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Cancer
Immunotherapy
Oncogene-targeted
Chemotherapies
Angiogenisis
inhibitors
The Ultimate Cancer Therapy
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Most contemporary anticancer agents have two
defects:
1) Poor selectivity toward
cancer cells versus normal
cells.
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2) Poor efficacy against slowgrowing tumors.
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Anti-cancer drugs
discovered this way work by
inhibiting cell replication
(e.g.DNA polymerase,
ribonucleotide reductase, DHFR
etc).
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These drugs discriminate
poorly between cancer and
normal cells and thus have
significant adverse side
effects.
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Strategies for Developing
New Anticancer Drugs
1) Identify the molecular "targets"
that distinguish cancer cells from
normal cells.
2) Identify compounds that interact
selectively with these molecular
"targets”.
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Principles of Cancer
Therapy
Total Cell Kill
Minimize toxicity to normal cells
Advanced cancers are
heterogeneous.
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Experimental cancer immunotherapy is
exploring a variety of approaches.
Some of these are:
• The enhancement of the costimulatory signal required for Tcell activation.
• Genetically engineering tumor cells
to secrete cytokines that may
increase the intensity of the immune
response against them.
• The therapeutic use of cytokines,
and
• Increasing the activity of antigen7/17/2015
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presenting
cells.
Tumor Antigens
• Tumor cells display tumor-specific antigens
and the more common tumor-associated
antigens . Among the latter are oncofetal
antigens and increased levels of normal
oncogene products.
• In contrast to tumor antigens induced by
chemicals or radiation, virally encoded
tumor antigens are shared by all tumors
induced by the same virus.
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Tumor antigens recognized by
T cells fall into one of four major
categories: antigens encoded by
genes with tumor-specific
expression; antigens encoded by
variant forms of normal genes
that have been altered by
mutation; certain antigens
normally expressed only at certain
stages of differentiation or
differentiation lineages; antigens
that are over-expressed in
particular tumors.
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• The use of a variety of genetic,
biochemical, and immunological
approaches has allowed the
identification of several tumorassociated antigens. In many cases
the antigen is expressed on more
than one type of tumor.
• Common tumor antigens offer hope
for the design of better therapies,
detection, and monitoring, and have
important implications for the
possibility of anti-tumor
immunization.
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Tumor Antigens
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Immune Response to
Tumors
• The immune response to tumors
includes CTL-mediated lysis, NKcell activity, macrophagemediated tumor destruction, and
destruction mediated by ADCC.
• Several cytotoxic factors,
including TNFa and TNFb , help
to mediate tumor-cell killing.
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Tumors may evade the immune response
by modulating their tumor antigens,
by reducing their expression of class
I MHC molecules, and by antibodymediated or immune complexmediated inhibition of CTL activity.
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Tumor Evasion of the Immune
System
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Cancer Immunotherapy
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Cancer Immunotherapy
• A number of encouraging clinical results have
been obtained with therapy using monoclonal
antibodies against tumor-associated and (in a
few cases) tumor-specific antigens. Coupling
of antibodies against tumor antigens with
toxins , chemotherapeutic agents, or
radioactive elements is being examined.
• The expectation is that such strategies will
focus the toxic effects of these agents on
the tumor and spare normal cells their
deleterious effects.
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New approaches are being
developed for antigen-specific
immunotherapy of human cancers.
Some are based on novel
technology that employs cellsized (5 micron diameter)
microspheres coated with cell
surface antigens to present
tumor antigen to CD8+ cells for
generation of tumor-specific
cytotoxic T lymphocytes (CTL).
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Cancer Immunotherapy
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Cancer Immunotherapy
• Key elements in the design of strategies for
vaccination against cancer are the
identification of significant tumor antigens
by genetic or biochemical approaches; the
development of strategies for the effective
presentation of tumor antigens; and the
generation of activated populations of helper
or cytotoxic T cells.
• In the case of the few human cancers known
to be caused by clearly identified tumor
viruses, vaccination against those viruses or
their subunits may be effective.
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The discovery of cellular
growth factors which can directly
suppress the malignant phenotype
or which can harness the immune
system to preferentially attack
cancerous cells raises the
prospect of developing other
immune intervention therapies.
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interleukins
Interleukins activate the
body's own lymphocytes to do
their work. IL-2 has been found
to be effective in some patients
with melanoma or with renal
cancer when it is administered
alone or with a patient's own
lymphocytes that have been
treated with Il-2 outside the
body.
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interferons
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Interferons act on the immune
system by stimulating both T cells and
macrophages. They also prevent cells
from multiplying. Scientists believe that
these two properties together enable
interferon to fight some tumors
effectively.
