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Professor Akseli Hemminki public presentation on oncolytic viruses (May 25, 2010)

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Research Professor Akseli Hemminki's presentation on oncolytic viruses for general public

Research Professor Akseli Hemminki's presentation on oncolytic viruses for general public

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  • 1. Syövän uuden geenihoidot  ‐ valoa tunnelin päässä [Gene therapy for cancer] [G th f ] Akseli Hemminki, MD, PhD Specialist in Oncology  Specialist in Oncology K. Albin Johansson Research Professor,  Finnish Cancer Institute Cancer Gene Therapy Group Molecular Cancer Biology Program &  Transplantation Laboratory &  Haartman Institute & FIMM University of Helsinki and  Disclaimer: AH is co‐founder and shareholder of  Disclaimer AH is co founder and shareholder of Oncos Therapeutics Inc., a company founded for  Helsinki Univ. Central Hospital facilitating clinical trials with oncolytic viruses
  • 2. Overview of presentation Why new treatments ? Gene therapy of cancer: what is the clinical evidence ? Gene therapy of cancer: what is the clinical evidence ? Oncolytic adenoviruses in our own patients Importance of immune response in determining  I t fi i d t i i efficacy: the next generation of oncolytic agents Tumor targeting: the next generation of oncolytic  agents Questions A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    2
  • 3. Cancer is not a beaten  disease CANCER > 1/2 of people alive today will get cancer*  • 1/3 of us will die of cancer • few disseminated solid tumors can be cured with  currently available treatments Novel treatments are needed! * Jemal CA Cancer J Clin 2005 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3
  • 4. Human molecular biology  in a nutshell Most normal and pathological events (diseases) are controlled  by proteins Proteins are coded by genes P t i d db The nucleus of all human cells contain all genes (ca. 30 000),  but expression is different in each cell but expression is different in each cell Expression cassette: promoter – gene – polyA signal Expression of genes ‐> expression of proteins ‐> phenotype  p g p p p yp and function  Virology in a nutshell:  ¬ Viruses are not cells, they use human cells for  reproduction ¬ Viruses reproduce by delivering their own genes into Viruses reproduce by delivering their own genes into  human cells A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    4
  • 5. Gene therapy is often protein therapy Vehicle for gene delivery = vector Gene that codes for  ‐ Lack of enzyme causes disease: Lack of enzyme causes disease:  missing or desired  missing or desired hereditary diseases, eg.  protein hemophilias, immune deficiencies Promoter Gene pA ‐ Disease can be  Promoter and poly‐A signal  treated with local  needed for protein production needed for protein production protein  Protein  production:  production in  cardiovascular  di l or near target  disease, cancer treats disease A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    5
  • 6. 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) N= 1579 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    6
  • 7. Mutation compensation Randomized ph. III trial: head & neck ca. ‐ 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 Infection of cells Infection of cells Normal cells Cancer cells Press release 23 Jul 2008: Ad‐p53 (Advexin®) with p53 mutation with healthy p53  phase III SCCHN trial positive in US: not  approved by FDA 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 7  M a y   2 0 1 0    |    7
