Principles of carcinogeneis and

anticancer therapy
Dr Indranil Ghosh
Senior consultant and Hony Prof (AHERF)
Department of Medical Oncology,
Apollo Cancer Center
Kolkata, India
 Overview
• Hallmarks of cancer
• Carcinogenesis
– Chemical
– Viral
– Physical
• Anticancer therapy
– chemotherapy
– Molecularly targeted therapy
– Immunotherapy
 Hallmarks of cancer
• Eight biologic capabilities acquired by cancer
cells during the multistep development of
human tumors.
 1. Sustaining Proliferative Signaling
• Normal tissues carefully control the production and
release of growth-promoting signals that instruct the
entry of cells into and progression through the cellular
growth-and-division cycle, thereby ensuring proper
control of cell number
• Maintenance of normal tissue architecture and function
• Cancer cells, by deregulating these signals, become
masters of their own destinies, being no longer
dependent on proliferation-promoting signals arising
from elsewhere in their tissue and elsewhere in the
body
• Growth factors bind cell-surface receptors,
typically containing intracellular tyrosine kinase
domains
• The latter proceed to emit signals via branched
intracellular signaling pathways that regulate
progression through the cell cycle as well as cell
growth (i.e., increase in cell size)
• Often these signals influence yet other cell-biologic
properties, such as cell survival and energy
metabolism
 Somatic Mutations Activate Additional
Downstream Pathways
• Tens of thousands of human tumors have been found to harbor mutant,

oncogenic alleles of the K-RAS protooncogene, most of which have sustained

point mutations in the 12th codon, which results in RAS proteins that are

constitutively active in downstream signaling.

• Downstream effectors that further transmit the signal conveyed by

guanosine triphosphate (GTP)–bound RAS proteins.

• <40% of human melanomas contain activating mutations affecting the

structure of the B-RAF protein, resulting in constitutive signaling through the

RAF oncoprotein to the mitogenactivated protein (MAP)–kinase pathway

 Disruptions of Negative-Feedback Mechanisms
that Attenuate Proliferative Signaling
• Negative-feedback loops normally operate to
dampen various types of signaling and thereby
ensure homeostatic regulation of the flux of
signals coursing through the intracellular
circuitry
 2. Evading Growth Suppressors
• Tumor suppressors operate in various ways to
limit cell proliferation or survival
• Two prototypical tumor suppressor genes
encode the retinoblastoma (RB)-associated
and TP53 proteins
 3. Resisting Cell Death
• The ability to activate the normally latent
apoptotic cell-death program appears to be
associated with most types of normal cells
throughout the body
• Cancer cells often, if not invariably, inactivate
or attenuate this program during their
development
Autophagy Mediates Both Tumor Cell Survival and Death
4. Enabling Replicative Immortality
• Cancer cells require unlimited replicative potential
• When cells are propagated in culture, repeated
cycles of cell division lead first to induction of
replicative senescence and then, for those rare cells
that succeed in surmounting this barrier, to the
crisis phase, in which the great majority of cells in
the population die
• On rare occasion, cells emerge from a population in
crisis and exhibit unlimited replicative potential.
This transition has been termed immortalization
• The telomere-associated DNA, composed of
multiple tandem hexanucleotide repeats,
shortens progressively in the chromosomes of
nonimmortalized cells propagated in culture,
eventually losing its ability to protect the ends
of chromosomal DNA from end-to-end fusions
• Telomerase, the specialized DNA polymerase
that adds telomere repeat segments to the
ends of telomeric DNA, is almost absent in
nonimmortalized human cells but is expressed
at functionally significant levels in the great
majority (>90%) of spontaneously
immortalized cells, including human cancer
cells.
 5. Inducing Angiogenesis
• Tumors require sustenance in the form of nutrients
and oxygen as well as an ability to evacuate
metabolic wastes and carbon dioxide
• The tumor-associated neovasculature, generated by
the process of angiogenesis, addresses these needs
• During tumor progression, an angiogenic switch is
almost always activated and remains on, causing
normally quiescent vasculature to continually sprout
new vessels that help sustain expanding neoplastic
growths
6. Activating Invasion and Metastasis
 7. Reprogramming Energy Metabolism
• Otto Warburg first observed an anomalous
characteristic of cancer cell energy metabolism
– Even in the presence of oxygen, cancer cells can
reprogram their glucose metabolism, and thus their
energy production, leading to a state that has been
termed aerobic glycolysis.
• A key signature of aerobic glycolysis is
upregulation of glucose transporters, notably
GLUT1, which substantially increases glucose
import into the cytoplasm
8. Evading Immune Destruction
• Two ubiquitous characteristics facilitate the
acquisition of hallmark capabilities
– Genome Instability and Mutation
– Tumor-Promoting Inflammation
Genomic instability
Tumor-Promoting Inflammation
TUMOR MICROENVIRONMENT
Carcinogenesis
Chemical carcinogenesis
 Lawrence A. Loeb, and Curtis C. Harris Cancer Res
2008;68:6863-6872

