Targeted therapy

1. Targeted therapy
A new generation in
cancer therapy

2. 20th century – major advance -emergence of effective
chemotherapy as a part of multimodal anticancer
treatment
New drugs and newer strategies have improved the
results- according to the chemo-sensitivity of the
tumour.
In chemosensitive neoplasms, eg. gestational
choriocarcinoma, childhood ALL, testicular cancers,
and subgroups of HL & NHL, chemot/t is often curative
and offers long- term survival and offsets the toxicity.

3. Adjuvant chemot/t- t/t of micro-metastases after the
surgery - improved the survival in many cancers eg
breast, bone, colon, and lung.
Chemot/t agents concurrently with radiation- major
survival benefits, eg. Ca. cervix, and head & neck .
In solid tumours with advanced stages or recurrences,
chemotherapy can offer prolonged survival or
worthwhile quality of life.
With metastatic disease- Majority, responses usually
partial, often disappointingly brief.

4. Major drawbacks of the chemo. Agents-
drug-resistance and
toxicity.
Therefore, there has been a constant search.
A major advance - heralded by the development of a class
of agents that have a greater degree of specificity for
the tumour cell the new generation of “Targeted
therapy”.

5. Critical pathways and molecules regulating the processes
in the cancer cell, namely:
 inhibition of apoptosis,
 an unlimited replicative potential,
 sustained angiogenesis,
 tissue invasion, and
 metastasis.
Molecules have been developed that block these specific
molecular targets.

6. In various pilot clinical trials,
• partial and complete responses in few,
• stabilization of the tumour in a good majority with
marginal survival benefit have been observed in the
heavily pre-treated patients or tumours where there
is no effective treatment available.
A new era of targeted therapy of cancer has thus been
launched
Integrating these agents into current multimodal
management of cancers, optimizing the benefits of both
strategies - a real challenge.

7. Types of targeted therapy
Identification of critical target on cell- a difficult task,
To ‘ve maximal therapeutic benefit, ideal target Ag must
‘ve following characteristics:
(a) it should be expressed only on tumour cells;
(b) expressed on all tumour cells;
(c) not expressed on critical host cells;
(d) expressed in high numbers;
(e) no mutants, variants should be present;
(f) should be critical to cells for survival; and
(g) Should not be shed or lost or circulated.

8. May not be possible to identify such an ideal target on the
cancer cell, but many meeting with most of the
requirements ‘ve been identified in variety of
malignancies.
Targeted therapies classified as:-
1.Monoclonal antibodies-unconjugated/ immuno-
conjugates
2.Proteasome-inhibitors
3.Angiogenesis-inhibitors
4.Anti-apoptotic agents
5.Tyrosine kinase inhibitors
6.Cancer vaccines

10. Monoclonal Antibodies
Concept of “magic bullets”(Paul Ehlrich) over a decade,
discovery of hybridoma technology(Kohler&Milstein’75)
Therapeutic efficacy of mAbs could not be demonstrated
till recently, due to several technical problems.
Recom. DNA technology in the last 2 decades, helped to
develop fully humanised mAbs, overcoming many of
these problems. Currently available mAbs elicit anti-
tumour effects through direct axn on signal transduction
pathways/through co-opted toxic compounds, such as
radionucleotides or chemotherapeutics specifically to
the tumour sites as enumerated:

11. Unconjugated mAbs
a.Antibody-dependent, cell-mediated toxicity
b.Complement fixation
c.Block the complicated signal pathways
Conjugated mAbs
d.Delivery of cytotoxins to cancer cells
e.Delivery of radioisotopes to cancer cells

12. Generic name Agent/Target Cancer indication
Unconjugated
Rituximab Chimeric AntiCD 20 IgG1 B cell Lymphoma
Trastuzumab Humanised anti-HER2 IgG 1 Breast
Alemtuzumab Humanised anti-CD52 CLL
Cetuximab Chimeric and anti-EGFR Colorectal, head & neck
Radio-conjugate
Satumomab
pendetide
111 In-murine anti-TAG-72 IgG Colorectal, ovarian
Nofetumomab 99m Tc-murine anti-EGP-1 Fab Small cell lung ca
Merpentan
Arcitumomab
99m Tc-murine anti-CEA Fab Colorectal
Capromab
pendetide
111 In-murine anti-PSMA Prostate
Ibritumomab
tiuxetan
90 Y-murine anti-CD-20 IgG
+rituximab
B-cell lymphoma
Drug-conjugates
Gemtuzumab Humanised anti- CD33 IgG 4 AML