  • 8. Prodrug converting enzymes Randomized Phase III trial for glioma (ASPECT): • Ad-TK + standard care vs. standard care: 1.43 HR (p=0.02) (p ) Ad coding for  Ad di f • 40d increase in median survival thymidine TK • More temozolomide use in control group due to kinase (TK) non blinded non-blinded gene therapy-> dilution of results therapy > • EMEA did not approve because non-standard end-point (time to re-intervention or death) o to c p od ug Non‐toxic prodrug Advantage vs.  Ad t = ganciclovir mutation  compensation:  bystander  effect via gap  Activated  Activated junctions CHALLENGE: even with bystander toxin Cell death effect, can we get effective penetration into established tumors ? SOLUTIONS: locally amplifying systems A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    8
  • 9. 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 7  M a y   2 0 1 0    |    9
  • 10. Short history of oncolytic viruses 1896. 1st report of response to oncolytic virus ( influenza Dock Am J Med 1896. 1st report of response to oncolytic virus (”influenza” Dock Am J Med  Sci 1904) 1940s. 1st systematic trials with oncolytic viruses (”Egypt 101”, Hoster  Cancer Res 1949) 1950s. Adenovirus used for treatment of cervical cancer patients (Smith  Cancer 1956) ¬ Various serotypes, intratumoral, intravenous and intra‐arterial delivery ¬ Poorly characterized preparations: titers unknown ¬ Treatment with and without immune suppression ¬ Good safety, similar side effects to modern trials ¬ Frequent responses ¬ Approach was abandoned: relapses, advent of chemotherapeutics 1960s & 1970s. Rational development of oncolytic viruses in test animals,  further trials (Asada Cancer 1974) f th t i l (A d C 1974) 1991 & 1996. Utilization of molecular features for making viruses selective  for tumor cells (Martuza Science 1991, Bischoff Science 1996) 2004. First phase III trial with oncolytic virus completed (”H101”, Yu Curr  2004 First phase III trial with oncolytic virus completed (”H101” Yu Curr Cancer Drug Targets 2007) A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    1 0
  • 11. H101 (Oncorine®) phase III trial in  advanced head and neck cancer  d dh d d k H101 (≈dl1520=ONYX‐015 descibed earlier in the US) Randomized phase III trial (N 105) Randomized phase III trial (N=105) H101 + cisplatin + 5‐FU vs. cisplatin + 5‐FU CR+PR = 79% vs. 38%, P<0.0001  CR PR 79% 38% P 0 0001 Mild tox: flu‐like symptoms, injection site pain More than 800 patients now enrolled H101 approved in China H101 approved in China Yu Curr Cancer Drug Targets 2007 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    1 1
  • 12. Personalized oncolytic adenovirus treatments  in the Advanced Therapy Access Program in the Advanced Therapy Access Program • 190 pts since Nov 2007. 9 different viruses (updated 14 May 2010) • All had metastatic solid tumors progressing after routine  All had metastatic solid tumors progressing after routine treatments (chemo, radiation, etc) • Written informed consent. Full GCP implemented. • Side effects: gr. 1‐2 flu‐like symptoms, fever, fatigue, pain in all pt Side effects: gr 1 2 flu like symptoms fever fatigue pain in all pt • SAE in < 5% (eg. pain, embolus, thrombosis, cholecystitis) • No treatment related deaths so far (compare to chemo, surgery) • Clinical benefit (imaging CR, PR, SD): 61% overall, 76% best virus • Some patients have benefited for > 2 years (= length of follow‐up) • Additive/synergistic benefits from 2nd ‐ 14th treatments Additive/synergistic benefits from 2 treatments  • Long term (>300 d) survival in 50% with best virus, best schedule A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    1 2
