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Onkolyyttiset virushoidot: 
                                     vaikutusmekanismit,,
                                  prekliiniset tutkimukset, 
                                    kokemukset potilailla,
                                    kokemukset potilailla,
                                   tulevaisuuden näkymät
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
Cancer is not a beaten 
                        disease


 CANCER
 > 1/2 of people alive today will get cancer* 
 • 1/3 of us will die of cancer
 • disseminated solid tumors cannot usually 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 3  F e b  2 0 1 0    |    2
Bert Vogelstein, ASCO 2009: Cancer 
            therapeutics after the cancer genome 
            therapeutics after the cancer genome
              project (http://cgap.nci.nih.gov/)
   Sequencing of complete genomes of tumors has revealed hundreds of 
   mutations in each tumor (Wood Science 2007, Parsons Science 2008)
   However, the combination of mutations is different in each tumor 
              ,
‐> Each tumor is an individual 
‐> Difficult to use small molecular inhibitors because a different 
   combination of inhibitors would have to be used for each tumor 
   combination of inhibitors would have to be used for each tumor
   (Wood Science 2007, Parsons Science 2008). 
‐> For long term efficacy, each patient would have to be treated with 
   hundreds of inhibitors (impossible because of side effects)
   hundreds of inhibitors (impossible because of side effects)
   However, all of these mutations seem to fall in 12 pathways (Jones 
   Science 2008).  
   Therefore, better to use pathway selective drugs (Vogelstein ASCO 
   Th f         b               h        l i d        (V l i ASCO
   2009). 
   For example, p16/Rb pathway selective oncolytic virus

                                                   A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    3
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 3  F e b  2 0 1 0    |    4
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 3  F e b  2 0 1 0    |    5
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
                                                 Cancer cells
          phase III SCCHN trial positive in US: not 
   Normal cells
                                                 with p53 mutation
          approved by FDA
   with healthy p53 


        Approved by EMEA for Li‐Fraumeni syndrome 
                              Cell death, also sensitation to 
        (orphan drug)
        ( h d )               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 3  F e b  2 0 1 0    |    6
Prodrug converting enzymes
             (suicide gene therapy) with Ad‐TK 
             (suicide gene therapy) with Ad TK
                          and GCV
Ad coding for 
                       TK                Advantage vs. 
thymidine kinase                         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 3  F e b  2 0 1 0    |    7
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) d )
Si il       lt i h t ll l Ph   Phase dj results 22 O t 2009 (ASPECT study):
                                       III   t lt i l (Li Cli C
                                               t        Oct          R 2007) t

                              • Cerepro vs standard care: 1.43 HR (p=0.02)
                              = positive primary end-point
                              • About 40d increase in median survival
                              • More temozolomide use in control group due
                                                                   g p
                              to non-blinded Cerepro -> dilution of results
                              • EMEA did not approve because non-standard
                              end point
                              end-point (time to re-intervention or death)
                                                 re intervention
                              • Appeal ongoing
                                                          A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    8
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 3  F e b  2 0 1 0    |    9
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 3  F e b  2 0 1 0    |    1 0
H101 (Oncorine®) phase III trial in 
         advanced head and neck cancer 
          d     dh d d         k

H101 is almost identical to dl1520 (=ONYX‐015) 
descibed earlier in the 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 3  F e b  2 0 1 0    |    1 1
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       |     2 3  F e b  2 0 1 0    |    1 2
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 ‐ 10th treatments
      Additive/synergistic benefits from 2           treatments 
  •   Long term (>500 d) survival in 48% with best virus




                                                A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    1 3
Inclusion and exclusion criteria for 
                              oncolytic virus treatment
                              oncolytic virus treatment

Inclusion criteria                                      Exclusion criteria
    Solid tumor (not leukemia or                            confirmed brain metastases or glioma
    lymphoma)                                               organ transplant, HIV
    Refractory disease = previously                         severe cardiovascular, metabolic or 
                                                                       d       l       b l
    treated with oncology treatments for                    pulmonary disease
    which there is strong scientific                        Other diseases that prevent oncolytic 
    evidence*                                               virus treatment
                                                             i t t         t
    Good performance status: WHO  0‐2.                      Elevated serum bilirubin
    (
    (WHO 3 is safe but less efficacy)
                                    y)                      Serum AST or ALT > 3 x upper limit of 
    Written informed consent                                normal
    No major organ function deficiencies                    Thrombocytes  < 75.  