13. Unconjugated antibodies: Rituximab
The first US FDA mAb approved for t/t of lymphoma.
A chimeric IgG1 unconjugated monoclonal antibody
directed at CD20 Ag , a B cell Ag.
CD20-role in B-cell activation, proliferation, &
differentiation.
Rituximab leads to cell apoptosis by inducing Ca2+ influx,
releasing caspase activity.
The indications for its use in NHL -clearly defined now.
Current standard of care in B cell CD 20 +ve diffuse B
cell NHL is rituximab along with chemot/t regime
(CHOP).

14. The response rates(RR)- 20 to 30 % higher
Disease free survival rates- statistically superior.
Maintenance therapy with rituximab after R-CHOP is
currently under evaluation.
In indolent lymphomas, RR- 12-20 % higher, relapse free
survival is better by 15-20%, and 4-year overall survival
by 13 %.
3-monthly maintenance with rituximab, for a period of two
years- shown beneficial results in overall and disease-
free survival in follicular lymphoma but may not be
beneficial in other indolent lymphomas

15. Useful for treatment of refractory, low- grade, follicular
NHL, with a RR - 48%.
Use in CLL, lymphoplasmocytic lymphoma and Mantle cell
lymphoma - proven less successful with RR- 14%,
37%, and 28% respectively.
Rituximab - also been used as an in vivo purging agent
before and after stem cell transplantation.
It is a well tolerated drug and main side-effects include
infusional reactions occurring in about 10 to 20%
patients.

16. Trastuzumab (Herceptin)
An anti-HER2/neu Ab - major impact on the t/t of Ca
breast
Is used alone/ combination with chemot/t agents.
Approximately 20-25% of Ca. breast are HER2/neu +ve
and the current use is restricted to HER2/neu +ve only.
Approved in combination with chemot/t both in weekly or
three-weekly schedules & administration - loading dose
(4mg/kg and 8 mg/kg respectively) followed by a
maintenance dose of 2 mg/kg weekly or 6 mg/kg three
weekly

17. . In metastatic Ca. breast, encouraging responses and
survival benefit observed.
Used in adjuvant setting after primary surgery for a period
of 1 year - an additional survival benefit of over 12%.
When used in newly diagnosed patients with locally
advanced Ca. breast combination of trastuzumab and
chemot/t has produced very good clinical &
pathological responses.
Side-effects - infusion reactions, reversible cardio- toxicity
for which cardiac monitoring is essential.

18. Cetuximab
A successful chimeric anti- EGFR mAb approved for use in
metastatic and recurrent colorectal, lung, and head and
neck cancers.
With EGFR being over expressed in many solid tumours this
molecule has immense clinical potential.
Administered in a loading dose of 400 mg/m2 as an IV infusion
over 2 hrs, followed by 250 mg/m2 every week.
S/E - acneform skin rash, occasional infusion reactions.
. Recently, it also got approval in combination with oxaliplatin,
leucovorin and 5-fluorouracil (5 FU) as first line use in
metastatic colorectal cancer.

19. Bevacizumab
A humanised mAb - inhibits angiogenesis signaling by
binding to VEGFR and its ligand.
February 2004- received approval for use in 1st line t/t of
metastatic Ca. colorectal in combination with 5-FU
based chemot/t - RR 45% and improved disease free
survival.
Progression-free survival (PFS) was 9.2 months for
patients who received 5- FU/LV/bevacizumab,
compared with 5.5 months for those who received 5-
FU/LV alone.
The dose recommended is 5 mg/kg every two weeks.

20. S/E- HT, bleeding tendencies, intestinal perforations.
Bevacizumab should not be administered for at least 28
days following surgery, in order to allow healing of
wound.
Recently, approved in
 metastatic Ca. breast in combination with paclitaxel,
 recurrent glioblastoma multiforme (GBM) with irinotecan, and
 Metastatic RCC in combination with interferon. It has 89%
improvement in median progression free survival in metastatic
RCC.
Currently being studied clinically in a number of other
non-haematological and haematological malignancies.

