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Tumor
immunotherapies:
To stimulate and
enhance tumor-specific
immunity
TUMOR
Tumor (neoplasia): a group of cells that escape immunosurveillance
(MacFarlane Burnet, 1950  immune system recognizes and
destroys transformed cells, and kills tumors)
Benignus: limited growth of cells
Malignus: unlimited growth of cells (cancer)
Metastasis: spreading of tumor cells clones
Carcinoma: derived from embrional ectoderm or endoderm
Sarcoma: derived from mesodermal connective tissues
Leukemia: haematopoietic origin
Lymphoma: derived from bone marrow haematopoietic cells
Malignant transformation of cells is caused by:
•Chemical carcinogenes
•Irradiation
•Virus
mutation, transformation
Tumors and the immune system
How does the immune system eliminate cancer cells?
How do cancer cells escape from Immunosurveilance?
How can we help to win the battle between immune system
and cancers?
Nature Reviews Cancer 4; 11-22 (2004); CYTOKINES IN CANCER
PATHOGENESIS AND CANCER THERAPY
The innate immune response functions as the first line of defence against infection. It consists of
soluble factors, such as complement proteins, and diverse cellular components including
granulocytes (basophils, eosinophils and neutrophils), mast cells, macrophages, dendritic cells
and natural killer cells. The adaptive immune response is slower to develop, but manifests as
increased antigenic specificity and memory. It consists of antibodies, B cells, and CD4+ and CD8+
T lymphocytes.
Possibilities to recognize and kill tumor cells
Lymph node
Inhibition of
angiogenesis
Innate immunity
Acquired immunity
Cancer immunoediting encompasses three processes:
Elimination
Equilibrium
Escape
Tumor heterogeneity, genetical instability
Developing tumor
cells are controled by
immunosurveilance
Survival tumor cell
variants
Immune system selects
and/or promotes the
generation of tumor cell
variants with increasing
capacities to survive
Tumor expands in an
uncontrolled manner in
the immunocompetent
host. New variants
appear.
A proposed model for the elimination phase of the cancer immunoediting process
Principal targets of genetic damage
•
Types of genes that control cancer
•
Four classes of regulatory genes
1.
2.
3.
4.
growth-promoting proto-oncogenes
growth-inhibiting tumor suppressor genes
genes that regulate programmed cell death (apoptosis)
genes involved in DNA repair
Nature Reviews Cancer 2; 850-861 (2002); doi:10.1038/nrc928
NEW ASPECTS OF NATURAL-KILLER-CELL SURVEILLANCE AND THERAPY OF CANCER
NK cells and immune responses to tumour cells.
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- Many tumors do elicit an immune
antigens
response due to tumor
- Many tumors evade host immune response through several
mechanisms
Classification of tumor antigens
• two categories
• based on their patterns of expression
• Tumor-specific antigens - present only on tumor cells and not
on any normal cells
• Tumor-associated antigens - present on tumor cells and also on
some normal cells
Classification of tumor antigens
•
based on their molecular structure and source:
1.
Products of Mutated Oncogenes and Tumor Suppressor Genes
2.
Products of other Mutated Genes
3.
Over expressed or Aberrantly Expressed Cellular Proteins
4.
Tumor Antigens Produced by Oncogenic Viruses
5.
Oncofetal antigens
6.
Altered glycolipids and glycoproteins
7.