* 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       |     2 3  F e b  2 0 1 0    |    1 4
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 3  F e b  2 0 1 0    |    1 5
Eriksson Mol Ther 2007, Bauerschmitz Cancer Res 2008
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 3  F e b  2 0 1 0    |    1 6
Ad5/3‐
              Cox2L‐D24 
               in neuro‐
               blastoma
→ CD56 staining (brown) for 
  tumor cells in bone 
  marrow

→ 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|    1 7
                                  A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0   
                                        Pesonen Acta Oncol 2010
Higher efficacy with a second round of 
                                       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       |     2 3  F e b  2 0 1 0    |    1 8
Pesonen in preparation
Higher efficacy with retreatment
                                         Adenovirus replication is 
                                         very immunogenic
                                         Second round of injection 
                                         results in enhanced 
                                         immune attack on tumor ?
                                         i          tt k t          ?
                                         Immunity against 
                                         adenovirus or also tumor ?
                                         adenovirus or also 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       |     2 3  F e b  2 0 1 0    |    1 9
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       |     2 3  F e b  2 0 1 0    |    2 0
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 3  F e b  2 0 1 0    |    2 1
Cerullo Cancer Res in press 2010




Treatments   A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    2 2
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 3  F e b  2 0 1 0    |    2 3
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 3  F e b  2 0 1 0    |    2 4
Cerullo Cancer Res in press 2010
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+,mgrk1-3   hypo-Na+   |    2 5
                                                                                                                    A k s e l i   H e m i n i       |   2 3  F e b  2 0 1 0
- PD 8/16
Efficacy of Ad5‐D24‐GMCSF in injected and 
                     non injected tumors: mesothelioma patient
                     non‐injected tumors: mesothelioma patient
                          •        60 yr old man, asbestos exposure
                          •        Prior treatment with cisplatin+pemetrexed
                                   Prior treatment with cisplatin+pemetrexed
                          •        WHO 1
                          •        Single intrapleural and i.v. injection 
                          •        More prominent reduction of non‐injected tumor than 
                                   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 3  F e b  2 0 1 0    |    2 6
Cerullo Cancer Res in press 2010
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 




Cerullo Cancer 
Cerullo Cancer
Res in press 
2010
                                                              A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    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       |     2 3  F e b  2 0 1 0    |    2 8
Cerullo Cancer Res in press 2010
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 3  F e b  2 0 1 0    |    2 9
   Cerullo Cancer Res in press 2010
Immunological response to GM‐CSF 
                                coding oncolytic adenovirus
                                coding oncolytic adenovirus
                                               Adenovirus: T cell response 
                                               towards adenovirus 
                                               towards adenovirus
                                               components (Hexon, Penton, 
                                               Fiber etc.) 
                                                         )
                                               Tumor: T cell response to 
                                               tumor specific epitopes
                                               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       |     2 3  F e b  2 0 1 0    |    3 0
CT guided injection displays 
              immunological response to adenovirus
              immunological response to adenovirus




3 h before oncolytic virus.     10 min after CT guided 
3 h before oncolytic virus. 10 min after CT guided
                                         injection (3 ml)

                                               A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    3 1
eceptor
                                                                                                 king of T‐Cell re
                                                                                             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       |     2 3  F e b  2 0 1 0    |    3 2
eceptor
                                                                                                  king of T‐Cell re
                                                                                              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       |     2 3  F e b  2 0 1 0    |    3 3
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       |     2 3  F e b  2 0 1 0    |    3 4
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       |     2 3  F e b  2 0 1 0    |    3 5
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       |     2 3  F e b  2 0 1 0    |    3 6
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 3  F e b  2 0 1 0    |    3 7
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 3  F e b  2 0 1 0    |    3 8
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 2002 s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    3 9
                                                                                                                Ak
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 3  F e b  2 0 1 0    |    4 0
Cancer stem cells can be killed with 
     oncolytic adenoviruses
     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 3  F e b  2 0 1 0    |    4 1
Ad5/3‐D24‐GMCSF