©2008 by American Association for Cancer Research

 Lawrence A. Loeb, and Curtis C. Harris Cancer Res
2008;68:6863-6872

©2008 by American Association for Cancer Research

Tobacco
Viral carcinogenesis
HPV
EBV
Physical factors
Radiation and cancer
• 1895- Roentgen discovered X-rays
• 1896- Henri Becquerel discovered radioactivity
• 1897- Rutherford discovered α and β rays
• 1898- Curies discovered polonium and radium
• 1902- First report on radiation-induced skin
cancer
• 1911- First report of leukemia in 5 radiation
workers
• Types of radiation
• Ionizing radiation:
• - α particles (2 protons and 2 neutrons)
• - β particles (electron equivalent)
• - Neutrons
• - Gamma rays
• - X-rays
• Non-ionizing radiation:
• - Microwaves
• - Visible light
• - Radio waves and TV waves
• - UV radiation (except shortest wavelengths)
• Radiation-induced cancer in human
– Atomic bomb survivors
– Accidents
– Medically exposed individuals including cancer
patients undergoing radiation therapy
 Anticancer therapy
• Surgery
• Radiotherapy
• Systemic therapy
– Chemotherapy
– Molecularly targeted therapy
– Immunotherapy
Precision
oncology
 Drugs directly interacting with
DNA
Intercalating agents
Mechanism of action

• Contain planar aromatic or heteroaromatic ring systems

• Planar systems slip between the layers of nucleic acid pairs and disrupt
the shape of the helix
• Preferenc e is often shown for the minor or major groove
• Intercalation prevents replication and transcription
• Intercalation inhibits topoisomerase II (an enzyme that relieves the strain
in the DNA helix by temporarily cleaving the DNA chain and crossing an
intact strand through the broken strand.
 Intercalating
agents

Dactinomycin Doxorubicin (Adriamycin)

(Extra binding to sugar (Extra binding to sugar

phosphate backbone by cyclic phosphate backbone by
peptide) NH3)
Intercalating reagents (II)
•During replic a tion, superco iled
DNA is unwound by the helic a se.
The thereby created tension is
removed by the topoisomerase II,
that cuts and rejoins the DNA
strands.
•When doxorubicin is bound to the
DNA it stabilizes the DNA-topoII
complex at the point where the
enzyme is co valently bound
Natural Products in Cancer
Therapy: Bleomycins

• intercalate via the bithiazole moiety

• the N-atoms of the primary amines, pyrimidine ring and imidazole
ring chelate Fe, which is involved in the formation of superoxide
radic a ls, which subsequently act to cut DNA between purine and
pyrimidine nucleotides
 Drugs directly interacting with DNA
Alkylating agents
• C ontain highly electrophilic groups
• Form covalent bonds to nucleophilic groups in DNA
• Attack N-1 and N-3 of adenine and N-3 of cytosine,
and in particular N-7 of guanine bases
• Prevent replication and transcription
• Useful as anti-tumour agents
• Toxic side effects (e.g. alkylation of proteins)

Intrastrand cross linking Interstrand cross

linking
 Nitrosoureas
• Lomustine and carmustine are lipid-soluble and can cross
the blood-brain barrier
• The drugs deco mpose to form alkylating and
c a rbamoylating