Cell type-specific differentiation antigens
Types and appearance of tumorantigens
peptides with
lymphocytes’
antigen
receptor origin
fetal proteins
peptides
due to gene
mutations
proteins with
enhanced
expression
viral
Viral
proteins
proteins
pathological
posttranslational
modifications
TUMOR ANTIGENS
TUMOR ANTIGENS
The role of inflammation in the maintenance of tumor
Modification of
connective tissues
Recruitment of
macrophages, directing
mf differentiation
Proliferation, invasion,
support of metastasis
Tolerance, anergy,
immunosuppression
TAM:
tumor
associated
macrophages
•Tumors arise from accumulated genetic mutations
•Carcinogenesis is a multistep process at both the
phenotypic and the genetic levels
•resulting from the accumulation of multiple mutations
Initiation (mutation)  Transzformation  Promotion:
increased capacity to proliferate uncontrolled
proliferation, Immortalization
TUMOR ANTIGENS
• Products of mutated genes
• derived from the products of mutant proto-oncogenes, tumor
suppressor genes, or other mutated genes
• synthesized in the cytoplasm of tumor cells, and like any
cytoplasmic protein, they may enter the class I MHC
antigenprocessing pathway and be recognized by CD8+ T
cells
• In addition, these proteins may enter the class II antigenprocessing pathway in antigen-presenting cells that have
phagocytosed dead tumor cells, and thus be recognized by
CD4+ T cells also
Oncogene:
Gene coding a protein inducing cell transformation
1910: Rous sarcoma virus: v-src (c-src) 1966 Nobel prize
In normal, non-malignant cells: proto-oncogenes
controling cell proliferation, cell cycle, survival, or
regulate apoptosis
Their are modified as a result of mutation, or
translocation
quantity,
function
Tumor genes
Several hundreds of tumor genes were identified, more
than 1 % of the human genom
90 % somatically mutated, 20 % embrional mutation,
10 % both
Very frequent: chromosomal translocation – chimera
gene
The most genes were identified in leukemia, lymphoma
and sarcoma
The most common domains coded by tumor genes:
protein kinases
Tumor specific antigenes
Carcinogen
effect
mutation
„private
antigenes”
protein
recognition by T cells
+ altered
peptide
Chromosomal translocation in Burkitt’s lymphoma
EBV (Epstein-Bar virus) infection: c-myc is translocated to
the enhancer region Ig H chain uncontrolled proliferation
of B cells
Specific molecular pathways (subway
lines) are responsible for programming
malignant transformation behaviours
The tumor and the immune system
Tumor cells’ attack against T cells
The Fas counterattack. Cancer cells are frequently resistant to apoptosis mediated through Fas. This might
be a result of downregulation of Fas or the release of soluble Fas, or abnormalities in the level of several
proteins involved in the signal transduction cascade.
Mechanisms of tumour-cell escape from T-cell recognition
• antigen processing is
inhibited in tumor
cells
MHCI, TAP,
proteasoma
• FasL expression
increases
apoptosis of T cells
• production of
inhibitory cytokines
(IL-10, TGFβ)
How to escape from immune attack
Lack of co-stimulation
Physical
protection
(mucin)
Tumor Immunotherapy:
incease tumorspecific immune rsponse of the host
TUMOR ANTIGENS – elicit immune response
lymphocyte dependent
specific
anti tumor antibodies can be detected
memory
„Immunsurveilance” – to destroy tumor cells
tumor specific antigens (TSA) – MHC bound peptides
tumor associated antigens (TAA) - product of embrionic tissues
50x- 100x higher expression
Isolation of tumor antigens:
•
cDNS library - CTL clones,
•
by elution of peptides from surface of tumor cells by acidic elution
The immune
system recognizes
tumor:
Anti-tumor response
Tumor specific
CTL induction
CD8+
Tc-sejt
cytokines
Separation of
tumor antigens
Upload of dendriic
cells with tumor ag
Genetical
modifications :
MHCII expression
Tumorspecific
CTL
Types of immunotherapy
• Passive immunotherapy:
• Adminstration of monoclonal antibodies
which target either tumour-specific or overexpressed antigens.
• Active immunotherapies:
• Cytokines- IL-2 / IFNs / TNFα
• Cancer vaccines
• Cell-based therapies
• tumour-specific CTL
• tumour-derived APC
• DC priming
Current strategies in experimental immunotherapy of tumors
FDA-approved therapeutic
monoclonal antibodies
CD20
Her2
CD33
CD52
CD20
CD20
EGF-R
VEGF
Monoclonal antibody therapy
• monoclonal antibodies that bind only to cancer cellspecific antigens and induce an immunological response
against the target cancer cell.
• Naked mAbs :antibodies that work by themselves. boost
a person’s immune response against cancer cells.
• blocking specific proteins that help cancer cells grow.
Eg. Trastuzumab-HER2
• Conjugated mAbs: are those joined to a chemotherapy
drug, radioactive particle, or a toxin
• Radiolabelled: Ibritumomab tiuxetan and tositumomab –
CD20Ag
• Chemolabeled: brentuximab vedotin -CD30 antigen
• Immunotoxins: denileukin diftitox
Therapeutic antibodies
Monoclonal antibodies for cancer. ADEPT, antibody directed enzyme pro
drug therapy; ADCC, antibody dependent cell-mediated cytotoxicity; CDC,
complement dependent cytotoxicity; MAb, monoclonal antibody; scFv
single-chain Fv fragment
Antibody directed enzyme-prodrog therapy
Checkpoint antibodies
Treatments that target PD-1 or PD-L1
PD-1 is a checkpoint protein on immune cells called T cells. It normally acts as a type of
“off switch” that helps keep the T cells from attacking other cells in the body. It does this
when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds
to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells have
large amounts of PD-L1, which helps them evade immune attack.