21. Immunoconjugates
Ab can also function as carriers of cytotoxic substances,
such as radioisotopes, drugs, and toxins.
When a radioisotope is linked to mAb, the treatment is
referred to “radioimmunotherapy”.
On administration, these agents “home” to antigen-
presenting cells, and the linked radioisotope kills
targeted cells as well as neighbouring cells that either
are inaccessible to the antibody or express insufficient
antigen for antibody binding (cross-fire effect).

22. Two commercially available and similar radio-
immunoconjugates that target CD20 - yttrium-90 (90Y)
labelled ibritumomab tiuxetan & iodine-131 (131I)
labelled tositumomab are approved for use in patients
with relapsed or refractory follicular or low-grade
lymphoma.
While they do have RR of 40-60% with a survival benefit-
myelotoxicity, secondary leukaemia are the major
complications observed.
Research is focused on proper selection of patients with
good bone marrow reserve and incorporation as first
line therapy in poor-risk patients.

23. Gemtuzumab ozogamicin
A conjugate of a humanised anti-CD33 IgG linked to
colicheamicin, potent anti-tumour agent isolated from a
bacterium and it is currently approved for AML.
Used in the treatment of relapsed AML in elderly patients
(> 60 yrs), unfit for standard cytotoxic chemotherapy.
RR is seen in 30% of patients when given at a dose of 9
mg/m2 for 2 doses at 2 weeks interval.
The prospects of using it as a front line T/t & expanding its
indications to include paediatric cancer patients & in
combination with chemotherapy are under evaluation.

24. Proteasome inhibitors
The vast majority of intracellular proteins are degraded via
the ubiquitin-proteasome pathway.
Key step is the “tagging” of proteins targeted for
degradation with the 76 amino acid protein, ubiquitin,
whose primary sequence is highly conserved from
yeast to mammals. Once the protein substrate is mono-
ubiquitinated, a polyubiquitin chain is formed through
subsequent multi-ubiquitination in which the carboxyl
group of ubiquitin is covalently linked to an internal Lys
residue of ubiquitin that is already conjugated to then
recognised by the 268 proteasome, which proceeds to
degrade them into short peptide fragments.

25. The discovery that several antitumour natural products
exert their action via proteasome-inhibitor provided
rationale to develop proteasome-inhibitor (PI) drugs for
cancer treatment.
Bortezomib, was approved in 2003 for treatment of MM,
and more recently for mantle cell lymphoma.
PI causes apoptotic induction via accumulation of the
proapoptotic Bcl-2 family of proteins.
Also leads to the up- regulation of several key cell cycle
checkpoints. In particular, activation of p53 in response
to proteasome inhibition induces the G0/G1 cell cycle

26. Bortezomib
Remarkable single-agent antitumour activity in a wide
range of haematologic malignancies, including MM,
NHL, Waldenstrom’s macroglobulinaemia, and other
diseases.
Bortezomib was approved for the T/t of MM based on a
single agent objective response rate (ORR) of 28% (4%
complete response {CR} rate) in a phase II study in 193
heavily pre- treated patients who were refractory to the
most recent therapy. Currently, it is being used in
relapsed MM patients & a part of up-front regime
alongwith other drugs in newly diagnosed patients.

27. Angiogenesis Inhibitor
One of the critical events required for tumour growth -
increased vascularisation & the formation of a new
network of blood vessels called angiogenesis.
Anti-angiogenic therapy stems from the fundamental
concept that tumour growth, invasion, and metastasis
are angiogenesis dependent.
The microvascular endothelial cell recruited by a tumour,
with its receptors, has become an important second
target in cancer therapy.

28. Unlike the cancer cell (the primary target of cytotoxic
chemotherapy) that is genetically unstable with
unpredictable mutations, the genetic stability of
endothelial cells may make them less susceptible to
acquired drug resistance.
Bevacizumab is the first monoclonal antibody against
VEGFR extensively studied in various solid tumours.
Following a phase III study showing a survival benefit in
metastatic colorectal cancer, it received its approval for
use by the US FDA.
There are two general classes of angiogenesis inhibitor

29. A direct angiogenesis inhibitor blocks vascular endothelial
cells from proliferating, migrating, or increasing their
survival in response to proangiogenic proteins.
These are less likely to induce acquired drug-resistance
because they target the genetically stable endothelial
cells.
Indirect angiogenesis inhibitors decrease or block
expression of a tumour cell product, neutralise the
tumour cell product, or block its receptor on endothelial
cells.
Eg bevacizumab, sorafenib, and sunitinib.