Alpha interferon was the first FDAapproved biological response modifier
for the treatment of cancer (it is
effective against a rare form of
leukemia).
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INFLAMMATORY MOLECULES,
which include tumor necrosis factor
(TNF) and other messenger
molecules of the immune system
as well as certain microbial
products, can bring about an
inflammatory reaction that
destroys tissues at the tumor site.
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Tumor necrosis factor
Tumor necrosis factor directly attacks and
kills tumor cells. Currently, it is being tested
alone and in conjunction with gamma interferon
to determine its potential efficacy in the
treatment of human cancers. B-cell growth
factors stimulate the multiplication of antibodyproducing cells. The hematopoietic growth
factors step up the production of both red and
white blood cells in the bone marrow, thereby
giving the body additional ammunition to fight
disease and protect itself against the
suppressive effects on the bone marrow of
radiation and chemotherapy.
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Cancer vaccines are intended
to induce T cells or other
components of the immune
system to recognize and
vigorously attack malignant
tissue.
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Growth Factors and Cancer
Epidermal Growth Factor (EGF)
Platelet-derived Growth Factor
(PDGF)
Fibroblast Growth Factor (FGF)
Transforming Growth Factors
Insulin-like Growth Factors (IGF1
and IGF2)
Nerve Growth Factors
Interleukins - Colony Stimulating
Factors (CSF1, CSF2, Multi-CSF)
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Chemotherapy: the use of
chemical reagents in disease
processes that have toxic
effects on microorganisms.
Antineoplastic/anticancer
agents-interfere with cell
functions and kill or destroy
malignant cells.
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Drugs in Clinical Trial
Lovastatin is widely used for the
treatment of high serum cholesterol.
When used at high doses, the drug
inhibits signal transduction leading to
growth arrest of high-grade glioma
cells.
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LIGHT-ACTIVATED
MOLECULES
Drugs that block activators of
angiogenesis
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Solid tumors (and even
some blood cancers) can't grow
beyond barely visible size until
they get new blood vessels
through the process of
angiogenesis. In fact, many
tumors remain at that
relatively innocuous stage for
years, and only become
dangerous if and when they
acquire blood circulation.
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The European Union's
commission of the European
communities has granted
marketing authorisation to
Schering-Plough Corp.'s
Temodal(R) (temozolomide)
Capsules for the treatment
ofpatients with glioblastoma
showing progression or
recurrence after standard
therapy.
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ultrasound hyperthermia.
Recombinant cytotoxins specific for cancer cells
Intraoperative image-directed dye marking of
tumor margins (methylene blue)
Gamma Knife radiosurgery
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Cells of the immune system, like those of
other body systems, can proliferate
uncontrollably; the result is cancer.
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Leukemias are caused by the proliferation of
white blood cells, or leukocytes. The uncontrolled
growth of antibody-producing (plasma) cells can
lead to multiple myeloma.
Cancers of the lymphoid organs, known as
lymphomas, include Hodgkin's disease. In general,
these disorders can be treated-some of them
very successfully-by drugs and/or irradiation.
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Burkitt's lymphoma is a solid
tumor of B lymphocytes.
It involves a reciprocal translocation has
moved the proto-oncogene c-myc from its
normal position on chromosome 8 to a
location close to the enhancers of the
antibody heavy chain genes on chromosome
14.
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Burkitt's Lymphoma
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Tumor Suppressor Genes
Tumor Suppressor Genes, like
other genes, are present in two
copies per cell.
When one copy is "knocked
out", cell growth is still normal,
relying on the surviving gene
copy.
Only when this second copy is
also lost does abnormal
proliferation take off.
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Examples of Tumor Supressor Genes
DPC-4 involved in pancreatic cancer; participates in a cytoplasmic pathway that
inhibits cell division
NF-1 involved in neurofibromas of the nervous system and myeloid leukemia;
codes for a protein that inhibits Ras, a cytoplasmic inhibitory protein
NF-2 involved in cancers of the nervous system; codes for a nuclear protein
RB involved in retinoblastoma as well as bone, bladder, small cell lung, and
breast cancers; codes of the pRB protein, a nuclear protein that is a major
brake in the cell cycle
p53 involved in a wide range of tumors; inactive or lost in more than 50% of
cancerous cells; codes for the cytoplasmic p53 protein that regulates cell
division and can induce cells to kill themselves (apoptosis); inheritance of p53
mutations through the germ line is also associated with the Li-Fraumeni cancer
syndrome
WT1 involved in Wilms tumor of the kidneys
BRCA1 involved in breast and ovarian cancer
BRCA2 involved in breast cancer
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Cancer can also result from mistakes in the
somatic recombination process that gives
rise to antibodies and T cell receptor
proteins.
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