the use of a tumor suppressor gene inserted inside an adenovirus to treat cancer.

1. GeneTherapy
for the
Treatment of Cancer
AMY G. DY, MD, FPPS, FPSPO, FPSO
Pediatric Oncologist, NKTI
Head, Pediatric Hematology-Oncology
St. Luke’s Global City – Cancer Institute

2. Mig’s story

3. Migs’ Story
2009
 11 years old, boy, Filipino
 Painless blood in urine
 Cystoscopy: bleeding mass in bladder
 Dx: Rhabdoid tumor of the urinary bladder
 Tx: Partial removal of urinary bladder

4. Migs’ Story
 Hospital in China
 Locoregional and systemic chemotherapy
(Gemcitabine/Cisplatin)
 Immunotherapy
 2 mos: pelvic recurrence
 Cryosurgery
 Brachytherapy

5. Mig’s story
 Progressive and metastatic
disease
 (R) flank pain
 Came back to Philippines
 Urologist: total excision of bladder and
rectum

6. Mig’s story
Feb 2011
Gendicine: IT 9
IA 2
IV 1
+ 6 Chemo (ICE)
Outcome: No tumor seen on 2nd
look surgery
PET CT : no active disease

8. OUTLINE
 WHAT IS A GENE?
 HOW IS GENE MEDICINE MADE?
 HOW DOES IT WORK?
 HOW IS IT USED?
 OTHER CASES

9. WHAT
IS
A
GENE ?

10. CELL
NUCLEUS

11. CHROMOSOMES
23 pairs or 46
chromosomes in
the nucleus of each
cell in our body

12. CHROMOSOME # 3
•ONCOGENES
•TUMOR
SUPPRESSOR
GENES

14. P53
chromosome 17
(17p13.1)
TUMOR SUPPRESSOR GENE

15. P53 tumor suppressor gene
 when a cell's
DNA is
damaged, it
acts as an
"emergency
brake" to stop
the resulting
cell division
that can lead
to cancer.

16. P53 tumor suppressor gene
 It also acts as
an
executioner,
programming
damaged cells
to self-destruct
before their
altered DNA
can be
replicated.

17. P53 tumor suppressor gene
 when it mutates, p53 can lose its
suppressive powers or have the
devastating effect of actually
promoting abnormal cell growth
 p53 is the most commonly mutated
gene found in human tumors

18. HOW IS
p53 GENE THERAPY MEDICINE
MADE?

19. ADENOVIRUS
TWO COMPONENTS
p53 gene
“common colds”

20. Genetic Engineering Adenovirus
rAd-p53
Remove
P53 Gene
bad gene
Inser
t
RECOMBINANT HUMAN ADENOVIRUS p53 INJECTION MEDICINE

21. HOW DOES
GENE THERAPY
WORK?

22.  The adenovirus
containing the
p53 tumor
suppressor gene
binds to the
receptor in the
cell membrane of
the cancer cell

23.  The
adenovirus is
then
packaged in a
vesicle inside
the cell
 The vesicle
proceeds to
the cell
nucleus

24.  The vesicle
breaks down,
releasing the
adenovirus
near the cell
nucleus

25.  The
adenovirus
injects its
gene, which
now includes
the p53
tumor
suppressor
gene, into the
cell nucleus

26.  The cancer
cell then
makes p53
protein

27.  The p53
protein
causes the
cancer cell to
self destruct
without
affecting
surrounding
normal cells

28. p53-Dependent Genep53-Dependent Gene
FunctionsFunctions
 Apoptosis – a kind of programmed cell death
mediated by specific p53-dependent genes
 Cell cycle arrest – “stressed” cells that tend to enter
mitosis get arrested (stop dividing)
 DNA repair – if “stress” involves DNA damage, repair
function genes go into action
 Differentiation/senescence—genes that limit
ability of cells to divide indefinitely are called to action
 Autophagy-a kind of “self” eating that leads to cell
death

29. Other p53 functionsOther p53 functions
 Down-regulation ofVEGF (vascular
endothelial growth factor) – prevents
angiogenesis in tumors.
 Down-regulation of MDR1 (multidrug
resistance gene 1) – wt p53 actively
suppresses MDR1, certain p53 mutants
stimulate MDR1 and other genes, thus
decreases resistance to chemotherapy and
radiotherapy.

