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Cancer immunotherapy

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Cancer immunotherapy

  1. 1. CANCERIMMUNOTHERAPYBYNEHA P PATELM.Sc PART I SEM II
  2. 2. Expermental evidence:-Methylcholantrene(MCA)-induced tumors
  3. 3. 5Evasion Of Immune System
  4. 4. 1.TUMOR SPECIFICANTIENS -tyrosinase2.TUMOR ASSOCIATEDANTIGENS-p53
  5. 5. TYPE OF ANTIGENS EXAMPLES OF HUMAN TUMORANTIGENS1 . PRODUCTS OFONCOGENES ,TUMOR SUPPRESSORGENESONCOGENES- RAS MUTATION,- p210 PRODUCT OF Bcr/AblREARRANGEMENTS,- OVEREXPRESSED Her-2/neuTSG- -MUTATED p532 .MUTANTS OFCELLULARGENES NOT INVOLVEDIN TUMORIGENESIS-P19 A MUTATION IN MUTAGENIZED MURINEMASTOCYTOMA3.PRODUCTS OF GENESTHAT ARE SILENT IN MOSTNORMAL TISSUES.MAGE,BAGE,GAGE PROTEINS EXPRESSED INMELANOMAS AND MANY CARCINOMAS4.PRODUCTS OFOVEREXPRESSEDGENESTYROSINASE,gp100,MART IN MELANOMAS
  6. 6. TYPE OF ANTIGENS EXAMPLES OF HUMAN TUMORANTIGENS5.PRODUCTS OFONCOGENIC VIRUSES-PAPILLOMAVIRUS E6 AND E7 PROTEINS (CERVICALCARCINOMAS)-EBNA-1 PROTEIN OF EBV-SV40 (SV40-INDUCED RODENTS TUMORS)-HTLV-16.ONCOFETAL ANTIGENS -CEA ON MANY TUMORS-ALPHA-FETOPROTEIN.(AFP)7.GLYCOLIPIDS&GLYCOPROTEINSGM-2,GD-2 ON MELANOMASCA-125 & CA-19-9,ovarian cancerMUC-1-breast cancer8.DIFFERENTIATIONANTIGENS NORMALLYPRESENT IN TISSUE OFORIGEN-PROSTATE SPECIFIC ANTIGEN-MARKERS OF LYMPHOCYTES: CD-10,CD -20Ig IDIOTYPES ON B-CELLS
  7. 7. Immune Response To Tumours
  8. 8. INDUCTION OF T-CELL RESPONSE TO TUMOR CELLS
  9. 9. [2] ANTIBODIESTUMOR BEARING HOST MAY PRODUCE Abs AGAINST VARIOUS TUMOR Ags .eg:-EBV ASSOCIATED LYMPHOMAS HAVE SERUM Abs AGAINST EBV –ENCODED Ag EXPRESSED ON THE SURFACE OF THE LYMPHOMA CELLSAbs MAY ACTIVATE COMPLEMENT SYSTEM OR KILL TUMOR CELLS BY ADCC
  10. 10.  Chediak-Higashi syndrome  NK cell impairment  increasedincidence of certain types of tumourNK cells release TNF- + NK cytotxic factorMechanism-ADCC-Fcγ IIIActivity increased by IL-2 & IL-12,INF’s capable of lysing a wide variety of tumour cells”.Respond to low level of MHC I[3] NK CELLS
  11. 11. Activated macrophages secrete lytic enzymesAlso secrete TNF-  tumour necrosisSecrete nitric oxide (potential antitumour effects)[4] Macrophages-activated by IFN-γ
  12. 12. Tumour cell presentBroken up torelease antigensAPCAPC recruits T cellsable to recognisetumour antigensTTThCTLCTL recogniseand destroy othertumour cellsCTLTh cells educateother T/B cellsBAb / ADCC /cytokine attack
  13. 13. S.No Type of tumor vaccine VaccinepreparationAnimalmodelsClinical trials1. Killed tumor vaccine •Killed tumorcells +adjuvants•Tumor celllysate+adjuvants•Melanoma,coloncancer•sarcoma•Melanoma,coloncancer•Melanoma2. Purified tumor antigens •Melanomaantigen•HSP•Melanoma•various•Melanoma•Melanomas,renal cancer,sarcoma3. Professional APCbasedDendritic cells+ tumorantigenMelanoma ,B-cell,lymphomasarcomaMelanoma ,prostatecancer,&others
  14. 14. S.No.Type of vaccine VaaccinepreparationAnimal model Clinical trials4. Cytokine & co-stimulatorenhancedvaccines•Tumor cellstransfected withcytokine or B-7 genes•APCs transfectedwith cytokine +tumorantigens•Renal cancer,sarcoma,B-cellleukemia,lung cancerMelanomaSarcoma& othersMelanoma,renal cancer& others5. DNA vaccine Immunoglobulin withplasmid encodingtumor antigensMelanoma Melanoma6. Viral vector •Adenovirus vaccine•Virus encodingtumor antigens+ cytokines•Melanoma•sarcoma•Melanoma• Melanoma