Fiber chimerism for enhanced 
transduction of cancer cells

Replication  in cells mutant in Rb‐p16               NK
                                                             NK
                                                                  CD8+
pathy                                                                         CD8+
                                                                             CD8+
                                                        NK                CD8+   CD8+
Includes most human cancers                                  NK
                                                                 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 3  F e b  2 0 1 0    |    4 2
Ad5/3‐D24‐GMCSF effective in vitro

MDA-MB-436               A549




 A549
                       As effective as wild type
                       GMCSF secretion verified
                       GMCSF secretion verified

                                Koski  Submitted 2010




                                     A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 3
Benefits of treatment (single injection 
                       of Ad5/3 D24 GMCSF)
                       of Ad5/3‐D24‐GMCSF)

Objective benefit in Computer Scans (RECIST 1.1):
Objective benefit in Computer Scans (RECIST 1 1):
     Minor Response (MR) 17% (best ‐15%)          Long term survival of 
     Stable Disease (SD) 50%
                                                             y
                                                  >250 days in circa 40%   
     Progressive Disease (PD) 33%
Clinical benefit (imaging): 67%
                                                  (ongoing)
Other benefits:
Other benefits:                                       Adverse events
                                                        d e se e e ts
     CR: ascites and pleural effusion           Monitored for 4 weeks
     CR: pleural effusion                       No grade 4‐5 events
     CR: non‐injected liver metastasis
     CR       i j    d li            i          One grade 3 cholecystitis
     1% reduction in injected tumor             Mild to moderate flu‐like 
     Injected tumor 6% smaller
       j                                        symptoms, fever, fatigue, 
                                                symptoms fever fatigue
Overall biological activity                     injection site pain common
(intent to treat population): 13/21= 62%        No elevations in cytokine 
                                                levels 
                                                l l
      Koski  Submitted 2010                          A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 4
Examples of Ad5/3‐D24‐GMCSF 
              nt
Before treatmen
       t                                        efficacy in patients




                        K75 NSCLC: CR in          O129 ovarian cancer:   I98 melanoma: - 39% (v/v)
                        p
                        pleural eff. & ascites   -17% (v/v)
                                                      (v/v)
                                                          )
              eatment
2 mo. after tre




                                                                            Koski  Submitted 2010    2 3  F e b  2 0 1 0    |    4 5
                                                                               Akseli Hemminki   |
Pretreatment prediction of CGTG‐102 
                                                     efficacy
                             2,5E+07
                              ,           V136                                                                       1,6E+05
                                                                                                                               K75
                                          Pleural effusion cells          ***                                                                                                       ***




                                                                                                        sion (RLU)
                                                                                                                     1,4E+05   Ascites cells
      ene expression (RLU)




                             2,0E+07
                                                                                                                     1,2E+05

                                                                                                                     1,0E+05




                                                                                             gene express
                             1,5E+07
                                                                                                                     8,0E+04

                             1,0E+07                                                                                 6,0E+04
Transge




                                                                                                                     4,0E+04
                                                                                                                     4 0E+04




                                                                                        Transg
                             5,0E+06
                                                                                                                     2,0E+04

                             0,0E+00                                                                                 0,0E+00

                                              Ad5luc1                 Ad5/3luc1                                                   Ad5luc1                                   Ad5/3luc1
                                                                                                                                                                               /
                                                                                                                                                                            Ad/3luc1
                                                                                                                                         ***p<0.005 against Ad5luc1

                                                           Pre‐treatments samples of malignant pleural effusion and ascites
                                                           Pre‐treatments samples of malignant pleural effusion and ascites
                                                                   Luciferase expression of cells infected with 5000 vp/cell
                                                           V136: SD in CT scan, liver metastasis disappeared
                                                           K75: CR in ascites formation 
                                                           K75: CR in ascites formation
                                       Koski  Submitted 2010                                                                             A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 6
Ad5/3‐D24‐GMCSF is able to kill 
                                        pleural effusion cells
                                        pleural effusion cells
                   200                                                                 250
                                  V136                                                              M137
                   180
                   160                                                                 200
                   140
   bility of (%)
               )




                   120                                                                 150




                                                                         ability (%)
                   100
                    80                                                                 100
                                                            ***




                                                                       Via
                    60
Viab




                    40                                                                 50                                                         ***
                    20
                     0                                                                   0

