Gene therapy for NKTI Feb2013

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

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Gene therapy for NKTI Feb2013

  1. 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. 2. Mig’s story
  3. 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. 4. Migs’ Story  Hospital in China  Locoregional and systemic chemotherapy (Gemcitabine/Cisplatin)  Immunotherapy  2 mos: pelvic recurrence  Cryosurgery  Brachytherapy
  5. 5. Mig’s story  Progressive and metastatic disease  (R) flank pain  Came back to Philippines  Urologist: total excision of bladder and rectum
  6. 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
  7. 7. OUTLINE  WHAT IS A GENE?  HOW IS GENE MEDICINE MADE?  HOW DOES IT WORK?  HOW IS IT USED?  OTHER CASES
  8. 8. WHAT IS A GENE ?
  9. 9. CELL NUCLEUS
  10. 10. CHROMOSOMES 23 pairs or 46 chromosomes in the nucleus of each cell in our body
  11. 11. CHROMOSOME # 3 •ONCOGENES •TUMOR SUPPRESSOR GENES
  12. 12. P53 chromosome 17 (17p13.1) TUMOR SUPPRESSOR GENE
  13. 13. 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.
  14. 14. P53 tumor suppressor gene  It also acts as an executioner, programming damaged cells to self-destruct before their altered DNA can be replicated.
  15. 15. 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
  16. 16. HOW IS p53 GENE THERAPY MEDICINE MADE?
  17. 17. ADENOVIRUS TWO COMPONENTS p53 gene “common colds”
  18. 18. Genetic Engineering Adenovirus rAd-p53 Remove P53 Gene bad gene Inser t RECOMBINANT HUMAN ADENOVIRUS p53 INJECTION MEDICINE
  19. 19. HOW DOES GENE THERAPY WORK?
  20. 20.  The adenovirus containing the p53 tumor suppressor gene binds to the receptor in the cell membrane of the cancer cell
  21. 21.  The adenovirus is then packaged in a vesicle inside the cell  The vesicle proceeds to the cell nucleus
  22. 22.  The vesicle breaks down, releasing the adenovirus near the cell nucleus
  23. 23.  The adenovirus injects its gene, which now includes the p53 tumor suppressor gene, into the cell nucleus
  24. 24.  The cancer cell then makes p53 protein
  25. 25.  The p53 protein causes the cancer cell to self destruct without affecting surrounding normal cells
  26. 26. 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
  27. 27. 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.
  28. 28. HOW IS GENE THERAPY ADMINISTERED?
  29. 29. Direct injection to tumor
  30. 30. Injection into pleural and peritoneal cavities
  31. 31. Intravenous infusion
  32. 32. Intra arterial infusion
  33. 33. 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
  34. 34. OTHER PATIENTS
  35. 35.  Philippines First 8 PEDIATRIC PATIENTS  103 Gendicine adminstrations (from 2-11-11 to 9-26-11) 32 intratumor 15 intraarterial 56 intravenous
  36. 36.  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
  37. 37. FEVER  Degree : 37.7-40.7  Duration : 3 – 16 hrs  Onset : 2 – 13 hrs
  38. 38. CHILLS  Duration : 30 min - 3 hrs  Onset : 1 – 7 hrs
  39. 39. 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
  40. 40. Case #3: IR, 14 yo/M secondary non-Hodgkin lymphoma, st III Gendicine: IT 6 IV 6 (+ 3 chemo) Outcome: Normal PET scan
  41. 41. IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III March 3, 2011 March 15, 2011 AP
  42. 42. March 3, 2011 March 15, 2011 IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III SAGITTAL
  43. 43. IR, 14 y.o. male sNon-Hodgkin lymphoma Stage III March 3, 2011 March 15, 2011 TRANSVERSE
  44. 44.  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
  45. 45. 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
  46. 46.  15 patients completed treatment  Partial Response = 6  Complete Response = 2 (breast, colon)  Progressive Disease = 7
  47. 47. 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
  48. 48. Breast Cancer – chest wall recurrence Dec 21, 2012 Jan 28, 2013
  49. 49.  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
  50. 50. Liver Cancer Male, 60 y.o. •治疗前 before treatment 介入 + 基因治疗后 after interventional therapy+gene therapy
  51. 51. Advanced Lung Cancer Male, 62 y.o. Before treatment after chemotherapy+gene therapy
  52. 52. Cancer of the lower lip Male, 67 y.o..
  53. 53. GENE THERAPY
  54. 54. GENE THERAPY
  55. 55. Landline: 63-2-9618035 Mobile: +639175536300 Email: surg.onc1@tullamarine.ph

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