gene therapy for nkti feb2013
DESCRIPTION
the use of a tumor suppressor gene inserted inside an adenovirus to treat cancer.TRANSCRIPT
Gene Therapy 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
Mig’s story
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
Migs’ Story
Hospital in China Locoregional and systemic chemotherapy
(Gemcitabine/Cisplatin) Immunotherapy
2 mos: pelvic recurrence Cryosurgery Brachytherapy
Mig’s story
Progressive and metastatic disease
(R) flank pain Came back to Philippines Urologist: total excision of bladder
and rectum
Mig’s story
Feb 2011Gendicine: IT 9
IA 2IV 1
+ 6 Chemo (ICE)
Outcome: No tumor seen on 2nd look surgery
PET CT : no active disease
OUTLINE
WHAT IS A GENE? HOW IS GENE MEDICINE MADE? HOW DOES IT WORK? HOW IS IT USED? OTHER CASES
WHAT IS A GENE ?
CELLNUCLEUS
CHROMOSOMES
23 pairs or 46 chromosomes in the nucleus of each cell in our body
CHROMOSOME # 3
•ONCOGENES
•TUMOR SUPPRESSOR GENES
P53chromosome 17 (17p13.1)
TUMOR SUPPRESSOR GENE
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.
P53 tumor suppressor gene It also acts as
an executioner, programming damaged cells to self-destruct before their altered DNA can be replicated.
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
HOW IS p53 GENE THERAPY MEDICINE MADE?
ADENOVIRUS
TWO COMPONENTS
p53 gene
“common colds”
Genetic Engineering Adenovirus
rAd-p53
Remove
P53 Gene
bad gene
Inse
rt
RECOMBINANT HUMAN ADENOVIRUS p53 INJECTION MEDICINE
HOW DOES GENE THERAPY WORK?
The adenovirus containing the p53 tumor suppressor gene binds to the receptor in the cell membrane of the cancer cell
The adenovirus is then packaged in a vesicle inside the cell
The vesicle proceeds to the cell nucleus
The vesicle breaks down, releasing the adenovirus near the cell nucleus
The adenovirus injects its gene, which now includes the p53 tumor suppressor gene, into the cell nucleus
The cancer cell then makes p53 protein
The p53 protein causes the cancer cell to self destruct without affecting surrounding normal cells
p53-Dependent Gene p53-Dependent Gene Functions Functions
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
Other p53 functionsOther p53 functions
Down-regulation of VEGF (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.
HOW IS GENE THERAPY ADMINISTERED?
Direct injection to tumor
Injection into pleural and peritoneal cavities
Intravenous infusion
Intra arterial infusion
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
OTHER PATIENTS
Philippines
First 8 PEDIATRIC PATIENTS 103 Gendicine adminstrations (from 2-11-
11 to 9-26-11)32 intratumor15 intraarterial56 intravenous
Side effects: 103 treatments1. Fever 812. local pain 613. chills 244. feels cold 105. headache 46. nausea/vomiting 57. abd pain 2
8. sore throat 1
FEVER
Degree : 37.7-40.7 Duration : 3 – 16 hrs Onset : 2 – 13 hrs
CHILLS
Duration : 30 min - 3 hrs Onset : 1 – 7 hrs
Case #2: JCG, 14yo/MOsteosarcoma, metastatic to
lungs
Gendicine: IT 1IA 5 primary
3 bronchial artIV 10
(+ 2 chemo)Outcome: 98% tumor necrosis stopped treatment
Case #3: IR, 14 yo/Msecondary non-Hodgkin
lymphoma, st III
Gendicine: IT 6IV 6
(+ 3 chemo)
Outcome: Normal PET scan
IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III
March 3, 2011 March 15, 2011
AP
March 3, 2011
March 15, 2011
IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III
SAGITTAL
IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III
March 3, 2011 March 15, 2011
TRANSVERSE
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
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
15 patients completed treatment
Partial Response = 6 Complete Response = 2 (breast, colon) Progressive Disease = 7
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
Breast Cancer – chest wall recurrence
Dec 21, 2012
Jan 28, 2013
Summary of principles of p53 gene therapy:
1. advanced solid tumors2. combined with conventional tx3. direct tumor injection4. 2-4 vials 2x a week
Liver CancerMale, 60 y.o.
• 治疗前 before treatment 介入 + 基因治疗后 after interventional therapy+gene therapy
Advanced Lung CancerMale, 62 y.o.
Before treatment after chemotherapy+gene therapy
Cancer of the lower lipMale, 67 y.o..
GENE THERAPY
GENE THERAPY