                         Uninfected      Ad5luc1         Ad5/3-d24-                          Uninfected    Ad5luc1                       Ad5/3-d24-
                           cells                          GMCSF                                cells                                      GMCSF
                                                                                                              ***p<0.005 against uninfected cells
                                                   Pre‐treatment samples of malignant pleural effusions
                                                   Pre‐treatment samples of malignant pleural effusions
                                                       Cells from sample infected with 100 vp/cell
                                                   V136: SD in CT scan, liver metastasis disappeared
                                                   M137: SD in CT scan, CR in pleural effusion formation
                                                   M137: SD in CT scan CR in pleural effusion formation
                           Koski  Submitted 2010                                                            A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 7
Higher amounts of virus at the tumor than 
                                                  in blood 
              8000
                                                                     6851
              7000               Serum
              6000               Ascites                                        Virus in ascites sample 
    r  (vp / ml)




              5000
                                                                                able to produce 
                                                                                 bl         d
                                                                                cytopathic effect in 70% 
              4000                                                              of wells in cell culture 
                                                                                (293 cells)
                                                                                (293 ll )
Titer




              3000

              2000
                                                                                Functional virus present
              1000                               <500
                                                                 0
                               0 NA                     NA
                   0
                              Day 0                1 Day         1 Week

                                               Patient (O82) had MR in tumor marker 
                                               levels during follow up


                       Koski  Submitted 2010                                           A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 8
Induction of anti‐adenoviral and anti‐
                             tumoral immunity in blood
                             tumoral immunity in blood
                                                                                                          ELISPOT- patient I80
                                                                                                          (had vitiligo)
Increase of CD8+ T lymphocytes after
         of CD8+ T lymphocytes
treatment in 10/14 patients




                                                                        an SFC per million  cells
                                                                                                    120
                                                                                                                                                                    Adenovirus
                         Average CD8+ cell count increases                                          100

                      1,60
                                                                                                    80
  CD cells x10e10/l




                      1,40                                                                          60
                      1,20                                                                          40
                      1,00                                N 10
                                                          N=10                                      20
           x




                                                                      Mea
                      0,80                                                                            0
                      0,60                                                                                     0               35
                      0,40                                                                                    Days (post‐treatment)
   D8+




                                                                 Mean SFC per million  cells
                      0,20
                                                                                                    60
                      0,00                                                                                                                                             Survivin
                             Pre-treatment   After treatment                                        50
                                                                                                    40
                                                                                                    30
Analysis of T cells specific for
         of T cells          for                                                                    20
adenovirus and tumor epitopes with                                                                  10
                                                                                                     0
interferon gamma ELISPOT                                                                                       0                35
                                                                                                              Days (post‐treatment)

                Koski  Submitted 2010                                                                          A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 9
Summary                                  Overall survival w/ CGTG‐102
                                                                       50% survival = 315d
                                                                   Survival at 200d = 75%
                                                                   Survival at 500d = 48%
                                                                                      N=25




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
Multiple injections more effective than single
Multiple injections more effective than single
Overall clinical benefit 76% in 110 treatments with our best 
virus CGTG‐102 (now being tested in a clinical trial)
48% overall survival at 500d with CGTG‐102
Earlier treatment and smaller tumor load increase benefits
Formal clinical trials are needed ! (€€€) 
Formal clinical trials are needed ! (€€€)
                                               A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    5 0

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Present and future of oncolytic virus therapies

