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.
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
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
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
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
22.
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
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
31.
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.
Hinweis der Redaktion
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.