bone, brain-mets)

– Tumor targeted, radioactive therapy (MIBG, Y90-DOTATOC,

Lu177 -DOTATATE)

177Lu-DOTA-octreotate therapy The Uppsala experience

Results: CR 1 (1%)

PR 57 (31%) 43%

MR 20 (11%)

SD 99 (54%)

PD 8 (4%)

32 patients who responded or had SD later progressed

• 229 patients 96 (midgut), 13 (lung), 17 (rectal), 44 (non-functioning

pNET), 9 (gastrinoma), 6 (glucagonoma), 7 (paraganglioma/

pheochromocytoma)

• No. treatments: 842

• Follow-up (n=185): Mean 13 mo (range 2–57 mo)

Chemotherapy

Capecitabin plus Temozolomide in

Pancreatic Endocrine Tumors

N=33

Capecitabin 750 mg/m2 x 2 Daily 1-14

Temozolomide 200 mg/m2 x 1 10-14

PR 70% (RECIST)

PFS 18 mo

Adverse events (Grade 3/4) 12%

Strosberg et al. Cancer. 2010 Sep.

Temozolomide-Based Chemotherapy

in Progressing PDECs After First-Line

Chemotherapy

N=25 (GI-NETS)

Treatment Tem alone N=5

Tem + Cap N=13

Tem + Cap + bev N=7

Responses

CR n=1 (4%) (48 mo)

PR n=7 (29%) (median 19 mo)

SP n=9 (38%) (median 18 mo)

Median PFS 6 mo (95%) CI 4-14 mo)

Median OS 22 mo (95% CI 8-27 mo)

Toxicity 1 Grade 3 hematol.tox

(Grade 3-4) 1 Grade 3 liver tox

1 patient developed diabetes

Welin S et al. Cancer 2011

Agent (s)

Target (s) N Tumour ORR Outcomes Comments

Bevacizumab +

octreotide VEGF 22 Carcinoid 18% 16.5 mo (PFS) -

Sunitinib VEGFR,

PDGFR, RET,

FLT3

41

66

Carcinoid

PNETs

2%

17%

10.5 mo (TTP)

7.7 mo (TTP)

-

Sorafenib VEGFR, PDGF,

Raf

51

42

Carcinoid

PNETs

7%

17%

7.8 mo (PFS)

11.9 mo (PFS)

-

Vatalanib

VEGFR, PDGFR 11 GEPNET 0% NR Ongoing

Pazopanib VEGFR,

PDGFR,

30

30

Carcinoid

PNET

-

-

-

-

Ongoing

Motesanib VEGFR,

PDGFR, RET

44 LGNET - - Ongoing

Atiprimod

Unclear 25 LGNET 0% 76% at 6 mo (TTP) Ongoing

Bevacizumab +

2-methoxyestradiol VEGF 31 Carcinoid 0 Median PFS not

reached at 8.9 mo

Ongoing

Angiogenesis inhibitors

Adapted from Phan and Yao, Oncology 2008

RECIST-Defined Objective Tumor

Response

Sunitinib

(n=86)

Placebo

(n=85)

Best confirmed tumor response, n (%)

Complete response

Partial response

Stable disease/no response

Objective progression

Not evaluable

2 (2.3)

6 (7.0)

54 (62.8)

12 (14.0)

12 (14.0)

0

0

51 (60.0)

23 (27.1)

11 (12.9)

Objective response rate, % (95% CI)

Two-sided p-value for treatment

difference

9.3 (3.2, 15.4)

0.0066

0

Median (range) duration of response,

months

8.1 (1.0–15.0) –

Stable disease >6 months, n (%) 30 (34.9) 21 (24.7)

Tumor responses were assessed using RECIST 1.1

Objective response rate = patients with complete or partial tumor response

Agent (s)

Target (s) N Tumour ORR Outcomes Comments

Everolimus+Octreotide

(MDACC)

mTOR 30

30

Carcinoid

PNETs

17

27

14.6 mo (PFS)

11.6 mo (PFS)

-

Everolimus

Everolimus+octreotide

(RADIANT-1)

mTOR 115

45

PNET

PNET

8

4

9.3 mo (PFS)

12.9 mo (PFS)

Patients with

PD at entry

Tensirolimus mTOR 21

15

Carcinoid

PNETs

5

7

6.0 mo (TTP)

10.6 mo (TTP)