•the formed isocyanate reacts with lysine

NH3 groups thereby inactivating DNA repair
enzymes
•the alkylating agent reacts first with O-6
of guanine followed with N-3 of cytosine
of the
other strand
 Pt-Alkylating agents

• Binds to DNA in regions rich in guanine units

• Intrastrand links rather than interstrand
• Inhibits transcription
•In solution the Cl- ligands are exchanged against water to
result in positively charged ligands that bind to the DNA (to N-
7 or O-6 of adjacent guanine groups)
• Results in localized unwinding of the DNA
 NH3
NH3
H3N Cl NH3
Pt NH3 Pt
Pt

H3N Cl

Cisplatin

Guanine N7 position
H
H ..
N O N
7 Replication inhibition
N
C N H G Transcription inhibition
N N N Cell-cycle arrest
O DNA repair
H N Cell death
H
 DNA chain
cutters

Calicheamicin
γ 1I
Antitumor
agent

• Generates DNA diradical

• DNA diradic a l reacts with oxygen
• Results in chain cutting
 Antimetabolites
• inhibit the synthesis of DNA or nucleotide building
blocks
• Dihydrofolate reductase inhibitors

methotrexate

source of one-C unit for methylations of

deoxyuridinemonophosphate (dUMP) to
form deoxythymidinemonophosphate
(dTMP)
 Antimetabolites
• Thymidylate synthase
inhibitors

• 5-Fluorourac il acts as an suicide

inhibitor
 Antimetabolites
• Inhibitors of ribonucleotide reductase
•enzyme converts ribonucleotide diphosphates into
desoxyribonucleotide diphosphates, inhibited by Hydroxycarbamide

• adenosine deaminase inhibitors, e.g.

Pentostatin

Pentostati
n
 Antimetabolites:
Pyrimidine Purine antagonists
antagonists
Hormone-based Anti-Cancer Therapies
• steroid hormones bind to nuclear receptors and act as transcription factors
• if the cancer requires a specific hormone, a hormone resulting in the
opposite effect can be administered
• Used: glucocorticoides (hormones involved in the biosynthesis of glucose,
e.g. prednisolone), oestrogens, progestins (e.g. medroxyprogesterone
acetate), analogues of the luteinizing hormone-releasing hormones (LHRH)
Drugs acting on structural proteins
•mitosis is a ordered series of events in which identical copies of
the genome are moved to discrete locations within the dividing
cell
•The mitotic spindle is very important for that event. The filaments in
the mitotic spindle are formed from microtubule

• microtubule are cytoskeletal elements present in all eukaryotic cells.

• they are composed of α- and β-subunits
•both, formation (polymerization) and destruction
(depolymerization) of microtubules are important for proper
execution of cell division
•drugs interfering with microtubule polymerization/depolymerization interfere with
mitosis , cause cell-cycle arrest and trigger apoptosis
Drugs acting on structural proteins
Inhibitors of tubulin polymerization

• vinca alkaloids from the Madagascar periwinkle

plant
• can be substrate for the P-glycoprotein efflux pump
Drugs acting on structural proteins
Inhibitors of tubulin depolymerization
Epothilon
Taxol e

• Taxol is harvested from the bark of the yew trees

• binds to the β-subunit of tubulin and ac c e lerates
polymerization
•the resultant microtubules are stabilized,
inhibiting depolymerization
• ce ll cycle is halted at the G 2/M stage
• prepared semi-synthetically from a compound
from yee needles
• cannot be taken orally
• c a uses multidrug resistanc e (substrate for
p-glyco protein)
•ephothilones are bacterial metabolites. They are not substrate
for P-GP
 Tyrosine Kinase Inhibitors
• Small molecule tyrosine kinase inhibitors (or TKIs) – generic names end in
“-nib”
• Generally oral
• Side effects vary, depending on which enzymes they inhibit (what their target
is)
• Several are effective against cancers resistant to most previous therapies