30. HOW IS
GENE THERAPY
ADMINISTERED?

31. Direct injection to tumor

32. Injection into pleural and peritoneal cavities

33. Intravenous infusion

34. Intra arterial infusion

35. P53 Gene Therapy is Safe
• First used since year 2003
• Over 16,000 patients already treated
• No serious side effects
• Common side effect is self-limited fever

36. OTHER PATIENTS

37.  Philippines
First 8 PEDIATRIC PATIENTS
 103 Gendicine adminstrations (from 2-11-11 to
9-26-11)
32 intratumor
15 intraarterial
56 intravenous

38.  Side effects: 103 treatments
1. Fever 81
2. local pain 61
3. chills 24
4. feels cold 10
5. headache 4
6. nausea/vomiting 5
7. abd pain 2
8. sore throat 1

39. FEVER
 Degree : 37.7-40.7
 Duration : 3 – 16 hrs
 Onset : 2 – 13 hrs

40. CHILLS
 Duration : 30 min - 3 hrs
 Onset : 1 – 7 hrs

41. Case #2: JCG, 14yo/M
Osteosarcoma, metastatic to
lungs
Gendicine: IT 1
IA 5 primary
3 bronchial art
IV 10
(+ 2 chemo)
Outcome: 98% tumor necrosis
stopped treatment

44. Case #3: IR, 14 yo/M
secondary non-Hodgkin
lymphoma, st III
Gendicine: IT 6
IV 6
(+ 3 chemo)
Outcome: Normal PET scan

45. IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III
March 3, 2011 March 15, 2011
AP

46. March 3, 2011
March 15, 2011
IR, 14 y.o. male
sNon-Hodgkin
lymphoma Stage
III
SAGITTAL

47. IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III
March 3, 2011 March 15, 2011
TRANSVERSE

48.  SUMMARY OF PEDIATRIC PATIENTS
1. FMZ 13 yo/M rhabdoid tumor st 4 CR
2. IR 14 yo/M sNHL St 3 CR
3. JCG 14 yo/M OS, mets (stopped tx)
4. DM 4 yo/M RMS
5. GP 7 yo/F Pontine glioma
6. EV 15 yo/M Ewing sarcoma st 4 PR
7. TAV 16 yo/M OS, mets
8. RT 7 yo/M Undiff sarcoma st 4 PR
9. FAV 3 yo/M Neuroblastoma St 4 PR
10.GHP 3 yo/F Ewing’s sarcoma St 3-4 CR
11.GL 4 yo/F Ewing’s sarcoma St 4 new

49. 22 ADULT PATIENTS
 Breast ca - 6
 Colon ca - 5
 Rectal ca - 2
 Lung ca - 2
 Pancreatic ca - 1
 Renal cell ca - 1
 Esophageal ca - 1
 Glioblastoma multiforme - 1
 Uterine ca - 1
 Malignant thymoma – 1
 Pleomorphic spindle cell sarcoma - 1

50.  15 patients completed treatment
 Partial Response = 6
 Complete Response = 2 (breast, colon)
 Progressive Disease = 7

51. Malignant Thymoma
•Dyspnea and hoarseness
(recurrent laryngeal nerve
palsy) – Nov 2011
•Unresectable mass; failed
chemotherapy
•12 X CT-guided
intratumoral injection
•No more dyspnea, voice
normal, back to work

52. Breast Cancer – chest wall recurrence
Dec 21, 2012
Jan 28, 2013

53.  Summary of principles of p53 gene therapy:
1. advanced solid tumors
2. combined with conventional tx
3. direct tumor injection
4. 2-4 vials 2x a week

54. Liver Cancer
Male, 60 y.o.
•治疗前 before treatment 介入 + 基因治疗后 after interventional therapy+gene therapy

55. Advanced Lung Cancer
Male, 62 y.o.
Before treatment after chemotherapy+gene therapy

56. Cancer of the lower lip
Male, 67 y.o..

57. GENE THERAPY

58. GENE THERAPY

59. Landline: 63-2-9618035
Mobile: +639175536300
Email: surg.onc1@tullamarine.ph