Download the immunobiology of cancer

Instituto Superior Técnico
Biomolecular and Cellular Engineering
2010/2011
Ana Ferreira no.58446
Marta Meneses no.58415
MEBM
WHAT IS A CANCER?
WHEN A CELL OR A GROUP OF CELLS DISPLAY:
Uncontrolled growth;
Invasion;
Metastasis (sometimes);
IS INDUCED BY A SET OF GENETICAL MUTATIONS:
Virus;
Drugs;
Radiation…
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Cancer Immunology
Study of interactions between the immune
system and cancer cells
Recognition of cancer-specific antigens
Knowledge gained drives the development of new vaccines and antibody therapies.
Over the past 10 years there has been notable progress and an accumulation of
scientific evidence for the concept of cancer immunosurveillance and immunoediting
Protection against development of
spontaneous and chemically-induced
tumors in animal systems
Identification of targets for immune
recognition of human cancer
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ADAPTATIVE IMMUNE SYSTEM
• Protects the host from infectious pathogens, evolving
mechanisms to generate a diverse repertoire of
antigens-specific T and B cells.
DISADVANTAGE
It contains cells that are able to recognise and attack the host’s own
tissues, but such cells are controlled and prevented from responding
to self tissues.
This is controled by
a network of
antigen-presenting
cells (APC)
Most important
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DENDRITIC CELLS
FUNCTION
Process antigen material and present it on the surface
to other cells of the immune system
THEY ARE PRESENT IN…
Tissues that are in contact with the external environment,
mainly in skin and the inner lining of the nose, lungs,
stomach and intestines.
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Tumors do not induce an effective inflammatory
response conducive for optimal activation of
DCs.
The primary purpose of
vaccinating individuals with
cancer is
LIMITATIONS:
•They
are
administered
therapeutically in the cancer
patient in the face of a
preexisting antigenic load (the
tumor);
•Immune
responses
are
suppressed in cancer patients
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SOLUTION
Immunize cancer patients with autologous,
patient-derived DCs loaded with tumor
antigens ex vivo.
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Ex-Vivo generation of DCs
Human DCs
CD34+ hematopoietic
progenitors
Goal
Generated
from
Peripheral blood-derived
monocytes
Generate population of antigen-loaded DCs that
stimulates robust and long-lasting CD4+ and CD8+ T cell
responses
Rate-limiting step
Inability to fully recapitulate activation process
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Activation Process
Two stages
In Periphery
Immature DCs undergo
maturation process
consequently
Response to inflammatory stimuli
DCs acquire capacity to home to lymph nodes ( migration)
DC migration
controlled by leukotrienes ( LTD4 and LTE4), which act
downstream of CCR7 signaling
Reaching the lymhp node ,antigen-loaded mature DCs
undergo other activation step - Licensing
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ENHANCING DC MATURATION
• Pathogen-mediated maturation of DCs is mediated
mainly through the TLRs that are expressed on
immature DCs.
• Cytokines are also capable of promoting DC
maturation
but cannot substitute for TLR
stimulation.
PROBLEM
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OPTIMAL EX VIVO DC MATURATION:
Require a combination of both cytokines and TLR
ligands, with enhanced antitumor immunity and
clinical efficacy.
Extending the persistence and presentation of antigen by DCs in the lymph node
enhances the ensuing immune response.
DCs that are presenting antigen in the lymph node are prone to elimination by
their cognate T cells.
METHODS TO ENHANCE DC
VIABILITY
Generating DCs expressing antiapoptotic proteins or using siRNA to decrease the
expression of proapoptotic proteins should also potentiate their immunogenicity.12
Design of cancer vaccines
Important things to consider
Form of antigen used to load DCs
How much antigen
Efficiency of loading
Persistence
Timing
Form of
antigen
Exogenous
Peptides,whole protein, tumor
lysate or complexed with antibody
Endogenous
Transfection with mRNA or cDNA
encoding the antigen
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Design of cancer vaccines
Antigen quantity, persistence and timing
There is a discrepancy between the amount of antigen expressed by DC and
stimulatory capacity of DC in vivo
Immune system is high sensitive in detection of antigen at very low
concentrations
Immune system has the ability to respond to antien at low concentration
Antigen loading increased
Protective immunity in patient might be
diminished
It takes several hours for DCs to reach lymoh nodes
There is a correlation between antigen persistence in DC and magnitude of
immune response
Nucleic acid-encoded antigens
provide supply of antigen over an
extended period of time
Loading immature DCs is more effective than loading mature DCs
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Design of cancer vaccines
Which antigens?
Debated
issue
Broadly expressed,
well defined antigens
Antigenic mixtures
More potent form of antigen
Contains tumor-specific
immunodominant antigens
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CLINICAL TRIALS
GOAL
Targeting different cancers using different
methods of generating DCs, different antigens, and
different antigen-loading techniques.
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DC
VACINATION
IMPORTANT
STEPS
• How the cells are frozen
and thawed;
• How long the cells are
matured;
• At what speed they are
centrifugated;
• The mechanisms of their
administration;
• Time intervals between
boostings.
IT CAN HAVE A CRITICAL IMPACT ON
THE OUTCOME OF THE TREATMENT
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HOW CAN DC VACINES BE IMPROVED?
• Only a few DCs from the vaccination mixture
migrate to the lymph node.
SOLUTION
Use a multineedle device
•The current consensus is that longer time
intervals between boostings are better
RECENT STUDIES
More frequent vaccinations generate a
long-lasting response
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•Are DCs the ultimate professional APC to use in the
setting of cancer vaccination with ex vivo–derived APCs?
What about monocytes, B cells or γδ T cells?
•Vaccination with ex vivo–generated DCs: is it worth the
trouble?
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