  • 13. Inclusion and exclusion criteria,  personalization of oncolytic virus treatment personalization of oncolytic virus treatment Inclusion criteria  c us o c te a Exclusion criteria c us o c te a Refractory solid tumor confirmed brain met. or glioma Failed treatments for which there is  organ transplant, HIV strong scientific evidence* severe comorbidity severe comorbidity Good performance status: WHO  0‐ Elevated serum bilirubin 2. (WHO 3‐4 safe but less efficacy) ( y) Serum AST or ALT > 3 x normal Written informed consent  Thrombocytes  < 75.   Personalization:  Personalization: Selection of virus (out of 9): existing preclinical data on capsids, promoters,  arming, pretreatment efficacy prediction Dose: tumor burden, comorbidities Route: ultrasound guided, CT‐guided, i.v. * In most cases this means 1st line chemotherapy  Virus sensitizers Vi iti for metastatic disease, and in some cases several  f t t ti di di lines of chemotherapy (eg. breast, ovarian and  l colorectal cancer) Seroswitching when intravenous efficacy sought In practice, the median number of prior chemo 1 3 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    regimens is 4 –> heavily pretreated
  • 14. Findings possible only in pts: Mechanisms of anti‐ tumor efficacy y inflammation 3. Induction of  cytotoxic T‐cells  1. Killing of differentiated tumor cells 1 Killing of differentiated tumor cells against tumors against tumors 6 CD8+ 5 vitiligo E+8 4 10E 3 2 0 17 41 48 2. Killing of tumor initiating ”stem” cells 4. Induction of specific immunity against tumor epitope (survivin) Cerullo Cancer Res in press 2010 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    1 4 Eriksson Mol Ther 2007, Bauerschmitz Cancer Res 2008
  • 15. 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 7  M a y   2 0 1 0    |    1 5
  • 16. Ad5/3‐ Cox2L‐D24  in neuro‐ blastoma → CD56 staining (brown) for  tumor cells in bone  marrow → Imaging of primary before  and after treatment Oncolytic replication alone is usually  Oncolytic replication alone is usually not enough to cure advanced tumors → 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 7  M a y   2 0 1 0    |    1 6 Pesonen Acta Oncol 2010
  • 17. Higher efficacy with a second round of  treatment: role of immune response ? treatment: role of immune response ? • 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       |     2 7  M a y   2 0 1 0    |    1 7 Pesonen in preparation
  • 18. Improving antitumor immunity: oncolytic  adenoviruses coding for GM‐CSF  adenoviruses coding for GM CSF Cerullo Cancer Res 2010 • GM‐CSF is the most potent inducer of anti‐ GM-CSF GM CSF anti G CS tumor immunity (Dranoff Immunol Rev 2002) GM-CSF • GM‐CSF in E3: expression starts at 8h ⇒ GM‐CSF expressed only in cells that allow replication of the virus • Hi h expression at tumor, l systemic High i low i GM CSF GM-CSF GM-CSF Cerullo Cancer Res 2010 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    1 8
  • 19. First immunotherapy product  approved 29 Apr 2010: Provenge  approved 29 Apr 2010: Provenge (Sipuleucel‐T) Hormone  Hormone refactory prostate  cancer Collection of  Collection of white blood cells Transduction w/  PAP & GMCSF to  activate antigen  presenting cells Return cells into  patient ti t First  immunotherapy  product ! product ! PAP = prostatic acid  phosphatase  GMCSF = granulocyte  macrophage colony  stimulating factor i l i f A k s e l i   H e m mwww.provenge.com |    1 9 i n k i       |     2 7  M a y   2 0 1 0   
  • 20. 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 = personalized NK Ca Ca cancer vaccine 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       |     2 7  M a y   2 0 1 0    |    2 0
  • 21. Cerullo Cancer Res in press 2010 Treatments A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    2 1
  • 22. Syrian hamsters cured of HapT1 tumors  with Ad5D24 GMCSF: protection from  with Ad5D24‐GMCSF: protection from HapT1 challenge N=5 ** *** *** N=5 * N=5 Cerullo Cancer Res in press 2010 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    2 2
  • 23. 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       |     2 7  M a y   2 0 1 0    |    2 3 Cerullo Cancer Res in press 2010
