Gene therapy for 
                                  treatment of breast 
                                        cancer 
 ...
Overview of presentation



Why new treatments ?
Gene therapy of cancer: what is the clinical evidence ?
Gene therapy of c...
Cancer is not a beaten 
                        disease


 CANCER
 > 1/2 of people alive today will get cancer* 
 • 1/3 of...
Bert Vogelstein: 
                     Cancer 
                     Cancer
                  therapeutics 
               ...
Deletion mutant oncolytic
                            adenoviruses: ∆24
                              d    i      ∆24

   ...
How Far is Clinical Gene Therapy ?

                     Phase I: Safety and toxicity ?
                     Phase II: Any...
Mutation compensation

                                Randomized ph. III trial: head & neck ca.
                         ...
Prodrug converting enzymes
                            Randomized Phase III trial for glioma (ASPECT):
                   ...
Oncolytic viruses

• Replication of virus 
     p
causes oncolytic death 
of cells




                   • Normal cells‐ ...
H101 (Oncorine®) phase III trial in 
        advanced head and neck cancer 
         d     dh d d         k

H101 (≈dl1520...
Cancer Gene Therapy is maturing 
                           as a treatment approach
                                      ...
Our own experience with oncolytic 
 adenovirus (update 5 Feb 2010)
 adenovirus (update 5 Feb 2010)
  •   171 patients sinc...
Inclusion and exclusion criteria for 
                              oncolytic virus treatment
                            ...
Findings possible only in pts: Mechanisms of anti‐
                     tumor efficacy
                                  y...
Case: Systemic efficacy of Ad5/3‐Cox2L‐D24 in 
                          chemo refractory neuroblastoma
                  ...
Ad5/3‐
              Cox2L‐D24 
               in neuro‐
               blastoma
→ CD56 staining (brown) for 
  tumor cell...
Higher efficacy with a second round of 
                         treatment: role of immune response ?
                    ...
Improving antitumor immunity: oncolytic 
                              adenoviruses coding for GM‐CSF 
                   ...
GMCSF approach validated in first approved 
                     immunotherapy product 29 Apr 2010 
                     i...
GM‐CSF can enhance antigen presentation 
            and induce NK and cytotoxic T cells
            and induce NK and cyt...
Cerullo Cancer Res in press 2010




Treatments   A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     2 1
Syrian hamsters cured of HapT1 tumors 
                               with Ad5D24 GMCSF: protection from 
                ...
Syrian hamsters cured of HapT1 tumors 
                           with Ad5D24‐GMCSF: no protection 
                      ...
Efficacy Ad5‐D24‐GMCSF: Single round of treatment
                                   Neutralizing Antibody Titer
         ...
Systemic efficacy of Ad5‐D24‐GMCSF in 
                          injected and non injected tumors: virus 
                ...
Complete response in OvCa pt 
                     with small disease burden
                      ith    ll di      b d
 ...
Rapid response upon re‐treatment with 
                           GM CSF coding oncolytic
                           GM‐CS...
Long term survival in 1/3 of patients 
   treated with Ad5 D24 GMCSF
   treated with Ad5‐D24‐GMCSF




                   ...
Immunological response to GM‐CSF coding 
                        oncolytic adenovirus: against virus or tumor?
           ...
king of MHC I
                                                                                             Block
Ad5 (hexo...
king of MHC I
                                                                                              Block
Tumor‐sp...
Inflammation due to virus and/or GM‐
CSF can falsely increase tumor markers 
CSF can falsely increase tumor markers
      ...
Baseline                 3 months              6 months




                                                        Senzer...
PET‐CT more useful for oncolytic viruses ?
                                   Park Lancet Oncol 2008




     Senzer J Cli...
Improving transduction to 
                      improve oncolysis
                      i            l i

Coxsackie‐     ...
Increasing infectivity of target cells: 
       transductional targeting

       Non-targeted               Targeted
     ...
Serotype chimerism for tumor targeting 
                                                                                  ...
Ad5/3‐D24‐GMCSF = CGTG‐102




Fiber chimerism for enhanced 
transduction of cancer cells
CGTG‐102 (Ad5/3‐D24‐GMCSF): 76% ...
Cancer stem cell (CSC) hypothesis

       CSC                                     Committed progenitors cells:
           ...
Breast cancer stem cells can be 
killed with oncolytic adenoviruses
killed with oncolytic adenoviruses




  Eriksson Mol ...
Survival of                                         Overall survival
                                                     ...
Gene therapy trials in breast cancer



Only a few phase 1, phase 2 trials with small 
numbers of patients
            p
G...
Summary of breast cancer treatment with 
                 oncolytic adenoviruses (26 Apr 2010)
                 oncolytic ...
Complete response in breast cancer 
                       patient with low tumor load
                       patient with...
Overall survival of breast cancer patients 
            treated with oncolytic adenoviruses 
            treated with onco...
Summary                                           Overall survival of 
                                                   ...
Acknowledgements




