Development of New Treatment Modalities Oncolytic Viruses and Nanotechnique By Professor Kjell Öberg, M.D., Ph.D. Dept. of Endocrine Oncology, University Hospital, Uppsala, Sweden Nashville Oct. 2011
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: Irradiation Somatostatin analogs α-interferon m-tor inhibitors VEGF R inhibitors Other TKI s External (bone, brain-mets) Tumor targeted, radioactive therapy (MIBG, Y 90 -DOTATOC, Lu 177 -DOTATATE)
177 Lu-DOTA-octreotate therapy The Uppsala experience 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) 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
Chemotherapy
Capecitabin plus Temozolomide in Pancreatic Endocrine Tumors N=33 Capecitabin 750 mg/m 2 x 2 Daily 1-14 Temozolomide 200 mg/m 2 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 Median OS Toxicity (Grade 3-4) 6 mo (95%) CI 4-14 mo) 22 mo (95% CI 8-27 mo) 1 Grade 3 hematol.tox 1 Grade 3 liver tox 1 patient developed diabetes Welin S et al. Cancer 2011
Adapted from Phan and Yao, Oncology 2008 Angiogenesis inhibitors Agent (s) Target (s) N Tumour ORR Outcomes Comments Bevacizumab + octreotide Sunitinib Sorafenib VEGF 22 Carcinoid 18% 16.5 mo (PFS) - VEGFR, PDGFR, RET, FLT3 VEGFR, PDGF, Raf 41 66 51 42 Carcinoid PNETs Carcinoid PNETs 2% 17% 7% 17% 10.5 mo (TTP) 7.7 mo (TTP) 7.8 mo (PFS) 11.9 mo (PFS) - - Vatalanib VEGFR, PDGFR 11 GEPNET 0% NR Ongoing Pazopanib Motesanib VEGFR, PDGFR, VEGFR, PDGFR, RET 30 30 Carcinoid PNET - - - - Ongoing 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
RECIST-Defined Objective Tumor Response Best confirmed tumor response, n (%) Complete response Partial response Stable disease/no response Objective progression Not evaluable Objective response rate, % (95% CI) Two-sided p-value for treatment difference Sunitinib (n=86) 2 (2.3) 6 (7.0) 54 (62.8) 12 (14.0) 12 (14.0) 9.3 (3.2, 15.4) 0.0066 Placebo (n=85) 0 0 51 (60.0) 23 (27.1) 11 (12.9) 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
mtor inhibitors 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 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 (Phase 1-12 trials) DNA-viruses Genetically modified viruses New Castle disease virus Seneca Valley virus Reovirus Adenovirus Herpes simplex (HSP-2) Vaccinia virus 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 Leja J et al. Clin Cancer Res 2007;13:2455-2462 2007 by American Association for Cancer Research
Specific cytotoxicity of Ad[CgA-E1A] on cells of neuroendocrine origin Leja J et al. Clin Cancer Res 2007;13:2455-2462 2007 by American Association for Cancer Research
Ad[CgA-E1A] suppresses carcinoid tumor growth in vivo Leja J et al. Clin Cancer Res 2007;13:2455-2462 2007 by American Association for Cancer Research
Freshly isolated hepatocytes do not express CgA Leja J et al. Clin Cancer Res 2007;13:2455-2462 2007 by American Association for Cancer Research
CgA RNA is highly expressed in midgut carcinoid cells and barely detectable in freshly isolated hepatocytes Leja J et al. Clin Cancer Res 2007;13:2455-2462 2007 by American Association for Cancer Research
Ad[CgA-E1A] provides weak E1A expression in hepatocytes Leja J et al. Clin Cancer Res 2007;13:2455-2462 2007 by American Association for Cancer Research
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 Leja J. et al. PLoS One. 2010; 5(1): e8916
mir122-mediated suppression of adenoviral protein expression in hepatic cells Leja J. et al. PLoS One. 2010; 5(1): e8916
Replication arrest and reduced cytolytic activity in hepatic cells for adenoviruses carrying mir122 target sites Leja J. et al. PLoS One. 2010; 5(1): e8916
Lack of hepatotoxicity in mice injected with Ad [CgA-E1A-miR122] Leja J. et al. PLoS One. 2010; 5(1): e8916
Stronger reduction of cytolytic ability in hepatic cells by doubletargeted than singletargeted adenovirus Leja J. et al. PLoS One. 2010; 5(1): e8916
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 Bicelles Dispersed lc Nanogels/microgels Nanodiscs Coated microgels Malmsten, M., Surfactants and Polymers in Drug Delivery, Marcel Dekker, 2003.
111In-octreotide uptake 125I-somatostatin uptake
Materials and Methods psectag2a vector 1) Vaso-expressing BON cells 2) Vector control
IFN-α sinaling Results A IFN-a signaling Adhesion and invasion Morphology WT Vector Cell proliferation IFN-α Inhibition of angiogenesis Control Vector Vector IFN-α IFN-α Vector IFN-α
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/ C e n t r e o f E x c e l l e n c e E n d o c r i n e T u m o r s endocrinetumors.org