Oncolytic viruses (Danish Cancer Institute Nobel Seminar)

Oncolytic adenoviruses for Oncolytic adenoviruses for treatment of cancer in humans Akseli Hemminki, MD, PhD Specialist in Oncology and Radiotherapy Specialist in Oncology and Radiotherapy K. Albin Johansson Research Professor, Finnish Cancer Institute Cancer Gene Therapy Group Molecular Cancer Biology Program & Transplantation Laboratory & Haartman Institute & Finnish Inst. for Mol. Medicine University of Helsinki and Helsinki Univ. Central Hospital

Although many treatments are available, few diseases are available few diseases can be cured. CANCER > 1/2 of people alive today will get cancer • 1/3 of us will die of cancer • disseminated solid tumors cannot be cured with currently available treatments (but many cases can be treated) Novel treatments are needed! A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 2

How Far is Clinical Gene Therapy ? Phase I: Safety and toxicity ? Phase II: Any evidence of efficacy ? Phase II: Any evidence of efficacy ? Phase III: Proof of efficacy (randomization) A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 3

Mutation compensation Randomized trial: head and neck cancer ‐ Ad p53 + radiation vs radiation alone Ad‐p53 + radiation vs. radiation alone ‐ 67% vs. 24% CR (N= 82, P<0.01) ‐ Pan J Clin Oncol 2008 ‐ Gendicine® for sale in China ‐ More than 10 000 patients treated Promoter p53 gene p53 gene pA Press release 23 Jul 2008: Ad Press release 23 Jul of cells p53 (Advexin ) Infection 2008: Ad‐p53 (Advexin®) Infection of cells phase III SCCHN trial positive in US Cancer cells Normal cells with healthy p53 with p53 mutation Already approved by EMEA for treatment of Li‐Fraumeni syndrome Cell death, also sensitation to chemotherapy and radiation h h d di i No cell death A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 4

Prodrug converting enzymes (suicide gene therapy) with Ad‐TK (suicide gene therapy) with Ad TK and GCV Ad coding for Advantage vs. thymidine kinase TK mutation mutation (TK) compensation: bystander effect via gap junctions Non‐toxic pro drug pro‐drug GCV Activated Activated toxin Cell death A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 5

Adjuvant Ad‐TK/GCV CHALLENGE: even with bystander Randomized phase 2b for glioma (N=36). effect, canA. Mol Ther 2004 penetration Randomized phase 2b for glioma (N 36). Immonen A. Mol Ther 2004 p Immonen we get effective , g Patients resected and randomized: into established tumors ? 1. follow‐up +/‐ XRT (= standard) SOLUTIONS: locally amplifying systems 2. Standard + Ad‐TK into resection margins, ganciclovir for 14d 2 Standard + Ad TK into resection margins ganciclovir for 14d Median survival 39.0 wk. vs. 70.6 wk. (p<0.0095) No increase in toxicity Similar results in hepatocellular ca. adjuvant trial (Li Clin Cancer Res 2007) Si il lt i h t ll l dj t t i l (Li Cli C R 2007) Phase III results 30 Jul 2008 ( Ph lt J l (press release): l ) Cerepro® w/ & w/o temozolomide vs controls w/ & w/o temozolomide: 42 d improvement in median survival (310 d vs 268 d, p , p<0.032). ) Orphan drug status already Hgiven by9 A p r 2 0 0 9 | 6 A k s e l i e m m i n k i | 2 EMEA

Oncolytic viruses • Replication of virus p causes oncolytic death of cells • Normal cells‐ no replication A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 7

H101 (Oncorine®) phase III trial in advanced head and neck cancer d dh d d k H101 is almost identical to dl1520 (=ONYX‐015) i H101 now entering H101 descibed earlier in the US phase 3 trials in US Randomized phase III trial (N=105) H101 + cisplatin + 5‐FU vs. cisplatin + 5‐FU H101 + cisplatin + 5 FU vs cisplatin + 5 FU CR+PR = 79% vs. 38%, P<0.0001 Mild tox: flu‐like symptoms, injection site pain p More than 800 patients now enrolled H101 approved in China Yu Curr Cancer Drug Targets 2007 Yu Curr Cancer Drug Targets 2007 A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 8