  • 1. Onkolyyttiset virushoidot:  vaikutusmekanismit,, prekliiniset tutkimukset,  kokemukset potilailla, kokemukset potilailla, tulevaisuuden näkymät 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. Cancer is not a beaten  disease CANCER > 1/2 of people alive today will get cancer*  • 1/3 of us will die of cancer • disseminated solid tumors cannot usually 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 3  F e b  2 0 1 0    |    2
  • 3. Bert Vogelstein, ASCO 2009: Cancer  therapeutics after the cancer genome  therapeutics after the cancer genome project (http://cgap.nci.nih.gov/) Sequencing of complete genomes of tumors has revealed hundreds of  mutations in each tumor (Wood Science 2007, Parsons Science 2008) However, the combination of mutations is different in each tumor  , ‐> Each tumor is an individual  ‐> Difficult to use small molecular inhibitors because a different  combination of inhibitors would have to be used for each tumor  combination of inhibitors would have to be used for each tumor (Wood Science 2007, Parsons Science 2008).  ‐> For long term efficacy, each patient would have to be treated with  hundreds of inhibitors (impossible because of side effects) hundreds of inhibitors (impossible because of side effects) However, all of these mutations seem to fall in 12 pathways (Jones  Science 2008).   Therefore, better to use pathway selective drugs (Vogelstein ASCO  Th f b h l i d (V l i ASCO 2009).  For example, p16/Rb pathway selective oncolytic virus A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    3
  • 4. 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 3  F e b  2 0 1 0    |    4
  • 5. 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 3  F e b  2 0 1 0    |    5
  • 6. 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 Cancer cells phase III SCCHN trial positive in US: not  Normal cells with p53 mutation approved by FDA with healthy p53  Approved by EMEA for Li‐Fraumeni syndrome  Cell death, also sensitation to  (orphan drug) ( h d ) 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 3  F e b  2 0 1 0    |    6
  • 7. Prodrug converting enzymes (suicide gene therapy) with Ad‐TK  (suicide gene therapy) with Ad TK and GCV Ad coding for  TK Advantage vs.  thymidine kinase  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 3  F e b  2 0 1 0    |    7
  • 8. 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) d ) Si il lt i h t ll l Ph Phase dj results 22 O t 2009 (ASPECT study): III t lt i l (Li Cli C t Oct R 2007) t • Cerepro vs standard care: 1.43 HR (p=0.02) = positive primary end-point • About 40d increase in median survival • More temozolomide use in control group due g p to non-blinded Cerepro -> dilution of results • EMEA did not approve because non-standard end point end-point (time to re-intervention or death) re intervention • Appeal ongoing A k s e l i   H e m m i n k i       |     2 3  F e b  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 3  F e b  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 3  F e b  2 0 1 0    |    1 0
  • 11. H101 (Oncorine®) phase III trial in  advanced head and neck cancer  d dh d d k H101 is almost identical to dl1520 (=ONYX‐015)  descibed earlier in the 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 3  F e b  2 0 1 0    |    1 1
  • 12. 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       |     2 3  F e b  2 0 1 0    |    1 2
  • 13. 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 ‐ 10th treatments Additive/synergistic benefits from 2 treatments  • Long term (>500 d) survival in 48% with best virus A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    1 3
  • 14. Inclusion and exclusion criteria for  oncolytic virus treatment oncolytic virus treatment Inclusion criteria  Exclusion criteria Solid tumor (not leukemia or  confirmed brain metastases or glioma lymphoma) organ transplant, HIV Refractory disease = previously  severe cardiovascular, metabolic or  d l b l treated with oncology treatments for  pulmonary disease which there is strong scientific  Other diseases that prevent oncolytic  evidence* virus treatment i t t t Good performance status: WHO  0‐2.  Elevated serum bilirubin ( (WHO 3 is safe but less efficacy) y) Serum AST or ALT > 3 x upper limit of  Written informed consent  normal No major organ function deficiencies Thrombocytes  < 75.   * 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       |     2 3  F e b  2 0 1 0    |    1 4
  • 15. 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 3  F e b  2 0 1 0    |    1 5 Eriksson Mol Ther 2007, Bauerschmitz Cancer Res 2008
