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