Your SlideShare is downloading. ×
Cancer immunotherapy
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Cancer immunotherapy

1,862
views

Published on

Published in: Technology, Business

0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,862
On Slideshare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
126
Comments
0
Likes
1
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • Cancer is a major health problem worldwide. It is most important cause of morbidity and mortality. Cancer arises from the uncontrolled growth proliferation and spread of clones of transformed cells.Cancer cells are self altered cells that have escaped normal growth-regulating mechanism.Although various immune responses can be generated to tumor cells, the response frequently is not sufficient to prevent tumor growth. One approach to cancer treatment is to augment or supplement these natural defense mechanisms.
  • IMMUNE SURVEILLANCE THEORY- The immune surveillance theory was first conceptualized in the early 1900s by Paul Ehrlich. He suggested that cancer cells frequently arise in the body but are recognized as foreign and eliminated by the immune system. Some 50 years later, Lewis Thomas suggested that the cell-mediated branch of the immune system had evolved to patrol the body and eliminate cancer cells.In 1950 Macfarlane Burnet proposed immune surveillance ,according to which a physiologic function of the immune system is to recognize & destroy clones of transformed ells before they grow into tumors and to kill tumors after they formedAccording to these concepts, tumors arise only if cancer cells are able to escape immune surveillance, either by reducing their expression of tumor antigens or by an impairment in the immune response to these cells.
  • IMMUNE RESPONSE FREQUENTLY FAIL TO PREVENT THE TUMOR GROWTH DUE TO Resemblance of tumor cells to with host cells. Most tumors express only a few antigens that may be recognised as non-self and as a result, most tumors tend to be weekly immunogenic. Tumors induced by oncogenic viruses & potent carcinogens are able to elicit strong immune response.Rapid growth & spread of tumors may overwhelm the capacity of the immune system to eradicate tumor requires that all the malignant cells be eliminated.Many tumors have specialised mechanism for evading host immune response.
  • May be expressed on foetal cellsShared by normal and tumor cells.{Tumor-associated developmental Ag (TADA)},but not adult cells.Unique to a tumor. Very difficult to detectPlay an important role in tumor rejection. Oncogenic mutants of normal cellular genes:ras, bcr-abl, p53Randomly mutated genes: TSTA‘s (tumor-specific transplantation antigens)Can be identified: biochemical cDNA cloning
  • Types of tumor antigens recognized by T cells. Tumor antigens that are recognized by tumor-specific CD8*T cells may be mutated forms of normal self proteins, products of oncogenes or tumor suppressor genes, over-expressed or aberrantly expressed self proteins, or products of oncogenic viruses. Tumor antigens may also be recognized by CD4* T cells, but less is known about the role that CD4* T cells play in tumor immunity. EBNA -Epstein-Barr virus nuclear antigen.
  • FIG-3:-Induction of CD8* T cell responses against tumors. CD8* T cell responses to tumors may be induced by cross-priming (also called cross-presentation), in which the tumor cells and/or tumor antigens are taken up by professional APCs, processed, and presented to T cells. In some cases, B7 co-stimulators expressed by the APCs provide the second signals for the differentiation of the CD8* T cells. The APCs may also stimulate CD4* helper T cells, which provide the second signals for CTL developmentDifferentiated CTLs kill tumor cells without a requirement for co-stimulation or T cell help.
  • Transcript

    • 1. CANCERIMMUNOTHERAPYBYNEHA P PATELM.Sc PART I SEM II
    • 2. Expermental evidence:-Methylcholantrene(MCA)-induced tumors
    • 3. 5Evasion Of Immune System
    • 4. 1.TUMOR SPECIFICANTIENS -tyrosinase2.TUMOR ASSOCIATEDANTIGENS-p53
    • 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. 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. Immune Response To Tumours
    • 8. INDUCTION OF T-CELL RESPONSE TO TUMOR CELLS
    • 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.  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. Activated macrophages secrete lytic enzymesAlso secrete TNF-  tumour necrosisSecrete nitric oxide (potential antitumour effects)[4] Macrophages-activated by IFN-γ
    • 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. 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. 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. 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. 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. ACTIVATION OF TUMOR SPECIFIC T- CELL
    • 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. 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. ADOPTIVE CELLULAR THERAPY
    • 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. 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. 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. Effectiveness of multiple antigen vaccinesPatient with multiple metastatic melanomastreated with tyrosinase / gp100 / MART vaccine
    • 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.