Akseli Hemminki      Marko Ahonen         Suvi Parviainen      Institut Catala     Univ. Helsinki & H...
Upcoming SlideShare
Loading in...5
×

CGTG-102 oncolytic virus in breast cancer (IIR Conference May 5, 2010)

1,904

Published on

Research professor Akseli Hemminki from Oncos Therapeutics and Cancer Gene Therapy Group presents CGTG-102 oncolytic virus data in breast cancer

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,904
On Slideshare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
0
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide

CGTG-102 oncolytic virus in breast cancer (IIR Conference May 5, 2010)

  1. 1. Gene therapy for  treatment of breast  cancer  cancer 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. 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 Results in breast cancer A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     2
  3. 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       |     5  M a y   2 0 1 0    |     3
  4. 4. 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       |     5  M a y   2 0 1 0    |     4
  5. 5. 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       |     5  M a y   2 0 1 0    |     5
  6. 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       |     5  M a y   2 0 1 0    |     6
  7. 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       |     5  M a y   2 0 1 0    |     7
  8. 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       |     5  M a y   2 0 1 0    |     8
  9. 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       |     5  M a y   2 0 1 0    |     9
  10. 10. 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       |     5  M a y   2 0 1 0    |     1 0
  11. 11. Cancer Gene Therapy is maturing  as a treatment approach h Safety has been good – over 15 000 pts treated with both repli‐ cation deficient and replication competent (oncolytic) viruses  Recent  randomized trials (N=5) have confirmed efficacy of even  early generation approaches* early generation approaches* No patients w/ metastatic cancer cured: much work remains TUMOR PENETRATION NEEDS IMPROVEMENT Replication competent oncolytic viruses Replication competent oncolytic viruses Transcriptional tumor targeting (activation only in tumor) Transductional tumor targeting (gene delivery only to tumor) g g (g y y ) Armed oncolytic viruses * Immonen Mol Ther 2004, Li Clin Cancer Res 2007, Yu Curr Cancer Drug  Targets 2007, Pan J Clin Oncol 2008, Ylä‐Herttuala ESGCT 2008,  A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     1 1
  12. 12. Our own experience with oncolytic  adenovirus (update 5 Feb 2010) adenovirus (update 5 Feb 2010) • 171 patients since Nov 07. 8 different viruses • 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 ‐ 12th treatments Additive/synergistic benefits from 2 treatments  • Long term (>300 d) survival in 50% with best virus A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     1 2
  13. 13. Inclusion and exclusion criteria for  oncolytic virus treatment oncolytic virus treatment Inclusion criteria  Exclusion criteria Solid tumor confirmed brain met. or glioma Refractory disease = failed  Refractory disease = failed organ transplant, HIV g p , treatments for which there is  severe cardiovascular, metabolic  strong scientific evidence* or pulmonary disease Good performance status: WHO  0‐ Elevated serum bilirubin Elevated serum bilirubin 2. (WHO 3‐4 safe but less efficacy) Serum AST or ALT > 3 x normal Written informed consent  Written informed consent Thrombocytes  < 75.   y * In most cases this means 1st line chemotherapy for metastatic  disease, and in some cases several lines of chemotherapy (eg.  di di l li f h th ( breast, ovarian and colorectal cancer) In practice, the median number of prior chemo regimens is 3 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     1 3
  14. 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       |     5  M a y   2 0 1 0    |     1 4 Eriksson Mol Ther 2007, Bauerschmitz Cancer Res 2008
  15. 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       |     5  M a y   2 0 1 0    |     1 5
  16. 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|     1 6 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    Pesonen Acta Oncol 2010
  17. 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       |     5  M a y   2 0 1 0    |     1 7 Pesonen in preparation
  18. 18. Improving antitumor immunity: oncolytic  adenoviruses coding for GM‐CSF  adenoviruses coding for GM CSF Cerullo Mol Ther ASGT suppl 2009 GM‐CSF • 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 in press 2010 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     1 8