Generic Name Brand Name Cancer

Imatinib Gleevec CML, GIST, others

Dasatinib Sprycel CML, ALL

Nilotinib Tasigna CML

Gefitinib Iressa Lung

Erlotinib Tarceva Lung, Pancreas

Lapatinib Tykerb Breast

Sorafenib Nexavar Kidney, Liver

Sunitinib Sutent Kidney

 Strategies for targeting kinases
Small molecule
inhibitors of ligand–
Proteolysis Anti-receptor Anti-ligand receptor binding
mAbs mAbs (unarmed
or armed) Ligand–
e toxin
conjugate
Protein

a AT
P

b
ATP competitors
Protein

c
RNA
Antisense to receptor or ligand
d Nucleus

DNA

• inhibition of ATP binding (a) • antibodies against the ligand-binding epitope

• inhibition of kinase folding (b)
• inhibition of translation (siRNA, c)
• inhibition of transcription
(antisense, d)
• antibodies against the bound ligand
• ATP co mpetitors
• ligand antagonists
Dancey et al. Nature Rev Drug Discov. 2
(2003),296
 Inhibitors of G rowth Factors: Targeting the EG F
receptors, a TK receptor

• Overexpression of altered Epidermal G rowth Factor rece ptors

results (EG FR, ERBB family) in formation of a onco gene.

Ligand (EGF,
TGF) Cl
EGFR
F

O NH
Autophosphorylation morpholine
N O
N groups improves
T T P TK
K K Gefitini TK P O N solubility
b
Gefitinib (ZD1839)
Activation of signal-transduction ATP
cascades (for example, MAPK)
competitor
IC50 (EGFR) = 0.033 M
Cell Invasion and IC50 (ERBB2) >3.7 M
proliferatio Apoptosis metastasis Angiogenesis
n IC50 (KDR) >3.7 M
IC50 (FLT-1) >100 M

metabolite of metabolite of
lead I I
Inhibitor of the Abelson Tyrosine
•
Kinase (BCR- ABL)
the BCR-ABL kinase is the sole oncogene responsible in
rare blood cancer
• Inhibition of autophosphorylation of BCR-ABL by Gleevec
• treatment of BCR-ABL transformed cell-lines with Gleevec
results in dose-dependent reduction of tumor growth
• the anti-tumor effect is specific for BCR-ABL expressing cells
• Gleevec re-activates apoptosis in BCR-ABL cells
 Angiogenesis Inhibitors
Targeting the VEG F rece ptor, a protein tyrosine

• elevated levels of fibroplast growth factors

(FGF) and vascular endothelial growth
factor (VEGF) receptor are associated
with angiogenesis
• VEG F is regulated by multiple cytokines,
e.g. the transforming growth factor (TGF-β),
the epidermal growth factor (EGF) and the
platelet- derived growth factor (PDGF)
• inhibitors mostly target the ATP binding site
other kinase targets: platelet-derived growth
factors (PDGF-R), mitogen-activated protein
kinases (MAPK), insulin growth factor 1
rece ptor (IGF-1R), protein kinase B (PKB), c-
Src tyrosine kinase, inositol triphosphate
kinase (IP3K)
 Inhibitors of cyclin-dependent kinases, S/T kinases
• CDKs are important for the Growth factors
CHK1 G0
control of the cell-cycle
(mainly at G1/G2 depending Cdc25
Cdk4,6 / Cyclin D1, D2, D3

on DNA damage for Cdk1 / Cyclin B

Mitosis
G1 Cdk2 / Cyclin E E2F
p53

example)
CHK2
BRCA1
Cdc25

• Ser/Thr kinases G2
S phase
Cdk3

• they are activated by Cdk1 / Cyclin A

Cdk2 / Cyclin A Cdk5
Cdk7
cyclins and inhibited by Non-
cell Opinion in Pharmacology
cyclin- dependent kinase Current
cycle

inhibitors Cdk8

funct
ions
Cdk9
Proteasome Inhibitors
• is the unit for degradation of damaged or misfolded proteins,
but also degrades protein involved in regulation
• protein marked for degradation are labeled with ubiquitin
• inhibiting the proteasome leads to accumulation of
regulatory proteins such as the apoptosis promoter Bax
• Accumulation of regulatory proteins leads to cell crisis
and triggers apoptosis