  • 16. 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 3  F e b  2 0 1 0    |    1 6
  • 17. Ad5/3‐ Cox2L‐D24  in neuro‐ blastoma → CD56 staining (brown) for  tumor cells in bone  marrow → 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|    1 7 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    Pesonen Acta Oncol 2010
  • 18. Higher efficacy with a second round of  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       |     2 3  F e b  2 0 1 0    |    1 8 Pesonen in preparation
  • 19. Higher efficacy with retreatment Adenovirus replication is  very immunogenic Second round of injection  results in enhanced  immune attack on tumor ? i tt k t ? Immunity against  adenovirus or also tumor ? adenovirus or also 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       |     2 3  F e b  2 0 1 0    |    1 9
  • 20. 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       |     2 3  F e b  2 0 1 0    |    2 0
  • 21. 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 3  F e b  2 0 1 0    |    2 1
  • 22. Cerullo Cancer Res in press 2010 Treatments A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    2 2
  • 23. 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 3  F e b  2 0 1 0    |    2 3
  • 24. 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 3  F e b  2 0 1 0    |    2 4 Cerullo Cancer Res in press 2010
  • 25. 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+,mgrk1-3   hypo-Na+   |    2 5 A k s e l i   H e m i n i       |   2 3  F e b  2 0 1 0 - PD 8/16
  • 26. Efficacy of Ad5‐D24‐GMCSF in injected and  non injected tumors: mesothelioma patient non‐injected tumors: mesothelioma patient • 60 yr old man, asbestos exposure • Prior treatment with cisplatin+pemetrexed Prior treatment with cisplatin+pemetrexed • WHO 1 • Single intrapleural and i.v. injection  • More prominent reduction of non‐injected tumor than  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 3  F e b  2 0 1 0    |    2 6 Cerullo Cancer Res in press 2010
  • 27. 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  Cerullo Cancer  Cerullo Cancer Res in press  2010 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    2 7
  • 28. 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 3  F e b  2 0 1 0    |    2 8 Cerullo Cancer Res in press 2010
  • 29. 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 3  F e b  2 0 1 0    |    2 9 Cerullo Cancer Res in press 2010
  • 30. Immunological response to GM‐CSF  coding oncolytic adenovirus coding oncolytic adenovirus Adenovirus: T cell response  towards adenovirus  towards adenovirus components (Hexon, Penton,  Fiber etc.)  ) Tumor: T cell response to  tumor specific epitopes 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       |     2 3  F e b  2 0 1 0    |    3 0
  • 31. CT guided injection displays  immunological response to adenovirus immunological response to adenovirus 3 h before oncolytic virus.     10 min after CT guided  3 h before oncolytic virus. 10 min after CT guided injection (3 ml) A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    3 1
  • 32. eceptor king of T‐Cell re 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       |     2 3  F e b  2 0 1 0    |    3 2
  • 33. eceptor king of T‐Cell re 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       |     2 3  F e b  2 0 1 0    |    3 3
  • 34. 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       |     2 3  F e b  2 0 1 0    |    3 4
  • 35. 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       |     2 3  F e b  2 0 1 0    |    3 5
  • 36. 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       |     2 3  F e b  2 0 1 0    |    3 6
  • 37. 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 3  F e b  2 0 1 0    |    3 7
  • 38. 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 3  F e b  2 0 1 0    |    3 8
  • 39. 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 2002 s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    3 9 Ak
  • 40. 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 3  F e b  2 0 1 0    |    4 0
  • 41. Cancer stem cells can be killed with  oncolytic adenoviruses 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 3  F e b  2 0 1 0    |    4 1
  • 42. Ad5/3‐D24‐GMCSF Fiber chimerism for enhanced  transduction of cancer cells Replication  in cells mutant in Rb‐p16  NK NK CD8+ pathy CD8+ CD8+ NK CD8+ CD8+ Includes most human cancers NK 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 3  F e b  2 0 1 0    |    4 2
  • 43. Ad5/3‐D24‐GMCSF effective in vitro MDA-MB-436 A549 A549 As effective as wild type GMCSF secretion verified GMCSF secretion verified Koski  Submitted 2010 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 3