31. Sorafenib
A small molecule inhibiting Raf kinase and VEGFR2
VEGFR3 pathways.
Approval for use in the T/t of patients with previously
treated advanced renal cell carcinoma (RCC).
The median PFS times were 5.5 months in sorafenib
group and 2.8 months in the placebo group, and the
objective RR - 10% in the sorafenib arm and 2% in the
placebo arm.
Also approved for use in metastatic HCC and has clinical
benefit in advanced pancreatic tumours.

32. Another antiangiogenic and immunomodulatory drug used
is thalidomide (in MM), although its exact mechanism
of action is still unclear.
Inhibiting angiogenesis has been show to suppress
tumour growth and metastasis in both pre-clinical
models and clinical studies.
Future research will focus on determining the tumour
types & stages that will benefit most from
antaingiogenic therapy.
Antiangiogenic therapy- the overall goal of the clinical use
of angiogenesis inhibitors being to convert cancer to a
chronic manageable disease.

33. Anti-apoptotic agents
Apoptosis - control mechanism by which cells die if DNA
damage is not repaired. Controls cell number &
proliferation. Essential for the elimination of self-reactive
lymphocytes.
Eg. B-cell CLL, follicular lymphoma, and tumours infected by
human T-cell leukaemia/lymphoma virus-1 - characterised
by defects in apoptosis leading to immortal clones of cells.
Other malignancies have defects in the apoptotic
regulatory pathways such as p53, the nuclear factor kappa
B (NFkB), or phosphatidylinositol 3-Kinase (PI3K)/Akt
leading to defects in apoptosis.

34. There are 2 major mechanisms necrosis & apoptosis-
Cells damaged by external injury- undergo necrosis,
Cells that are induced to commit programmed suicide
because of internal or external stimuli undergo
apoptosis.
Apoptosis occurs through two main pathways.
1st- extrinsic or cytoplasmic pathway - triggered, through
the Fas death receptor, a member of TNF receptor
superfamily.
2nd intrinisic or mitochondrial pathway - that when
stimulated leads to the release of cytochrome-c from
the mitochondria and activation of the death signal.

35. Activation of the extrinsic pathway is initiated with the ligation
of cell surface receptors called death receptors (DRs).
Several pathways and proteins regulate the activation of
the extrinsic pathway.
In the intrinsic pathway, the Bcl-2 family are key regulators
of apoptosis and are over expressed in many
malignancies even without the presence of the t (14;18)
chromosomal translocations.
The final pathway that leads to execution of the death signal
is the activation of a series of proteases termed as
caspases.

36. The extrinsic and intrinsic apoptotic pathways are
regulated by proteins such as p53, the ubiquitin-
proteasome system and the P13K pathway.
p53 functions as a transcription factor regulating
downstream genes important in cell cycle arrest, DNA
repair, and apoptosis.
Ubiquitin/proteasome system is composed of a large
proteinase complex that is responsible for the turnover
of most intracellular proteins and consequently
regulates cell growth and apoptosis.

37. Therapeutic agents classified as agents that target extrinsic
pathway, intrinsic pathway, common pathway, (through
caspases),/proteins regulating apoptosis.
Agents targeting extrinsic pathway include recombinant
human TRAIL, monoclonal antibodies agonistic to DR4
and DR5, and all trans retinoic acid(ATRA).
ATRA is one of the 1st examples of targeted therapy in
human cancer. ATRA is used in acute promyelocytic
leukaemia (APL). One of the main side-effects of ATRA is
the ATRA syndrome that is characterised by respiratory
distress, fever, pulmonary infiltrates, and pleural effusions
which can be easily treated with dexamethasone.

38. Agents targeting intrinsic pathway include agents that act
directly on the mitochondrial inner membrane (arsenic
trioxide and ionidamine), agents that antagonise the
anti-apoptotic members of the Bcl-2 protein family, and
agents that enhance the activity of the proapoptotic
members of the Bcl-2 family of proteins such as Bax.
Agents targeting common pathway or caspase activators
are apopton and survivin.
Agents targeting modulators of the apoptosis pathways
include proteasome inhibitors, mTOR inhibitors, and
p53 inhibitors.

