Cancer immunotherapy
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This document discusses cancer immunotherapy. It begins by describing tumor antigens that can be recognized by the immune system, such as tumor-specific antigens, tumor-associated antigens, and antigens from oncogenic viruses. It then discusses how tumors evade the immune system and various approaches to immunotherapy, including active immunotherapies using vaccines made of tumor cells, purified antigens, or antigen-loaded dendritic cells. Passive immunotherapies discussed include adoptive cellular therapy, monoclonal antibodies, and immunotoxins. Clinical trials and effectiveness of different immunotherapies are also summarized.
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Cancer immunotherapy
- 1. CANCER IMMUNOTHERAPY BY NEHA P PATEL M.Sc PART I SEM II
- 5. 5 Evasion Of Immune System
- 6. 1.TUMOR SPECIFIC ANTIENS -tyrosinase 2.TUMOR ASSOCIATED ANTIGENS-p53
- 7. TYPE OF ANTIGENS EXAMPLES OF HUMAN TUMOR ANTIGENS 1 . PRODUCTS OF ONCOGENES , TUMOR SUPPRESSOR GENES ONCOGENES- RAS MUTATION, - p210 PRODUCT OF Bcr/Abl REARRANGEMENTS, - OVEREXPRESSED Her-2/neu TSG- -MUTATED p53 2 .MUTANTS OF CELLULAR GENES NOT INVOLVED IN TUMORIGENESIS -P19 A MUTATION IN MUTAGENIZED MURINE MASTOCYTOMA 3.PRODUCTS OF GENES THAT ARE SILENT IN MOST NORMAL TISSUES. MAGE,BAGE,GAGE PROTEINS EXPRESSED IN MELANOMAS AND MANY CARCINOMAS 4.PRODUCTS OF OVEREXPRESSED GENES TYROSINASE, gp100, MART IN MELANOMAS
- 8. TYPE OF ANTIGENS EXAMPLES OF HUMAN TUMOR ANTIGENS 5.PRODUCTS OF ONCOGENIC VIRUSES -PAPILLOMAVIRUS E6 AND E7 PROTEINS (CERVICAL CARCINOMAS) -EBNA-1 PROTEIN OF EBV -SV40 (SV40-INDUCED RODENTS TUMORS) -HTLV-1 6.ONCOFETAL ANTIGENS -CEA ON MANY TUMORS -ALPHA-FETOPROTEIN.(AFP) 7.GLYCOLIPIDS &GLYCOPROTEINS GM-2,GD-2 ON MELANOMAS CA-125 & CA-19-9,ovarian cancer MUC-1-breast cancer 8.DIFFERENTIATION ANTIGENS NORMALLY PRESENT IN TISSUE OF ORIGEN -PROSTATE SPECIFIC ANTIGEN -MARKERS OF LYMPHOCYTES: CD-10,CD -20 Ig IDIOTYPES ON B-CELLS
- 9. Immune Response To Tumours
- 10. INDUCTION OF T-CELL RESPONSE TO TUMOR CELLS
- 11. [2] ANTIBODIES TUMOR 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 CELLS Abs MAY ACTIVATE COMPLEMENT SYSTEM OR KILL TUMOR CELLS BY ADCC
- 12. Chediak-Higashi syndrome NK cell impairment increased incidence 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
- 14. Activated macrophages secrete lytic enzymes Also secrete TNF- tumour necrosis Secrete nitric oxide (potential antitumour effects) [4] Macrophages-activated by IFN-γ
- 17. Tumour cell present Broken up to release antigens APC APC recruits T cells able to recognise tumour antigens T T Th CTL CTL recognise and destroy other tumour cells CTL Th cells educate other T/B cells B Ab / ADCC / cytokine attack
- 20. S.No Type of tumor vaccine Vaccine preparation Animal models Clinical trials 1. Killed tumor vaccine •Killed tumor cells + adjuvants •Tumor cell lysate+ adjuvants •Melanoma ,colon cancer •sarcoma •Melanoma, colon cancer •Melanoma 2. Purified tumor antigens •Melanoma antigen •HSP •Melanoma •various •Melanoma •Melanomas ,renal cancer, sarcoma 3. Professional APC based Dendritic cells + tumor antigen Melanoma , B-cell, lymphoma sarcoma Melanoma , prostate cancer,& others
- 21. S.No . Type of vaccine Vaaccine preparation Animal model Clinical trials 4. Cytokine & co- stimulator enhanced vaccines •Tumor cells transfected with cytokine or B-7 genes •APCs transfected with cytokine +tumor antigens •Renal cancer, sarcoma,B-cell leukemia, lung cancer Melanoma Sarcoma & others Melanoma, renal cancer & others 5. DNA vaccine Immunoglobulin with plasmid encoding tumor antigens Melanoma Melanoma 6. Viral vector •Adenovirus vaccine •Virus encoding tumor antigens + cytokines •Melanoma •sarcoma •Melanoma • Melanoma
