CANCER

IMMUNOTHERAPY

BY
NEHA P PATEL
M.Sc PART I SEM II
Expermental evidence:-Methylcholantrene(MCA)-
induced tumors
Evasion Of Immune System

5
1.TUMOR SPECIFIC
ANTIENS -tyrosinase

2.TUMOR ASSOCIATED
ANTIGENS-p53
TYPE OF ANTIGENS EXAMPLES OF HUMAN TUMOR
ANTIGENS
1 . PRODUCTS OF ONCOGENES- RAS MUTATION,
ONCOGENES , - p210 PRODUCT OF Bcr/Abl
TUMOR SUPPRESSOR REARRANGEMENTS,
GENES - OVEREXPRESSED Her-2/neu
TSG- -MUTATED p53
2 .MUTANTS OF -P19 A MUTATION IN MUTAGENIZED MURINE
CELLULAR MASTOCYTOMA
GENES NOT INVOLVED
IN TUMORIGENESIS
3.PRODUCTS OF GENES MAGE,BAGE,GAGE PROTEINS EXPRESSED IN
THAT ARE SILENT IN MOST MELANOMAS AND MANY CARCINOMAS
NORMAL TISSUES.

4.PRODUCTS OF TYROSINASE,
OVEREXPRESSED gp100,
GENES MART IN MELANOMAS
TYPE OF ANTIGENS EXAMPLES OF HUMAN TUMOR
ANTIGENS
5.PRODUCTS OF -PAPILLOMAVIRUS E6 AND E7 PROTEINS (CERVICAL
ONCOGENIC VIRUSES 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 GM-2,GD-2 ON MELANOMAS

&GLYCOPROTEINS CA-125 & CA-19-9,ovarian cancer
MUC-1-breast cancer

8.DIFFERENTIATION -PROSTATE SPECIFIC ANTIGEN

ANTIGENS NORMALLY -MARKERS OF LYMPHOCYTES: CD-10,CD -20
PRESENT IN TISSUE OF Ig IDIOTYPES ON B-CELLS
ORIGEN
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

[3] NK CELLS

 capable of lysing a wide variety of tumour cells”.

Respond to low level of MHC I

Mechanism-ADCC-Fcγ III

Activity increased by IL-2 & IL-12,INF’s

NK cells release TNF- + NK cytotxic factor

 Chediak-Higashi syndrome  NK cell impairment  increased

incidence of certain types of tumour
[4] Macrophages-activated by IFN-γ

Activated macrophages secrete lytic enzymes

Secrete nitric oxide (potential antitumour effects)

Also secrete TNF-  tumour necrosis

Tumour cell present
Ab / ADCC /
cytokine attack

B Th
Th cells educate
other T/B cells

CTL CTL
APC recruits T cells
Broken up to able to recognise CTL recognise
release antigens tumour antigens and destroy other
T tumour cells

APC T
S.No Type of tumor vaccine Vaccine Animal Clinical trials
preparation models
1. Killed tumor vaccine •Killed tumor •Melanoma •Melanoma,
cells + ,colon colon
adjuvants cancer cancer
•Tumor cell •sarcoma •Melanoma
lysate+
adjuvants

2. Purified tumor antigens •Melanoma •Melanoma •Melanoma

antigen
•HSP •various •Melanomas
,renal cancer,
sarcoma

3. Professional APC Dendritic cells Melanoma , Melanoma ,

based + tumor B-cell, prostate
antigen lymphoma cancer,&
sarcoma others
S.No Type of vaccine Vaaccine Animal model Clinical trials
. preparation

4. Cytokine & co- •Tumor cells •Renal cancer, Melanoma

stimulator transfected with sarcoma,B-cell Sarcoma
enhanced cytokine or B-7 genes leukemia, & others
vaccines •APCs transfected lung cancer
with cytokine +tumor Melanoma,
antigens renal cancer
& others

5. DNA vaccine Immunoglobulin with Melanoma Melanoma

plasmid encoding
tumor antigens

6. Viral vector •Adenovirus vaccine •Melanoma •Melanoma

•Virus encoding •sarcoma • Melanoma
tumor antigens
+ cytokines
IMMUNOTHERAPY WITH GENE TRANSFECTED TUMOR CELLS
S.No. Cytokine Tumor Inflammatory Immunity Clinical
rejection infiltrate against trials
in animals parental tumor
(animal model)

1. IL-2 YES; Lymphocytes In some cases Renal

mediated neutrophils of renal cancer,
by T- cell cancer, melanoma
melanoma
2. Il-4 yes Eosinophil , No long lasting Melanoma
macrophages immunity in Renal
human trials cancer
3. INF-γ Variable Macrophages, sometimes
Other cells
4. TNF variable Neutrophils & No
lymphocytes
5. GM-CSF yes Macrophages, Yes(long lived Renal
Other cells T-cell immunity) cancer
6. Il-2 sometimes Macrophages, Sometimes
Other cells
 SYSTEMIC CYTOKINE THERAPY FOR TUMORS
S.No CYTOKINE TUMOR CLINICAL TRIALS TOXICITY
REJECTION IN
ANIMALS
1. IL-2 YES Melanoma,renal cancer Vascular
,colon cancer,limited leak,shock,
success pulmonary
edema
2. TNF Only with Sarcoma,melanoma Septic syndrome
local
administratio
n
3. Il-12 YES, Variable Toxicity trials (phase I) in Abnormal liver
melanoma,others fuction

4. IL-6 Melanoma Renal cancer Fever ,liver,&CNS

toxicity,hyperte-
sion
5. GM-CSF NO In routine use to promote Bone pain
bone marrow rcovery
ACTIVATION OF TUMOR SPECIFIC T- CELL
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)
 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
ADOPTIVE CELLULAR THERAPY
• Adminstration of monoclonal antibodies which target either tumour-
specific or over-expressed antigens.
• Kill tumour cells in a variety of ways:

MØ NK

Apoptosis Complement- ADCC Conjugated to

induction mediated toxin / isotope
cytotoxicity
 Effective therapies

Complete regression of a
large liver metastasis from
kidney cancer in a patient
treated with IL-2.

Regression is ongoing
seven years later

Rosenberg (2001) Nature, 411;381-4

 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)
Effectiveness of multiple antigen vaccines

Patient with multiple metastatic melanomas

treated with tyrosinase / gp100 / MART vaccine
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.