39. Tyrosine kinase inhibitors
TK transfer -phosphate groups from ATP to hydroxyl group
of tyrosine residues on signal transduction molecules.
Phosphorylation is a major activating event leading to
dramatic changes in tumour growth.
Some TKs, EGFR-TK, can autophosphorylate when
activated, as well as phosphorylating other signalling
molecules. The resulting phosphotyrosine residues in the
EGFR-TK cytoplasmic domain serve to further activate the
TK activity of the receptor and to act as docking sites for
cytoplasmic signal transduction molecules containing Src
homology or phosphotyrosine binding motifs.

40. TKs play a central role in signal.
Strict regulation of TK activity in normal cells controls
most fundamental cellular processes, ie. cell cycle,
proliferation, differentiation, motility, and cell death or
survival.
In tumour cells, key TKs are no longer adequately
controlled, and excessive phosphorylation sustains
signal transduction pathways in an activated state.
Thus, control of TKs would result in control of cellular
processes.

41. Two types of TKs - receptor and non-receptor - exist in
the cells.
Receptor TKs of transmembrane proteins with a ligand
binding extracellular domain and a catalytic intracellular
kinase domain,
Non-receptor TKs lack trans- membrane domains and are
found in the cytosol, the nucleus, and the inner surface
of the plasma membrane.
The enzymatic activities of both types of TK are under
tight control, so that non-proliferating cells have very
low levels of tyrosyl phosphorylated proteins.

42. Activation of TKs is essential to initiate the abnormal cellular
processes and this can occur by any one or a combination :-
a. A common mechanism of TK activation in haematologic
cancers is the fusion of a receptor or non-receptor TK with a
partner protein, usually as a consequence of a balanced
chromosomal translocation.
b. TK dysregulation by a mutation that disrupts autoregulation of
the kinase.
c. Increased or aberrant expression of a receptor TK, its ligand, or
both.
d. Lastly, increased TK activity by decrease in factors that limit TK
activity eg impaired tyrosine phosphatase activity or decreased
expression of TK inhibitor proteins.

43. Abnormally elevated EGFR-TK activity is associated with
the most common human solid tumours, including non-
small cell lung cancer (NSCLC), colorectal
adenocarcinoma, glioblastoma, squamouscell
carcinoma of the head and neck, and gastric,
pancreatic, breast, ovarian, cervical, and prostate
cancers.
EGFR- TK activity plays a key role in numerous processes
that affect tumour growth and progression, including
proliferation, dedifferentiation, inhibition of apoptosis,
metastasis and angiogenesis.

44. TKs can be inhibited pharmacologically through multiple
mechanisms. The idea is to find small molecules that
directly inhibit the catalytic activity of the kinase by
interfering with the binding of ATP or substrates .
Other anti-TK drugs may inhibit activation of fusion TKs
by blocking their dimerisation. Ab against receptor TKs
or their ligands interrupt TK signaling through
neutralisation of ligand, blockade of ligand binding,
receptor internalisation, and perhaps antibody-
mediated cytotoxicity.

45. The prime example of a dysregulated TK in the
haematologic cancers is BCR-ABL, implicated as
direct cause of CML.
Imatinib mesylate, is a specific inhibitor of several TKs-
induces complete haematologic and cytogenetic
remissions in most patients with chronic phase CML
but is much less effective in the accelerated and blast
crisis phases.
The extreme sensitivity of some cancers to TK inhibition
may reflect their absolute dependence on the targeted
TK-signalling pathway for survival.

46. This phenomenon of “oncogene addiction” seen when
imatinib suppresses myeloid colony formation in
Philadelphia Ch. +ve BM without affecting colonies from
normal progenitors.
Imatinib inhibits both BCR-ABL & c-KIT in haematopoeitic
progenitors, & this dual activity account for its efficacy in
CML.
Dasatinib- a novel agent, approved for t/t of adults with
chronic phase, accelerated phase or blast crisis phase
CML following imatinib-resistance or intolerance.
Nilotinib- a novel oral inhibitor of Bcr-Abl, recently approved
in the USA and Europe for patients with imatinib-resistant
or - intolerant CML.

47. Bosutinib an oral dual Src/Abl inhibitor, 10-20-times more
potent than imatinib against CML cell lines, with no in
vitro activity against the Bcr-Abl T315I mutant. Has
minimal inhibitory activity against c-Kit and PDGF
receptor.
Gastrointestinal stromal tumours (GISTs) develop at a
high frequency in adults with germ-line KIT mutations,
suggesting that c-KIT activation is insufficient for
tumourigenesis.
Trials of imatinib in GIST demonstrated partial responses
in more than half the patients.