Patients with

PD at entry

Everolimus + bevacizumab mTOR, VEGF 36 NET - - Ongoing

Everolimus + pasireotide mTOR, SMS Phase

1

NET - - Ongoing

Everolimus +

temozolomide

mTOR, chemo Phase

1/2

NET - - Ongoing

mTOR inhibitors

Adapted from Phan and Yao, Oncology 2008

Oncolytic Viruses as Anticancer

Agents

Replicating viruses as anticancer agents has three

major advantages over conventional therapy

i. A virus can kill drug-resistant cancer stem cells

ii. A virus propagates inside tumor cells before

lysing them lytic cell death leads to release of

large amount of progeny viruses which can infect

neighboring cells

iii. Presence of immunogenic virus within a tumor

can alter the otherwise immunosuppressive

milieu in favor of an anti-tumor immune

response. Stimulate dendritic cells to produce

IFN-α and IL-12 with induction of cytotoxic T-cell

Oncolytic Viruses

RNA viruses New Castle disease virus

(Phase 1-12 trials) Seneca Valley virus

Reovirus

DNA-viruses Adenovirus

Herpes simplex (HSP-2)

Vaccinia virus

Genetically modified

viruses ONYX-015 H101

Structure of Adenovirus

The Life Cycle of Adenovirus

Transcription map of the Adenovirus Genome

The adenovirus genome is organized in early (red),

intermediate (blue) and late (green) transcriptional units

Adenovirus Gene Products and

Their Functions

The Biogenesis and Functions of Micro RNAs

(miRNAs) and Other Small Interfering RNAs (siRNAs)

Neuroendocrine cells support E1A expression after Ad[CgA-

E1A] transduction

Leja J et al. Clin Cancer Res 2007;13:2455-2462

©2007 by American Association for Cancer Research

Selective replication of Ad[CgA-E1A] in cells of

neuroendocrine origin



Specific cytotoxicity of Ad[CgA-E1A] on cells of

neuroendocrine origin



Ad[CgA-E1A] suppresses carcinoid tumor growth in vivo



Freshly isolated hepatocytes do not express CgA



CgA RNA is highly expressed in midgut carcinoid cells and

barely detectable in freshly isolated hepatocytes



Ad[CgA-E1A] provides weak E1A expression in hepatocytes



Schematic illustration of

recombinant adenoviruses

Leja J. et al. PLoS One. 2010; 5(1): e8916


Specific silencing

of luciferase

expression in liver

cells by miR122 in

vitro and in vivo


miR122-mediated

suppression of

adenoviral

protein

expression in

hepatic cells


Replication arrest

and reduced

cytolytic activity

in hepatic cells

for adenoviruses

carrying miR122

target sites

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811733/figure/pone-0008916-g004/


Lack of hepatotoxicity in mice injected

with Ad [CgA-E1A-miR122]



Stronger reduction of

cytolytic ability in

hepatic cells by double-

targeted than single-

targeted adenovirus


Leja J, et al. Gene

Therapy 2011

Leja J, et al. Gene

Therapy 2011

Virus Delivery

Co-administration of immunosuppressive

agents

Coat the virus with PEG

Hide the virus within T-cells with specificity

for a tumor-associated antigen

Incorporation of transgenes to increase cell

penetration

Local delivery

Combination with cytotoxic or targeted small

molecules

Nanoparticles

communication for

amplified tumor

targeting

von Maltzahn G, et al. Nature

Materials. Vol 10, july 2011

Amplified tumor therapy with

communicating NPs

von Maltzahn G, et al. Nature

Materials. Vol 10, july 2011

Novel nanosystems for targeting

and diagnostics

Nanotubes

Dispersed lc

Bicelles

Nanogels/microgels

Nanodiscs Coated microgels

Malmsten, M.,“Surfactants and Polymers in Drug Delivery”,

Marcel Dekker, 2003.

111In-octreotide “uptake”

125I-somatostatin “uptake”

1) Vaso-expressing BON cells

2) Vector control

pSecTag2A vector

Materials and Methods

IFN-a signaling

A

WT Vector

IFN-α

Vector IFN-α

Control Vector

IFN-α

Vector

IFN-α

Inhibition of angiogenesis

Adhesion and invasion Morphology

Results IFN-α sinaling

Cell

proliferation

Conclusions

There is an unmet need for more

effective antitumor therapy in

metastatic NETs

Cytotoxic viruses demonstrates

potential for cure in metastatic NET

Combinations of cytotoxic viruses and

cytotoxic agents as well as targeting

small molecules might be the future

therapy for NETs

Nanoparticles for diagnosis and

therapy seems promising for

“targeting” therapy

Thank you!

Centre of Excellence Endocrine

Tumors, Uppsala University

http://www.endocrinetumors.org/

E n d o c r i n e T u m o r s C e n t r e o f E x c e l l e n c e

endocrinetumors.org

Development of New Treatment Modalities Oncolytic Viruses and Nano

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