  • 24. Systemic efficacy of Ad5‐D24‐GMCSF in  injected and non injected tumors: virus  injected and non‐injected tumors: virus circulation, immune response • 60 yr mesothelioma patient, asbestos exposure 60 yr mesothelioma patient asbestos exposure • Prior treatment with cisplatin+pemetrexed • WHO 1 • Single intrapleural and i.v. injection  Single intrapleural and i v injection • More prominent reduction of non‐injected tumor than injected tumor A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    2 4 Cerullo Cancer Res in press 2010
  • 25. Complete response in OvCa pt  with small disease burden ith ll di b d Operation, adjuvant CEF x6, taxol+carbo x6, docetaxel,  O ti dj t CEF 6 t l b 6 d t l bevacizumab, topotecan, erlotinib, aromatase inhibitor Progressive disease, WHO 1 Single intraperitoneal treatment Complete response (CT, markers) for 9 mo  Cerullo Cancer  Cerullo Cancer Res in press  2010 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    2 5
  • 26. 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       |     2 7  M a y   2 0 1 0    |    2 6 Cerullo Cancer Res in press 2010
  • 27. Long term survival in 1/3 of patients  treated with Ad5 D24 GMCSF treated with Ad5‐D24‐GMCSF A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    2 7 Cerullo Cancer Res in press 2010
  • 28. Improving transduction to  improve oncolysis i l i Coxsackie‐ LOW CAR  ‐ LOW CAR ‐ adenovirus  receptor (CAR):  key to Ad entry key to Ad entry LOW GENE  DELIVERY ! CAR IS AN  CAR IS AN ADHESION  MOLECULE ‐ LOW  LOW EXPRESSION  IN TUMORS  A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    2 8
  • 29. 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 7  M a y   2 0 1 0    |    2 9
  • 30. Serotype chimerism for tumor targeting  120 Ad5 CAR 100 3x 1x108 VP i.p. Ad3 receptor 80 % Survival Negative  M1 60 40 Kanerva Mol Ther 2003 20 0 15 25 35 45 55 65 75 85 95 105 115 125 135 Day Kanerva Clin Cancer Res 2002 1,E+06 Biodistribution Ad3 receptor CAR 1,E+05 RLU / mg protein 1,E+04 1,E+03 Ad5/3  1,E+02 , with knob domain  1,E+01 * from Ad3 1,E+00 Kanerva Mol Ther 2002s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 0 Ak
  • 31. Cancer stem cell (CSC) hypothesis CSC Committed progenitors cells: Rapid replication PCa Limited lifespan Self-renewal: fibro CSC Slow replication other Unlimited lifespan inflam vasc Ca Ca Most ca. treatments select target Ca cells based on higher replication Ca Ca Ca Ca Ca stem cells may not actively y y replicate: not killed Ca C Ca Ca Differentiated Ca Ion transporters remove drugs ca. cells from cells: not killed CSC Ca Tumors T mors are mixed mi ed Clinical research may have missed populations of cells CSC specific agents A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 1
  • 32. Breast cancer stem cells can be  killed with oncolytic adenoviruses killed with oncolytic adenoviruses Eriksson Mol Ther 2007 Bauerschmitz Cancer Res 2008 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 2
  • 33. Ad5/3‐D24‐GMCSF = CGTG‐102 Fiber chimerism for enhanced  transduction of cancer cells CGTG‐102: 76% clinical  NK Replication  in cells mutant in Rb‐p16  pathy benefit in advanced ca. pts benefit in advanced ca pts NK NK CD8+ CD8+ CD8+ CD8+ NK CD8+ Includes most human cancers CD8+ CD8+ CD8+ NK NK GM‐CSF  can enhance antigen  NK Ca Ca presentation and induce NK and  GM-CSF Ca cytotoxic CD8+ T‐cells Ca Ca DC Ca Expressed under the control of E3 Ca Ca Starts at 8h Ca = personalized Expression coupled to virus  GM-CSF cancer vaccine replication p Koski  Submitted 2010 A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 3
  • 34. Survival of  Overall survival Serial treatment patients treated  patients treated 50% survival 320 days 50% survival = 320 days Survival at 300 days = 50% with CGTG‐102  N= 23 (Ad5/3 D24 (Ad5/3‐D24‐ GMCSF) Overall survival All treatments 50% survival = 157 days Survival at 300 days = 34% All patients were chemo refractory and  N= 144 progressing at treatment progressing at treatment Overall clinical benefit  in imaging = 76% Criteria: death due to any cause Censoring: alive at last follow up Censoring: alive at last follow‐up Median overall survival of chemotherapy  resistant patients 30‐115 days (eg.  Vigano Palliat Med 2000, Llobera Eur J of  Cancer 2000) C 2000) A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 4