Bortezomi Aclarubicin
b
 Antibody Cancer Therapy
•The killing of tumour cells using monoclonal antibodies (mAbs)
can result from direct action of the antibody (through receptor
blockade, for example), immune-mediated cell killing mechanisms,
payload delivery, and specific effects of an antibody on the tumour
vasculature and stroma.
•Tumour antigens that have been successfully targeted include
epidermal growth factor receptor (EGFR), ERBB2, vascular endothelial
growth factor (VEGF), cytotoxic T lymphocyte- associated antigen 4
(CTLA4), CD20, CD30 and CD52.
•Serological, genomic, proteomic and bioinformatic databases have
also been used to identify antigens and receptors that are
overexpressed in tumour cell populations or that are linked to gene
mutations identified as driving cancer cell proliferation (tumor
markers).
 Antibody Cancer Therapy

Weiner et al., Nature Rev. Cancer 15, 361–370

 Antibody Applications

Scott, Nature Rev. Cancer, 12 (2012),

278
Antibody Modifications

Weiner et al., Nature Rev. Cancer 15, 361–370 (2015)

 Nomenclature of Monoclonal
Antibodys
• Last syllable is always –mab
• Next to last syllable
▪ -u- human (100%) : Panitumumab
▪ -zu- humanized (95%) : Trastuzumab
▪ -xi- chimeric (65%) : Rituximab
▪ -o- mouse, -a- rat, -e- hamster, -i- primate :
Tositumomab
• Previous syllable
– -tu(m)- for tumor in general [-ma(r)- breast, -pr(o)-
prostate,
-co(l)- co lon, etc.]
– -ci(r)- for circulatory : Bevacizumab
Scott, Nature Rev. Cancer, 12
(2012),
Cytotoxic T-cell Targeting
bispecific antibody
HEA125xCD3

carcinoma cell
cytotoxic
T
lymphocyte
Ep-
CD3
CAM

Kill
Targets of
Antibody Targets
VEGF Bevacizumab Tumour vasculature
anti-angiogenic VEGFR IM-2C6 and CDP791 Epithelium-derived solid tumours
mAbs
Integrin αVβ3 Etaracizumab Tumour vasculature
Integrin α5β1 Volociximab Tumour vasculature

Growth EGFR Cetuximab, Glioma, lung, breast, colon, and head

and panitumumab, and neck tumours
differentia nimotuzumab and
tion 806
signalling ERBB2 Trastuzumab and pertuzumab Breast, colon, lung, ovarian and prostate
tumours
ERBB3 MM-121 Breast, colon, lung, ovarian and prostate,
tumours
MET AMG 102, METMAB and SCH 900105 Breast, ovary and lung tumours
IGF1R AVE1642, IMC -A12, MK-0646, Glioma, lung, breast, head and neck,
R1507 and CP 751871 prostate and thyroid cancer
EPHA3 KB004 and IIIA4 Lung, kidney and colon tumours, melanoma,
glioma and haematological malignancies
TRAILR1 Mapatumumab (HGS-ETR1) Colon, lung and pancreas
TRAILR2 HGS-ETR2 and CS -1008 tumours and haematological
malignancies
RANKL Denosumab Prostate cancer and bone metastases
Stromal and FAP Sibrotuzumab and F19 Colon, breast, lung, pancreas, and head
extracellular and neck tumours
matrix
CAIX, antigens
carbonic Tenascin
anhydrase IX; 81C6EGFR, epidermal growth factor receptor;Glioma,
CEA, carcinoembryonic antigen; breast and
EpCAM, epithelial prostate
cell adhesion tumours
molecule; EPHA3,
ephrin receptor A3; FAP, fibroblast activation protein; gpA33, glycoprotein A33; IGF1R, insulin-like growth factor 1 receptor; Le y, Lewis Y antigen; mAbs,
monoclonal antibodies; PSMA, prostate-specific membrane antigen; RANKL, receptor activator of nuclear factor -κB ligand; TAG-72, tumour-associated
glycoprotein 72; TRAILR, tumour necrosis factor-related apoptosis-inducing ligand receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGF
receptor.
Table 2 | Tumour-associated antigens targeted by therapeutic monoclonal antibodies in
oncology
Antigen category Examples of Tumour types expressing antigen
Examples of
antigens therapeutic mAbs
raised against these
targets
Haematopoie CD20 Rituximab Non-Hodgkin’s lymphoma
tic Ibritumomab tiuxetan and tositumomab Lymphoma
differentiation
antigens CD30 Brentuximab vedotin Hodgkin’s lymphoma
CD33 Gemtuzumab ozogamicin Acute myelogenous leukaemia
CD52 Alemtuzumab Chronic lymphocytic leukaemia
Glycoproteins EpCAM IGN101 and adecatumumab Epithelial tumours (breast, colon and lung)
expressed by CEA Labetuzumab Breast, colon and lung tumours
solid tumours
gpA33 huA33 Colorectal carcinoma
Mucins Pemtumomab and oregovomab Breast, colon, lung and ovarian tumours
TAG-72 CC49 (minretumomab) Breast, colon and lung tumours
CAIX cG250 Renal cell carcinoma
PSMA J591 Prostate carcinoma
Folate-binding protein MOv18 and MORAb-003 Ovarian tumours
(farletuzumab)
Glycolipids Gangliosides (such 3F8, ch14.18 and KW-2871 Neuroectodermal tumours and some
as GD2,
Scott, Nature Rev. Cancer, GD3 and
12 (2012), epithelial tumours
278 GM2)
Carbohydrates Ley hu3S193 and IgN311 Breast, colon, lung and prostate tumours
blocks binding receptor can receptor
site of EGF still cannot
IMMUNOTHERAPY
 T-Cell Activation:
Signal 1 – Antigen Recognition
MHC with
antigen