Adenoviral Gene Therapy Strategies for Cancer f Safety has been good – over 15 000 pts treated with both repli‐ S f t h b d 15 000 t t t d ith b th li cation deficient and replication competent (oncolytic) viruses Recent randomized trials (N 5) have confirmed efficacy of even Recent randomized trials (N=5) have confirmed efficacy of even early generation approaches No patients w/ metastatic cancer cured: much work remains TUMOR PENETRATION NEEDS IMPROVEMENT Replication competent oncolytic viruses Transcriptional tumor targeting (activation only in tumor) Transductional tumor targeting (gene delivery only to tumor) d i l i ( d li l ) Armed oncolytic viruses Oncolytic replication is not enough to cure advanced tumors O l ti li ti i t ht d dt A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 9

Increasing infectivity of target cells: transductional targeting Non-targeted Targeted T t d adenovirus adenovirus Adenovirus receptor CAR High Low transduction Benign cell transduction Tumor associated receptor p Low High transduction Cancer cell transduction A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 1 0

Serotype chimerism for tumor targeting Ad5 107 SKOV3.ip1 cells intraperitoneally (i.p.) 10 days later 10 days later CAR 3x1x108 VP i.p. Follow survival Ad3 receptor 120 100 3x 1x108 VP i p 3x 1x10 VP i.p. 80 urvival Ad5/3 60 % Su with knob 40 domain 20 from Ad3 0 15 25 35 45 55 65 75 85 95 105 115 125 135 Kanerva Clin Cancer Res 2002 Day Kanerva Mol Ther 2003e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 1 1 Aks

Government approved compassionate use of oncolytic adenovirus (update 21 Apr 2009) oncolytic adenovirus (update 21 Apr 2009) • 115 patients and 202 treatments since Nov 07. 6 different viruses • All had metastatic solid tumors progressing after routine treatments (chemo, radiation, etc) • Side effects: gr. 1‐2 flu‐like symptoms, fever, fatigue, pain in all pt • SAE: 3 x gr 3 abd. pain, constipation (OvCa). 1 x gr 4 embolus SAE: 3 x gr 3 abd. pain, constipation (OvCa). 1 x gr 4 embolus (LungCa). 2x gr 3 venous thrombosis. • No treatment related deaths (compare to chemotherapy). • Objective benefit including tumor marker data ( biological Objective benefit including tumor marker data (“biological activity”): 69% all viruses, 75% best virus • Clinical benefit (imaging CR, PR, SD): 41% overall, 67% best virus • Benefit lost in a few months in most patients • Many patients benefited (even more) from 2nd ‐ 6th treatment A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 1 2

Findings possible only in pts: Mechanisms of anti‐ tumor efficacy of oncolytic adenovirus y y inflammation 3. Induction of 1. Killing of differentiated tumor cells 1 Killing of differentiated tumor cells cytotoxic T cells cytotoxic T‐cells against tumors 6 CD8+ 5 vitiligo 10E+8 4 3 2 0 17 41 48 2. Killing of tumor initiating ”stem” cells 4. Induction of specific immunity against tumor epitope (survivin) against tumor epitope (survivin) CD8+ cells 4 4 0 0 Before virus 0.46% 10 before virus0.46 0 3 wk after 4.09% after virus 4.09 03 10 3 Survivin specific C FL2-H 2 2 0 10 n 01 10 1 0 0 99.5 0 95.9 0 A k s 0 l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 1 3 10 e 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 Eriksson Mol Ther 2007, Bauerschmitz Cancer Res 2008 FL1-H FL1-H

Case: Systemic efficacy of Ad5/3‐Cox2L‐D24 in chemo refractory neuroblastoma chemo refractory neuroblastoma • Ad5/3‐Cox2L‐D24 replicates in cells overexpressing Cox2 and defective in the Rb/p16 pathway Previous Previous treatments: • 6 yr old boy, WHO 1 Vincristine + • Progressive disease in bone marrow, left kidney, lymph nodes. cis/carboplatin • Single oncolytic adenovirus treatment: i v intratumoral cis/carboplatin Single oncolytic adenovirus treatment: i.v., intratumoral. + etoposide + • Gr. 1 stomach pain, diarrhea, flu‐like symptoms, liver enzymes cyclophospham • 4 wk later: complete response in bone marrow, partial ide response in primary i i Doxorubicin + etoposide + iphosphamide; iphosphamide; Intensive chemo and autologous stem cell stem cell transplant; Oral 13‐cis‐retinoic acid A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 1 4

Ad5/3‐ Cox2L‐D24 in neuro‐ blastoma → CD56 staining (brown) for Oncolytic replication alone is usually tumor cells in bone marrow not enough to cure advanced tumors not enough to cure advanced tumors → Imaging of primary before and after treatment → Increase in cytotoxic T‐cells →→ Increase in virus neutralizing antibodies →→→ Extended presence of virus in blood 0 →→→→ Cox2 expression in 6540 tumor (reason for ( f 500 selectivity and efficacy) Pesonen Submitted 2008 A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 1 5