- 23. IMMUNOTHERAPY WITH GENE TRANSFECTED TUMOR CELLS S.No. Cytokine Tumor rejection in animals Inflammatory infiltrate Immunity against parental tumor (animal model) Clinical trials 1. IL-2 YES; mediated by T- cell Lymphocytes neutrophils In some cases of renal cancer, melanoma Renal cancer, melanoma 2. Il-4 yes Eosinophil , macrophages No long lasting immunity in human trials Melanoma Renal cancer 3. INF-γ Variable Macrophages, Other cells sometimes 4. TNF variable Neutrophils & lymphocytes No 5. GM-CSF yes Macrophages, Other cells Yes(long lived T-cell immunity) Renal cancer 6. Il-2 sometimes Macrophages, Other cells Sometimes
- 24. S.No CYTOKINE TUMOR REJECTION IN ANIMALS CLINICAL TRIALS TOXICITY 1. IL-2 YES Melanoma,renal cancer ,colon cancer,limited success Vascular leak,shock, pulmonary edema 2. TNF Only with local administratio n Sarcoma,melanoma Septic syndrome 3. Il-12 YES, Variable Toxicity trials (phase I) in melanoma,others Abnormal liver fuction 4. IL-6 Melanoma Renal cancer Fever ,liver,&CNS toxicity,hyperte- sion 5. GM-CSF NO In routine use to promote bone marrow rcovery Bone pain SYSTEMIC CYTOKINE THERAPY FOR TUMORS
- 25. ACTIVATION OF TUMOR SPECIFIC T- CELL
- 26. Bacterial Extracts: Non-Specific Immune Adjuvants BCG: Bacillus Calmette-Guerin (Attenuated Bovine Tuberculosis Bacterium) Membrane Extracts of BCG C Parvum: Corynebacterium parvum (related to diphtheria bacillus) Bacterial Endotoxins: Muramyl Dipeptide Chemical Adjuvants: Levamisole Poly IC (Poly-inosinic-Poly-cytidyllic acid)
- 27. PASSIVE IMMUNOTHERAPIES: TRANSFER OF IMMUNE EFFECTORS INTO PATIENTS RAPID RESPONSE NOT LONG LIVED TYPES OF PIT- 1.ADOPTIVE CELLULAR THERAPY 2.GRAFT VERSUS LEUKEMIA EFFECTS 3.MONOCLONAL ANTIBODIES 4.IMMUNOTOXINS
- 30. • Adminstration of monoclonal antibodies which target either tumour- specific or over-expressed antigens. • Kill tumour cells in a variety of ways: Apoptosis induction Complement- mediated cytotoxicity ADCC NKMØ Conjugated to toxin / isotope
- 32. Complete regression of a large liver metastasis from kidney cancer in a patient treated with IL-2. Regression is ongoing seven years later Effective therapies Rosenberg (2001) Nature, 411;381-4
- 33. Name Malignancy Target Rituxan B cell lymphoma CD20 Herceptin Breast, lymphoma Her-2/neu Campath B-CLL CD52 Erbitux Colo-rectal EGFR Avastin Colo-rectal VEGF Mylotarg AML CD33 (calicheamicin) Bexxar B cell lymphoma CD20 (131In / 90Y)
- 34. Effectiveness of multiple antigen vaccines Patient with multiple metastatic melanomas treated with tyrosinase / gp100 / MART vaccine
- 35. Advances in immunotherapy chimeric molecules→immune-stimulatory cytokine +antibody → targets the cytokine's activity to a specific environment such as tumor →destroying the cancer-causing cells without the unwanted side-effects •On Wednesday 7 September 2011 Scientists in Singapore suggested antibody-based therapies can be used to target proteins inside cancer cells. •Mechanism of Ab entering the cell is not known. It will be the subject of future research. • An interesting recent variation on the idea of boosting host immune responses against tumors is to eliminate normal inhibitory signals for lymphocytes. •In some animal models, blocking the inhibitory T cell receptor CTLA-4 has led to strong immune responses against transplanted tumors.
Editor's Notes
- 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.