  • 44. Benefits of treatment (single injection  of Ad5/3 D24 GMCSF) of Ad5/3‐D24‐GMCSF) Objective benefit in Computer Scans (RECIST 1.1): Objective benefit in Computer Scans (RECIST 1 1): Minor Response (MR) 17% (best ‐15%) Long term survival of  Stable Disease (SD) 50% y >250 days in circa 40%    Progressive Disease (PD) 33% Clinical benefit (imaging): 67% (ongoing) Other benefits: Other benefits: Adverse events d e se e e ts CR: ascites and pleural effusion Monitored for 4 weeks CR: pleural effusion  No grade 4‐5 events CR: non‐injected liver metastasis CR i j d li i One grade 3 cholecystitis 1% reduction in injected tumor Mild to moderate flu‐like  Injected tumor 6% smaller j symptoms, fever, fatigue,  symptoms fever fatigue Overall biological activity injection site pain common (intent to treat population): 13/21= 62% No elevations in cytokine  levels  l l Koski  Submitted 2010 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 4
  • 45. Examples of Ad5/3‐D24‐GMCSF  nt Before treatmen t efficacy in patients K75 NSCLC: CR in O129 ovarian cancer: I98 melanoma: - 39% (v/v) p pleural eff. & ascites -17% (v/v) (v/v) ) eatment 2 mo. after tre Koski  Submitted 2010    2 3  F e b  2 0 1 0    |    4 5 Akseli Hemminki   |
  • 46. Pretreatment prediction of CGTG‐102  efficacy 2,5E+07 , V136 1,6E+05 K75 Pleural effusion cells *** *** sion (RLU) 1,4E+05 Ascites cells ene expression (RLU) 2,0E+07 1,2E+05 1,0E+05 gene express 1,5E+07 8,0E+04 1,0E+07 6,0E+04 Transge 4,0E+04 4 0E+04 Transg 5,0E+06 2,0E+04 0,0E+00 0,0E+00 Ad5luc1 Ad5/3luc1 Ad5luc1 Ad5/3luc1 / Ad/3luc1 ***p<0.005 against Ad5luc1 Pre‐treatments samples of malignant pleural effusion and ascites Pre‐treatments samples of malignant pleural effusion and ascites Luciferase expression of cells infected with 5000 vp/cell V136: SD in CT scan, liver metastasis disappeared K75: CR in ascites formation  K75: CR in ascites formation Koski  Submitted 2010 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 6
  • 47. Ad5/3‐D24‐GMCSF is able to kill  pleural effusion cells pleural effusion cells 200 250 V136 M137 180 160 200 140 bility of (%) ) 120 150 ability (%) 100 80 100 *** Via 60 Viab 40 50 *** 20 0 0 Uninfected Ad5luc1 Ad5/3-d24- Uninfected Ad5luc1 Ad5/3-d24- cells GMCSF cells GMCSF ***p<0.005 against uninfected cells Pre‐treatment samples of malignant pleural effusions Pre‐treatment samples of malignant pleural effusions Cells from sample infected with 100 vp/cell V136: SD in CT scan, liver metastasis disappeared M137: SD in CT scan, CR in pleural effusion formation M137: SD in CT scan CR in pleural effusion formation Koski  Submitted 2010 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 7
  • 48. Higher amounts of virus at the tumor than  in blood  8000 6851 7000 Serum 6000 Ascites Virus in ascites sample  r  (vp / ml) 5000 able to produce  bl d cytopathic effect in 70%  4000 of wells in cell culture  (293 cells) (293 ll ) Titer 3000 2000 Functional virus present 1000 <500 0 0 NA NA 0 Day 0 1 Day 1 Week Patient (O82) had MR in tumor marker  levels during follow up Koski  Submitted 2010 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 8
  • 49. Induction of anti‐adenoviral and anti‐ tumoral immunity in blood tumoral immunity in blood ELISPOT- patient I80 (had vitiligo) Increase of CD8+ T lymphocytes after of CD8+ T lymphocytes treatment in 10/14 patients an SFC per million  cells 120 Adenovirus Average CD8+ cell count increases 100 1,60 80 CD cells x10e10/l 1,40 60 1,20 40 1,00 N 10 N=10 20 x Mea 0,80 0 0,60 0 35 0,40 Days (post‐treatment) D8+ Mean SFC per million  cells 0,20 60 0,00 Survivin Pre-treatment After treatment 50 40 30 Analysis of T cells specific for of T cells for   20 adenovirus and tumor epitopes with 10 0 interferon gamma ELISPOT 0 35 Days (post‐treatment) Koski  Submitted 2010 A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    4 9
  • 50. Summary Overall survival w/ CGTG‐102 50% survival = 315d Survival at 200d = 75% Survival at 500d = 48% N=25 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 Multiple injections more effective than single Multiple injections more effective than single Overall clinical benefit 76% in 110 treatments with our best  virus CGTG‐102 (now being tested in a clinical trial) 48% overall survival at 500d with CGTG‐102 Earlier treatment and smaller tumor load increase benefits Formal clinical trials are needed ! (€€€)  Formal clinical trials are needed ! (€€€) A k s e l i   H e m m i n k i       |     2 3  F e b  2 0 1 0    |    5 0