Higher efficacy with 2nd treatment • Metastatic pancreatic ca. WHO 2 • Prior gemcitabine and gemcitabine chemoradiation • Second round of treatment with Ad5‐24‐RGD (Bauerschmitz Cancer Res 2002) produced response A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 1 6

Higher efficacy with retreatment ? Adenovirus replication is very immunogenic Induction of cytotoxic T‐ cells and NK cells ? Second round of injection results in enhanced immune attack on tumor ? immune attack on tumor ? Cytotoxic Cytotoxic lymphocytes in pt treated with Ad5/3‐ with Ad5/3 Cox2L‐D24 Cytotoxic T‐lymphocytes approaching tumor cells (pic from Natl Geographic) A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 1 7

Improving antitumor immunity: oncolytic adenoviruses coding for GM‐CSF adenoviruses coding for GM CSF GM‐CSF • Tumor selectivity: Rb binding site deletion restricts replication to Rb/p16 mutant cells p /p G CS GM-CSF •GM‐CSF is a potent inducer of antitumor GM-CSF immunity (Dranoff G Immunol Rev 2002) • GM‐CSF under control of the endogenous Ad E3 gene expression system: expression starts 8h after infection ⇒ GM‐CSF expressed only in cells that allow replication of the virus p GM CSF GM-CSF GM-CSF • High expression at tumor, low systemic A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 1 8 exposure

GM‐CSF can enhance antigen presentation and induce NK and cytotoxic T cells and induce NK and cytotoxic T‐cells Tumor cells killed with 3 mechanisms: - Oncolytic effect of virus replication - NK cell mediated direct cell killing - DCs mediated tumor specific immunity NK NK CD8+ CD8+ CD8+ NK NK CD8+ CD8+ CD8+ NK CD8+ CD8+ NK NK Ca Ca GM-CSF Ca Ca Ca Ca C DC Ca Ca Ca GM-CSF A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 1 9

Treatments A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 0

Syrian hamsters cured of HapT1 tumors with Ad5D24 GMCSF: protection from with Ad5D24‐GMCSF: protection from HapT1 challenge N=5 ** *** *** N=5 * N=5 A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 1

Syrian hamsters cured of HapT1 tumors with Ad5D24‐GMCSF: no protection with Ad5D24 GMCSF: no protection from HaK challenge A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 2

Schematic of Oncolytic Virus Treatment 60 A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 3

Patient features: Ad5‐D24‐GMCSF (N=19) Single round of treatment Single round of treatment A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 4

Summary of side effects (work in progress): -All pt get gr 1-2 flu-like symptoms, fatigue, fever - O Gr 3 constipation One G ti ti (OvCa pt with similar previous episodes) - L b gr 1 2 li Lab: 1-2 liver enzyme elevations, hypokalemia, hyponatremia - One gr 3 hyponatremia A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 5

Efficacy and virus replication SD Overall efficacy (RECIST 1.1) single injection: * Indicates patients still CR 2/14 alive at the time of cutoff. li t th ti f t ff SD 5/14 A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 6 PD 7/14

Complete response in OvCa pt with small disease burden ith ll di b d Metastatic ovarian ca. 2002 M t t ti i 2002 Operation, adjuvant CEF x6, taxol+carbo x6, docetaxel, bevacizumab, topotecan, erlotinib, aromatase inhibitor Progressive disease, WHO 1 Single intraperitoneal treatment Complete response (CT, markers) for 9 mo A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 7

Rapid response upon re‐treatment with GM CSF coding oncolytic GM‐CSF coding oncolytic adenovirus • Peritoneally metastatic ovarian cancer since 2005. • 5 lines of chemo (paclitaxel‐carbo, liposomal doxorubicine, gemcitabine+carbo, gemcitabine, topotecan) • Progressive disease, WHO 1 • 52.5% tumor size reduction in 17 days after 2nd treatment y A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 8

Immunological response to GM‐CSF coding oncolytic adenovirus coding oncolytic adenovirus Adenovirus: T cell response p towards adenovirus components (Hexon, Penton, Fiber etc.) b ) Tumor: T cell response to tumor specific epitopes 6 CD8+ 5 10E+8 8 4 3 2 0 17 41 48 A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 2 9