Infected
APC

Pathogen

T cell

APC
TCR MHC

APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor.
Adapted from Coico R, et al. Immunology: A Short Course. 5th ed. Wiley-Liss, 2003; Abbas AK, et al. Cellular and Molecular Immunology. 5th ed. 2005, Elsevier
Saunders.
 T-Cell Activation:
Signal 2 – Costimulation

CD28 B7
Costimulatory
molecules

T cell

APC

TCR MHC

APC = antigen -presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor.
Adapted from Coico R, et al. Immunology : A Short Course . 5th ed. Wiley-Liss, 2003.
 T-Cell Activation: Consequences
Proliferation

CD28 B7
Costimulatory
molecules
Survival

T-cell
activation
T cell
APC

Cytokine
TCR MHC production

APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor.
Adapted from Coico R, et al. Immunology : A Short Course . 5th ed. Wiley-Liss, 2003; Male D, et al. Immunology. 7th ed. Mosby Elsevier, 2006.
 Immune Tolerance
• Immunological tolerance is the failure to mount
an immuneresponse to an antigen
• Immune system must distinguish self antigens from
non-self antigens to function properly1
– Immune response must avoid using destructive mechanisms meant for foreign
substances against own host tissues

• Immune system discriminates self from non-self

through central and peripheral tolerance2
• Recognition of tumor antigens as non-self keeps tumor
growth in check3
– Some tumors escape the immune system by altering components of immunity
resulting in induction of tolerance (failure to recognize non-self)
1. Chaplin DD. J Allergy Clin Immunol. 2010;125(suppl 2):S3-23. 2. Simmonds MJ, Gough SC. Br Med Bull. 2005;71:93-113. 3. Drake CG, et al. Adv Immunol.
2006;90:51-81.
 The Three E’s of Cancer Immunoediting
Elimination Equilibrium Escape
Cancer Immunosurveillance Cancer Dormancy Cancer Progression
• Effective antigen • Genetic instability • Tumors may avoid elimination
processing/presentation • Tumor heterogeneity by the immune system
• Effective activation and • Immune selection through outgrowth tumor cells
function of effector cells that can suppress, disrupt, or
– eg, T-cell activation without “escape” the immune system
co-inhibitory signals

CD4+ T cell
NK cell
CD8+
T cell
Treg

Tumor Cells

Normal Cells

Treg = regulatory T cell.