Monoclonal antibody treatments that target either PD-1 or PD-L1 can boost the immune
response against cancer cells and have shown a great deal of promise in treating certain
cancers. Examples of treatments that target PD-1 include:
Pembrolizumab (Keytruda®)
Nivolumab (Opdivo®)
Treatments that target CTLA-4
CTLA-4 is another protein on some T cells that acts as a type of “off switch” to keep the
immune system in check.
Ipilimumab (Yervoy®) is a monoclonal antibody that attaches to CTLA-4 and stops it from
working. This can boost the body’s immune response against cancer cells.
This drug is used to treat melanoma of the skin. It is also being studied for use against other
cancers.
Because ipilimumab affects the immune system, it can sometimes cause serious or even lifethreatening side effects. In fact, compared to drugs that target PD-1 or PD-L1, serious side
effects seem to be more likely with ipilimumab.
„Signaling” antibodies
binding - signal  intracellular signaling  apoptosis
anti-CD20 (Rituximab)
CD20: B cells, Ca2+ chanel,
Non-Hodgkin lymphoma: 50%
Her2 (neu) (Herceptin)
Her-2 protoonkogen product, EGFR family
breast cancer: 14%
anti-CD52: Campath-1H
CLL, T prolympocytic leukaemia
Solid tumor: anti-Her-2: receptortis inhibited and downregulated
tyrosine kinase 
Cytokine based cancer therapy
Cancer vaccines
• Tumor cell vaccines: made from actual cancer
cells that have been removed during surgery.
• Antigen vaccines: These vaccines boost the
immune system by using only one antigen
rather than whole tumor cells
• Dendritic cell vaccines: special immune cells
in the body that help the immune system
recognize cancer cells
• DNA vaccines: Vectors can be given bits of
DNA that code for protein antigens.
• When the vectors are then injected into the body,
this DNA might be taken up by cells and can
instruct them to make specific antigens
 Tumor specifikus CTL
+
 Tumor antigént
bemutató sejtek
 tumor ag.
Induction of tumor specific T cell response
Vaccination with dendritic cells
Dendritic Cell based Immunotherapy
Methods of
purification of
naturally processed
tumor peptides
 Liposome (MHCII)
 chimeric bacteria
(MHCII)
Virus chimera –
minigene (MHCI)
Therapeutical application of peptides
Synthetic peptides
Native peptides
advantages
Specificity of the response
mixture of many antigens
unlimited
can be used in many patients
Homogeneous, pure
CD4, CD8+T cells are activated
Can be controlled by a few cells
CD4, CD8 T activation
disadvantages
No tumor specificity,
many tumor cells are needed
For a few patients only,
low concentration
Mutant cells may escape,
autoimmunity?
Autoimmunity
Vaccination with tumor cells
Therapeutic cancer vaccines
Pramod K Srivastava
The immunological bases of current approaches to therapeutic
cancer vaccination (or ‘vacci-treatment’) have been
established for a decade or longer. The new developments lie
mostly in the lessons learnt from clinical testing of these
approaches. Three lessons are particularly worthy of note.
First, recently completed randomized Phase 3 trials suggest
that vacci-treatment with autologous dendritic cells expressing
prostatic acid phosphatase (for prostate cancer) or with
autologous tumor-derived heat shock protein (gp96)–peptide
complexes show promise in enhancing survival of cancer
patients. These two approaches are undergoing further
randomized clinical testing. Second, immunological
monitoring of many clinical trials has failed to identify a
surrogate marker for clinical outcomes. Finally, an increasing
volume of literature suggests that protective immunity to
human cancers is elicited by the mutated antigenic repertoire
unique to each cancer.
Adoptive-cell-transfer therapy for patients with cancer
Limfocita depletion
”non-myeloablative”
Melanoma metastasis treatment
Vaccines to protect against HPV infection
and the subsequent risk of cervical cancer have recently
become available, based on virus-like particle (VLP)
technology. VLPs are produced by expressing the capsid
proteins of the virus using recombinant DNA
technology. When expressed in eukaryotic cells, the L1
major capsid protein self-assembles into 360-mer
particles that physically and immunologically resemble
the native virion. These highly immunogenic
particles can, when administered as a vaccine
with alum based adjuvants, protect not only
against infection with the HPV types incorporated
in the vaccine and some cross-reactive HPV types
but also against the consequent premalignant
disease
Protection is durable over at least five years, and the
vaccine appears to protect nearly 100% of immunised
subjects.
Human
Papilloma
Virus
Human papilloma virus
Manipulation of antitumour immune responses by therapeutic
vaccination.
Metastases that continue to grow are composed of
tumour cells that lack antigens recognized by T cells and
antibodies or are otherwise resistant to immune
Manipulation of antitumour immune responses by prophylactic
vaccination.
„high risk” indviduals
Reactivation of
tumor specific
memory cells