Ad5(hexon)‐Specific Immunity 1000 10 4 10 4 0 0.21 0 21 0.21 0 21 Ad5Hex) 800 3 3 10 10 tter 600 CD3 3 FSC-H Size Scat Before B FL2-H H FL3-H H ramer (A 2 2 10 10 400 48.4 61.7 1 1 10 10 200 Tetr 0 0 0.085 99.7 0 10 10 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 FL3-H FL1-H FL1-H CD3 CD8 CD8 1000 10 4 10 4 0 2.72 2.72 Hex) 800 10 3 3 Tetramer (Ad5H 10 e Scatter After 600 CD3 FL2-H FSC-H FL3-H 2 2 10 10 400 47.8 Size 68.8 68 8 1 10 10 1 200 0 0.68 96.6 0 10 0 10 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 FL1-H FL3-H FL3 H FL1-H FL1 H CD3 CD8 CD8 Data confirmed in ELISPOT assay A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 3 0

Tumor‐specific Immunity (pentamer staining for survivin) o su ) Before virus: R73 3 weeks after virus: R73 104 104 0 0.46 0.46 0 4.09 4.09 Pentamer 103 103 ↓ ↓ All analyzed patients y p r‐specific P FL2-H FL2-H 102 102 Tumor 1 1 10 10 0 99.5 0 95.9 100 100 4 100 101 102 103 104 100 101 102 103 104 FL1-H FL1-H CD8 ↑ Patient Code: R73 ↑ Patient Code: R73 A k s e l i H e m m i n k i | 8 O c t 2 0 0 8 | 3 1

Summary 1. 1 Initial clinical proof‐of‐principle is available for many cancer gene Initial clinical proof of principle is available for many cancer gene therapy approaches 2. Safety has generally been excellent 3. Effective gene delivery continues to be key to efficacy ff d l b k ff 4. Oncolytic viruses amplify local dose and help in tumor penetration 5. Current regulations make translational work difficult 6. Patients can also be treated outside of clinical trials but this does not reduce the need for trials (may increase it) not reduce the need for trials (may increase it) 7. More than 50% of our patients have obtained benefit from treatment with oncolytic adenovirus 8. 8 Patient data has revealed central role of immune reponse in Patient data has revealed central role of immune reponse in patient benefit 9. Clinical trials are needed to confirm promising preliminary results and to make technology available to more patients and to make technology available to more patients A k s e l i H e m m i n k i | 2 9 A p r 2 0 0 9 | 3 2

Acknowledgements Akseli Hemminki Marko Ahonen Maria Rajecki Transgene Univ. Helsinki & HUCH: Monika Lusky Martti Ala‐Opas Sari Pesonen Iulia Diaconu Mari Raki Henrik Alfthan Laura Ahtiainen La ra Ahtiainen João Dias João Dias Tuuli Ranki T li Ranki Delsitech D li h Petri Bono Petri Bono Sophie Escutenaire Kilian Guse Marta Sloniecka Mika Koskinen Maija Harrela Mika Jalonen Pekka Häyry Vincenzo Cerullo Theresia Gutmann Merja Särkioja Krister Höckerstedt Anna Kanerva Otto Hemminki Matteo Ugolini Helena Isoniemi Institut Catala Kalevi Kairemo Camilla Ribacka Camilla Ribacka Lotta Kangasniemi Lotta Kangasniemi d Oncologica: d’Oncologica: Tuula Kiviluoto Minna Oksanen Anniina Koski Päivi Hannuksela Ramon Alemany Jorma Paavonen Elina Haavisto Sergio Lavilla‐Alonso Kikka Holm Ari Ristimäki Ilkka Liikanen Aila Karioja‐Kallio Univ. Glasgow Mirja Ruutu Laura Denby Jarmo Salo Petri Nokisalmi Eerika Karli Andy Baker Andy Baker Ulf Håkan Stenman Ulf‐Håkan Stenman Maija Tarkkanen The Patients Salk Institute Mikko Tenhunen Matt Weitzman Pekka Virkkunen Timo Joensuu Grant support: Grant support: Saila Eksymä‐ ERC Sillman EU FP6 APOTHERAPY Mauri Kouri EU FP6 THERADPOX Jenni Kylä‐Kause HUCH Research Funds (EVO) Leena Laasonen Pekka Simula Academy of Finland y Satu Nikander S Nik d Finnish Cancer Organizations Marina Rosliakova Biocentrum Helsinki Katri Silosuo Sigrid Juselius Foundation Arja Vilkko National Cancer Institute (USA) Heini Välijeesiö

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Oncolytic viruses (Danish Cancer Institute Nobel Seminar)

by Oncos Therapeutics on Mar 15, 2010

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Oncolytic viruses (Danish Cancer Institute Nobel Seminar) — Presentation Transcript