  15. 15. IMMUNOTHERAPY WITH GENE TRANSFECTED TUMOR CELLSS.No. Cytokine Tumorrejectionin animalsInflammatoryinfiltrateImmunityagainstparental tumor(animal model)Clinicaltrials1. IL-2 YES;mediatedby T- cellLymphocytesneutrophilsIn some casesof renalcancer,melanomaRenalcancer,melanoma2. Il-4 yes Eosinophil ,macrophagesNo long lastingimmunity inhuman trialsMelanomaRenalcancer3. INF-γ Variable Macrophages,Other cellssometimes4. TNF variable Neutrophils &lymphocytesNo5. GM-CSF yes Macrophages,Other cellsYes(long livedT-cell immunity)Renalcancer6. Il-2 sometimes Macrophages,Other cellsSometimes
  16. 16. S.No CYTOKINE TUMORREJECTION INANIMALSCLINICAL TRIALS TOXICITY1. IL-2 YES Melanoma,renal cancer,colon cancer,limitedsuccessVascularleak,shock,pulmonaryedema2. TNF Only withlocaladministrationSarcoma,melanoma Septic syndrome3. Il-12 YES, Variable Toxicity trials (phase I) inmelanoma,othersAbnormal liverfuction4. IL-6 Melanoma Renal cancer Fever ,liver,&CNStoxicity,hyperte-sion5. GM-CSF NO In routine use to promotebone marrow rcoveryBone painSYSTEMIC CYTOKINE THERAPY FOR TUMORS
  17. 17. ACTIVATION OF TUMOR SPECIFIC T- CELL
  18. 18. Bacterial Extracts: Non-Specific ImmuneAdjuvants BCG: Bacillus Calmette-Guerin (AttenuatedBovine Tuberculosis Bacterium) Membrane Extracts of BCG C Parvum: Corynebacterium parvum (relatedto diphtheria bacillus)Bacterial Endotoxins: Muramyl DipeptideChemical Adjuvants: Levamisole Poly IC (Poly-inosinic-Poly-cytidyllic acid)
  19. 19. PASSIVE IMMUNOTHERAPIES:TRANSFER OF IMMUNE EFFECTORS INTO PATIENTSRAPID RESPONSENOT LONG LIVEDTYPES OF PIT-1.ADOPTIVE CELLULAR THERAPY2.GRAFT VERSUS LEUKEMIA EFFECTS3.MONOCLONAL ANTIBODIES4.IMMUNOTOXINS
  20. 20. ADOPTIVE CELLULAR THERAPY
  21. 21. • Adminstration of monoclonal antibodies which target either tumour-specific or over-expressed antigens.• Kill tumour cells in a variety of ways:ApoptosisinductionComplement-mediatedcytotoxicityADCCNKMØConjugated totoxin / isotope
  22. 22. Complete regression of alarge liver metastasis fromkidney cancer in a patienttreated with IL-2.Regression is ongoingseven years laterEffective therapiesRosenberg (2001) Nature, 411;381-4
  23. 23. Name Malignancy TargetRituxan B cell lymphoma CD20Herceptin Breast, lymphoma Her-2/neuCampath B-CLL CD52Erbitux Colo-rectal EGFRAvastin Colo-rectal VEGFMylotarg AML CD33(calicheamicin)Bexxar B cell lymphoma CD20(131In / 90Y)
  24. 24. Effectiveness of multiple antigen vaccinesPatient with multiple metastatic melanomastreated with tyrosinase / gp100 / MART vaccine
  25. 25. Advances in immunotherapychimeric molecules→immune-stimulatory cytokine +antibody →targets the cytokines activity to a specific environment such astumor →destroying the cancer-causing cells without the unwantedside-effects•On Wednesday 7 September 2011 Scientists in Singapore suggestedantibody-based therapies can be used to target proteins inside cancercells.•Mechanism of Ab entering the cell is not known. It will be the subjectof future research.• An interesting recent variation on the idea of boosting host immuneresponses against tumors is to eliminate normal inhibitory signals forlymphocytes.•In some animal models, blocking the inhibitory T cell receptor CTLA-4has led to strong immune responses against transplanted tumors.

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