  • 35. All CGTG‐102 treatments Summary Overall survival 50% survival=157d 50% survival=157d Survival @ 300d=34% N= 144 Clinical proof‐of‐principle available  for many ca. gene therapy approaches y g py pp Safety has generally been excellent Effective gene delivery continues to be key to efficacy Oncolytic viruses amplify and help in tumor penetration  Anti‐viral and anti‐tumoral immunity key in efficacy Clinical benefit 76% (radiology) with CGTG‐102 (N=110) Clinical benefit 76% (radiology) with CGTG 102 (N=110) Survival up to 500d (ongoing) 50% overall survival at 300d with CGTG‐102 (serial treatments) ( ) Earlier treatment and smaller tumor load increase benefits CGTG‐102 now being tested in clinical trial (Oncos Therapeutics) Clinical trials very expensive (3.5 mil€ for phase 1‐2 with 21 pts)  A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 5
  • 36. Acknowledgements Akseli Hemminki Marko Ahonen Suvi Parviainen Institut Catala Univ. Helsinki & HUCH: d’Oncologica: Petteri Arstila Sari Pesonen Karoliina Autio Maria Rajecki Petri Bono Laura Ahtiainen La ra Ahtiainen Iulia Diaconu I lia Diacon Tuuli Ranki T li Ranki Ramon Alemany a o e a y Pekka Häyry P kk Hä Sophie Escutenaire João Dias Noora Rouvinen U. Washington Krister Höckerstedt Vincenzo Cerullo Kilian Guse Andre Lieber Helena Isoniemi Kalevi Kairemo Anna Kanerva Theresia Gutmann Päivi Hannuksela Tuula Kiviluoto Minna Oksanen Minna Oksanen Otto Hemminki Otto Hemminki Kikka Holm Kikka Holm Transgene Monika Lusky Jorma Paavonen Jorma Paavonen Anniina Koski Eerika Karli Risto Renkonen Ilkka Liikanen U. Ottawa Ari Ristimäki Petri Nokisalmi John Bell Mirja Ruutu Jarmo Salo Kalle Saksela Kalle Saksela Ulf‐Håkan Stenman The Patients Mikko Tenhunen Pekka Virkkunen Timo Joensuu Tuomo Alanko Tuomo Alanko Pekka Simula Grant support: Grant support: Saila Eksymä‐Sillman Timo Ahopelto ERC Anu Koskela Charlotta Backman Academy of Finland Mauri Kouri Elina Haavisto ASCO Jenni Kylä‐Kause Lotta Kangasniemi Biocentrum Helsinki Leena Laasonen Leena Laasonen Biocenter Fi l d Bi t Finland Aila Karioja‐Kallio Satu Kauppinen Sigrid Juselius Foundation Kaarina Partanen Maija Salo University of Helsinki Marina Rosliakova Mikko Salo HUCH Research Funds (EVO) Antti Vuolanto
  • 37. Bert Vogelstein:  Cancer  Cancer therapeutics  after the cancer  ft th genome project  (ASCO 2009) ( ) Sequencing of tumor genomes revealed hundreds of mutations in each (Wood  S i ft l dh d d f t ti i h (W d Science 2007, Parsons Science 2008) Combination different in each tumor ‐> Each tumor is an individual  ‐> Each tumor would require a different combination of inhibitors ‐> For long term efficacy, each pt would have to be treated with hundreds of inhibitors ‐ > Impossible because of side effects > Impossible because of side effects All of these mutations seem to fall in 12 pathways (Jones Science 2008).   ‐ > Use pathway selective drugs (Vogelstein ASCO 2009) For example, p16/Rb pathway selective oncolytic virus http://cgap.nci.nih.gov/ A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 7
  • 38. Deletion mutant oncolytic adenoviruses: ∆24 d i ∆24 Fueyo Oncogene 2000 Heise Nature Med 2000 E2F • S-phase E2F Rb • Virus replication • normal cell • wt Ad Rb E1A & cell lysis E1A 24 bp deletion in Rb binding site of E1A • normal cell E2F Rb E2F Rb • No S phase entry S-phase • ∆24 • No virus replication • Replication in cells ∆24-E1A ∆24-E1A mutant in Rb-p16 Rb p16 pathway E2F E2F • cancer cell E2FE2F E2FE2F • S-phase • ∆24 • Virus replication • Includes all human ∆24 E1A ∆24-E1A ∆24-E1A ∆24 E1A & cell lysis cancers (Sherr Science 1996) A k s e l i   H e m m i n k i       |     2 7  M a y   2 0 1 0    |    3 8