Vesely et al. Ann Rev Immunol. 2011;29:235–271.
 Regulation of T-Cell Activation
APC/ T-cell
Tumor
• The amplitude and quality of a
T-cell response is regulated by B7-2 (CD86) CD28 Activation
a balance between multiple
co-stimulatory and co-inhibitory B7-1 (CD80) CTLA-4 Inhibition
signals
PD-L1 PD-1 Inhibition
• Immune checkpoints limit, or “check,”
PD-L2 B7-1 (CD80) Inhibition
an ongoing immune response, thereby
maintaining self-tolerance and LAG-3 Inhibition
preventing damage to the body’s
healthy tissues MHC TCR

– Negative co-stimulation, also

CD40 CD40L Activation
called “co-inhibition,” helps shut
down immune responses
CD137L CD137 Activation
– PD-1, CTLA-4, and B7-1 are
examples of co-inhibitory OX40L OX40 Activation
“checkpoint” molecules

APC=antigen-presenting cell; MHC=major histocompatibility complex; TCR=T-cell receptor.

Pardoll DM. Nat Rev Cancer. 2012;12:252-264.
 Immuno-Oncology: an emerging immunotherapy strategy for
treating cancer

Immunotherapy

Passive (adoptive)
Active
Designed to act at tumour;
Designed to act on the immune system itself immune-based mechanism

Antigen Antitumour
Antigen dependent Adoptive
independent mAbs

Enhancing
Therapeutic Modulate T cell
immune
vaccines function
cell function

GSK1572932A
TG4010 Immuno-Oncology
Belagenpumatucel-L
Bavituximab Adoptive
Cytokines Tergenpumatucel-L CTLA-4 inhibition EGFR inhibition cell transfer
Racotumomab
L-BLP25
PD-1 inhibition
CIMAvax PD-L1 inhibition

.
• EGFR = epidermal growth factor receptor.
• www.clinicaltrials.gov. Accessed April 2014; NCCN Guidelines. Non-small cell lung cancer. v3.2014; Peters S, et al. Ann Oncol. 2012;23:vii56–vii64.
B. Checkpoint Inhibitory Molecules
Types of immune checkpoint inhibitors

Anti PD1 Nivolumab

Pembrolizumab
Anti PD-L1 Durvalumab
Atezolizumab
Anti CTLA4 Tremelimumab

104
 Nivolumab
Nivolumab
(anti-PD-1; BMS-936558; ONO-4538)
• Fully human, IgG4 PD-1 receptor-blocking monoclonal antibody 1-3
• Inhibits a major immunosuppressive mechanism directly at the tumor site
– Prevents inactivation or reactivates ability of T cells to attack the tumor 2
• Binds to PD-1 receptors on T cells with high affinity 1
– Selectively disrupts inhibitory signaling triggered by PD-L1 and PD-L2 3
– Restores normal T-cell antitumor function 1,3

Tumor nivolumab T cell

PD-L1 PD-1

PD-L2

Adapted from Pardoll DM, et al. Nat Rev Cancer. 2012.

Abbreviations and references can be found in the speaker notes.

 Anti-PD-1 (Nivolumab): mechanism of
action
Recognition of tumour by T cell through
MHC/antigen interaction mediates IFNγ release
and PD-L1/2 up-regulation on tumour
Priming and activation of T cells through
MHC/antigen & CD28/B7 interactions with
antigen-presenting cells

IFNγ

T cell T cell
IFNγR receptor
receptor
MHC MHC

PI3K
NFκB Dendritic
CD28 B7
PD-L1
Other cell
Tumour Shp-2 T cell
cell PD-1 PD-1 PD-L1
PD-L2 Shp-2

PD-1 PD-L2
PD-1

Anti-PD-1 MAb blocks the PD-1 receptor

Adapted from Pardoll DM. Nat Rev Cancer. 2012;12:252–264.

 Key messages
• Hallmarks of cancer common to all cancers
• Genomic assays widening understanding of
carcinogenesis and development of newer anticancer
therapies
• Paradigm shift from 'carpet bombing' of chemotherapy to
'surgical strike' of precision oncology
THANK YOU