  19. 19. GMCSF approach validated in first approved  immunotherapy product 29 Apr 2010  immunotherapy product 29 Apr 2010 Provenge (Sipuleucel‐T) Hormone  Hormone refactory prostate  cancer Collection of  Collection of white blood cells Gene therapy w/  PAP & GMCSF to  activate antigen  presenting cells Return cells into  patient ti t First product  using active  immunotherapy PAP = prostatic acid  phosphatase  GMCSF = granulocyte  macrophage colony  stimulating factor i l i f A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     1 9 www.provenge.com
  20. 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       |     5  M a y   2 0 1 0    |     2 0
  21. 21. Cerullo Cancer Res in press 2010 Treatments A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     2 1
  22. 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       |     5  M a y   2 0 1 0    |     2 2
  23. 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       |     5  M a y   2 0 1 0    |     2 3 Cerullo Cancer Res in press 2010
  24. 24. Efficacy Ad5‐D24‐GMCSF: Single round of treatment Neutralizing Antibody Titer g y Virus Load in Serum Response p Patient Dosea Primary Week post-treatment Days post-treatment code (VP) Tumor RECISTa 0 1 2 4 0 1 2 3-7 8-12 21-40 Density/o Marker Survival ther C3 8x109 Jejunum ca 0 1024 16834 0 0 <500 <500 0 MR 120 M3 1 1010 1x10 HCC 0 16384 4096 0 0 4896 0 0 0 SD (+5.2%) ( 5 2%) 548b O12 3.6x1010 Ovarian ca 0 16384 16384 0 0 0 0 0 SD (+7.7.%) SD 106 O14 1x1011 Ovarian ca 64 64 0 0 0 <500 0 0 CR (-100%) CR 528b G15 1x1011 Gastric ca 1024 16384 16384 0 0 565 <500 0 0 -4.6% 308b K18 2x1011 NSCLC 16384 16384 16384 0 <500 0 0 856 PD (+15%) 59 T19 2x1011 Thyroid ca 0 16384 0 765 <500 <500 0 0 SD (-8.9%) MR 490b U89 2x1011 Renal ca 64 16384 0 0 0 PD (+13%) 144 S100 2x1011 Leiomyosar 0 0 16384 0 <500 <500 PD (+39%) 121 c S108 2x1011 Synovial 0 0 256 0 <500 <500 0 PD (+59%) 74 sarc M50 2.5x1011 Mesothelio 256 16384 0 0 <500 0 SD (-5.7%) 403b ma R8 3x1011 Breast ca 64 16384 0 <500 <500 0 CR (-100%) PR 447b M32 3x1011 Mesothelio 0 256 16384 0 0 0 0 PDc 125 ma X49 3x1011 Cervical ca 16 4096 1024 0 4290 1211 PD (+55%) -27% 92 I52 3x1011 Melanoma 0 256 256 0 576 PD (+25%) 112 I78 3x1011 Choroideal 0 64 0 44876 <500 63 mel C58 4x1011 Colon ca 256 16384 16384 0 1978 4236 PD (+37%) 118 R73 4x1011 Breast ca 0 256 1024 0 <500 25787 SD (-3.6%) 245b O88 4 1011 4x10 Ovarian O i ca 0 1024 0 <500 yesd PR 126 O9e 2x1011 Ovarian ca 16384 16384 0 2133f MR (-20%) 142 Overall efficacy (radiology) Summary of side effects - CR 2/16 - All pts: gr 1-2 flu-like symptoms, fatigue, fever - MR 1/16 - One gr 3 ileus (OvCa pt w similar previous episodes) - SD 5/16 Cerullo Cancer Res in press 2010 - Lab: gr 1-2 AST/ALT, hypo-K+, m i n k i       |  hypo-Na+   |     2 4 A k s e l i   H e m gr 1-3   5  M a y   2 0 1 0 - PD 8/16
  25. 25. 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       |     5  M a y   2 0 1 0    |     2 5 Cerullo Cancer Res in press 2010
  26. 26. 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       |     5  M a y   2 0 1 0    |     2 6
  27. 27. 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       |     5  M a y   2 0 1 0    |     2 7 Cerullo Cancer Res in press 2010
  28. 28. 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       |     5  M a y   2 0 1 0    |     2 8 Cerullo Cancer Res in press 2010
  29. 29. Immunological response to GM‐CSF coding  oncolytic adenovirus: against virus or tumor? oncolytic adenovirus: against virus or tumor? 3 h before CT guided injection (3ml       10 min after 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       |     5  M a y   2 0 1 0    |     2 9
  30. 30. king of MHC I Block Ad5 (hexon) Specific  Immunity Cerullo Cancer Res in press 2010 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     3 0
  31. 31. king of MHC I Block Tumor‐specific  Immunity y (Survivin) Cerullo Cancer Res in press 2010 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     3 1
  32. 32. Inflammation due to virus and/or GM‐ CSF can falsely increase tumor markers  CSF can falsely increase tumor markers and enlarge tumors  Virus replication  • 59 old man with esophageal cancer  59 old man with esophageal cancer activates tumor  cell metabolism • Prior chemo: oxaliplatin+capesitabine,  oxaliplatin, docetaxel, irinotecan‐ paclitaxel, cyklo‐doxo‐cisplatin, oxali‐ irino‐cetuximab, capecitabine • Progressive disease WHO 1 • Intratumoral and i.v. virus injection Necrosis A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     3 2
