cancer immunotherapy
TRANSCRIPT
CANCERIMMUNOTHERAPY
BYNEHA P PATEL M.Sc PART I SEM II
Treatment of cancer by immunologic approaches.
What is cancer immunotherapy?
EVIDENCE SUPPORTING THE CONCEPT OF THE IMMUNE SYSTEM REACTS AGAINST TUMORS
Expermental evidence:-Methylcholantrene(MCA)-induced tumors
5
Evasion Of Immune System
TWO TYPES OF TUMOR ANTIGENS
1.TUMOR SPECIFIC ANTIENS -tyrosinase
2.TUMOR ASSOCIATED ANTIGENS-p53
TUMOUR ANTIGENS
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/neuTSG- -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
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 MELANOMASCA-125 & CA-19-9,ovarian cancerMUC-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
Immune Response To Tumours
INDUCTION OF T-CELL RESPONSE TO TUMOR CELLS
[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
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
Activated macrophages secrete lytic enzymes
Also secrete TNF- tumour necrosis
Secrete nitric oxide (potential antitumour effects)
[4] Macrophages-activated by IFN-γ
How can we harness the immune response?
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
Some Examples of Active, Specific Immunotherapy (Tumor Vaccines)
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
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
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
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 administration
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
ACTIVATION OF TUMOR SPECIFIC T- CELL
Active Non-Specific Immunotherapy
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 DipeptideChemical Adjuvants: Levamisole Poly IC (Poly-inosinic-Poly-cytidyllic acid)
PASSIVE IMMUNOTHERAPIES:
TRANSFER OF IMMUNE EFFECTORS INTO PATIENTSRAPID RESPONSENOT LONG LIVED
TYPES OF PIT-
1.ADOPTIVE CELLULAR THERAPY
2.GRAFT VERSUS LEUKEMIA EFFECTS
3.MONOCLONAL ANTIBODIES
4.IMMUNOTOXINS
ADOPTIVE CELLULAR THERAPY
GRAFT VERSUS LEUKEMIA EFFECT
Adminstration of al loreactive T-cel ls +Hematopoetic stem cells
Eradicate tumors
Directed at allogenic MHC molecules
On hematopoeitic cells of reiepient
MONOCLONAL ANTIBODY
• 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
Monoclonal antibodies
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
Antibody-based immunotherapyName 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)
Effectiveness of multiple antigen vaccines
Patient with multiple metastatic melanomas treated with tyrosinase / gp100 / MART vaccine
Advances in immunotherapychimeric 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.
Thank you