  33. 33. Baseline                 3 months              6 months Senzer J Clin Oncol 2009 Effects of  Effects of oncolytic inflammation  inflammation on tumor size Reid Cancer Res 2002 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     3 3
  34. 34. PET‐CT more useful for oncolytic viruses ? Park Lancet Oncol 2008 Senzer J Clin Oncol 2009 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     3 4
  35. 35. 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       |     5  M a y   2 0 1 0    |     3 5
  36. 36. 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       |     5  M a y   2 0 1 0    |     3 6
  37. 37. 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 2002k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     3 7 A
  38. 38. Ad5/3‐D24‐GMCSF = CGTG‐102 Fiber chimerism for enhanced  transduction of cancer cells CGTG‐102 (Ad5/3‐D24‐GMCSF): 76%  NK Replication  in cells mutant in Rb‐p16  clinical benefit in advanced ca. pts  clinical benefit in advanced ca pts pathy NK NK CD8+ CD8+ CD8+ CD8+ NK CD8+ (Koski et al submitted 2010)  Includes most human cancers NK CD8+ CD8+ CD8+ 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       |     5  M a y   2 0 1 0    |     3 8
  39. 39. 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       |     5  M a y   2 0 1 0    |     3 9
  40. 40. 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       |     5  M a y   2 0 1 0    |     4 0
  41. 41. 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       |     5  M a y   2 0 1 0    |     4 1
  42. 42. Gene therapy trials in breast cancer Only a few phase 1, phase 2 trials with small  numbers of patients p Good safety,  Evidence of biological effects Evidence of biological effects Efficacy usually not studied A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     4 2
  43. 43. Summary of breast cancer treatment with  oncolytic adenoviruses (26 Apr 2010) oncolytic adenoviruses (26 Apr 2010) Patient No. treatments Safety Radiology Markers • Overall any benefit Overall any benefit  1 R8 6 Gr. 1-2 AE only CR PR 11/16 (69%) MR 2 3 R10 R34 2 2 Gr. 1-2 AE only Gr. 1-2 AE only PD • Imaging 4 5 R39 R42 1 1 Gr. 1-2 AE only Gr. 1-2 AE only MR MR – CR 1/9 6 R55 2 Gr. 1-2 AE only PD. Density PD – SD 2/9 response 7 R73 6 Gr. 1-2 AE only SD – other response: other response:  8 R77 1 Gr. 1-2 AE only 2/9 PD 9 10 R85 R161 1 2 Gr. 1-2 AE only Gr. 1-2 AE only – PD 6/9 11 12 R170 1 0 R172 3 1 Gr. 1-2 AE l G 1 2 A only Gr. 1-2 AE only PD • T Tumor markers k 13 R184 5 Gr. 1-2 AE only PD. response Effusion – PR 1/13 14 R191 3 Gr. Gr 1-2 AE only PD SD – MR 5/13 / 15 16 R195 R196 3 3 Gr. 1-2 AE only Gr. 1-2 AE only PD PD PD – SD 3/13 17 R201 4 Gr. 1-2 AE only SD SD – PD 4/13 18 R203 3 Gr. 1-2 AE only SD MR 19 R223 1 Gr. 1-2 AE only MR 20 R247 2 Gr. 1-2 AE only 21 R248 3 Gr. 1-2 AE only A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     4 3
  44. 44. Complete response in breast cancer  patient with low tumor load patient with low tumor load • 60 yr woman. WHO 2 • Progressing after 7 lines of chemotherapy • 3x10e11 VP of Ad5‐D24‐GMCSF intraperitoneally and intrapleurally • Complete response  for 26 mo (ongoing). Disappearance of pleural effusion.  • Persistent ascites. Tumor markers not zero  Cerullo Cancer  Res in press  Res in press 2010 A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     4 4
  45. 45. Overall survival of breast cancer patients  treated with oncolytic adenoviruses  treated with oncolytic adenoviruses (26.4.2010) All breast cancer  All b t patients treated  with oncolytic  with oncolytic Overall survival adenoviruses 50% survival = 142 days All patients were  p Survival at 200 days = 43% Survival at 600 days = 30% chemo refractory  N= 20 and progressing  at treatment tt t t Criteria: death  due to any cause due to any cause Censoring: alive  at last follow up at last follow‐up A k s e l i   H e m m i n k i       |     5  M a y   2 0 1 0    |     4 5
  46. 46. Summary Overall survival of  breast ca patients  treated with  treated with oncolytic Ad 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% with our best virus CGTG‐102 (N=110) Clinical benefit 76% with our best virus CGTG 102 (N=110) 50% overall survival at 300d with CGTG‐102 Earlier treatment and smaller tumor load increase benefits CGTG‐102 now being tested in clinical trial 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       |     5  M a y   2 0 1 0    |     4 6
  47. 47. 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

×