48. Either over-expression of mutation of EGFR, or both, are
observed in many solid tumours.
Gefitinib and erlotinib are anilinoquinazolines that are
specific, competitive inhibitors of ATP binding by EGFR
and were approved by the US Food and Drug
Administration (FDA) in 2004, for refractory locally
advanced or metastatic non-small cell lung cancer.
Lapatinib an oral dual kinase inhibitor of the EGFR and
ErbB2 (HER2) and has been found to be effective in
metastatic breast cancer patients

49. Pazopanib, a broad-spectrum kinase- inhibitor has shown
encouraging results in a phase II randomised trial in
patients with untreated or previously treated metastatic
renal cell carcinoma (RCC) and now undergoing phase
III trials.
Axitinib is another multi-kinase inhibitor (VEGFR,
PDGFR- , and c-Kit) demonstrated an objective
response rate of 46%in a phase II trial of 52 cytokine-
refractory, nephrectomised patients of RCC

50. Cancer vaccines
“Cancer immunotherapy” (William Coley) - Observation of
spontaneous regression of human tumours suggested that
the immune system has the potential to control the
uncontrolled growth of neoplastic cells
Cancer vaccines represent a non-toxic therapeutic modality
potentially capable of inducing strong anti-tumour immune
responses by establishment of immune memory leading to
tumour regression, or stabilisation of a tumour and also
help in prevention of tumour recurrence after a complete
treatment.
The present knowledge and experience of cancer vaccines is
in infancy, but could be a good strategy in future.

51. Unlike in infections, several obstacles at cellular and host
cell levels such as
 multiplicity of tumour antigens,
 mutations of antigens,
 ability to evade the host immunity,
 tumour- induced immune deviation,
 tolerance of tumour antigens by host cells are
encountered for the cancer vaccines,
 hindering their potential clinical benefits.

52. If successful, anti- tumour vaccines may be used in a
variety of ways:-
• as monotherapy in advanced, metastatic cancers
• as adjuvant therapy following surgery, radiation, or
chemotherapy to debulk tumours in advanced diseases
• as maintenance therapy to ensure active immune
responses against future recurrences
• as preventative agents in selected asymptomatic
populations at high risk as general immunisation agents
(based on selected populations using such criteria as
age, family history, etc.) (identified by markers).

53. Based on the mechanism of action, cancer vaccines can
be grouped into various categories.
Tumour cell-based vaccines: Various tissues in modified
forms, from the patient’s tumour (autologous) or
another patient (allogeneic) or a mixed-type of tissues
are used to prepare cancer vaccine and have been
used with encouraging results.
Tumour associated antigen specific vaccines: An
antigen is used as the immunogen that can be a tissue
antigen, a cancer specific antigen or an overexpressed
antigen, to induce the antibodies.
Cell-based vaccines such as dendritic cell vaccines

54. Dendritic cells are the most potent antigen presenting
cells with exquisite capacity to interact with T-cells &
initiate their responses; the antigen presenting
capabilities of these cells is used for the delivery of
therapeutic cancer vaccines.
Anti-idiotype vaccines. These are made of antibodies
that see other antibodies as the antigen and bind to it.
They can stimulate the body to produce antibodies
against tumour cells.
Vaccines against carcinogenic infectious agents such
as human papilloma virus or hepatitis B virus

55. Virus, bacteria, & parasites - implicated in the
pathogenesis of human cancers (18 %)
The development of effective vaccines against infectious
carcinogenic agents represents a potentially powerful
form of intervention.
The identified oncogenic infectious agents share at least
three characteristics:
the ability to establish chronic infection,
the establishment of chronic infection for many
years before the development of malignancy, and
a benign (i.e., non- malignant) outcome for most
infected individuals.

56. An ideal vaccine would be effective both in preventing and
treating pre-malignant disease, as well as in reducing
the likelihood of transmitting the agent to uninfected
individuals.
The most critical information for vaccine development lies
in determining which antigens can induce protective
immunity.
Persistent infection with HBV appears to lead to
hepatocellular carcinoma, mainly as the result of
chronic inflammation and repeated cellular
regeneration. The HBV vaccine is the prototype
prophylactic vaccine against an oncogenic infectious
agent.

57. Infection with HPV types 16, 18, and 81 is a strong risk
factor for cervical cancer, and HPV DNA from one or
more of these types is found in virtually all cervical
tumours. Efficacy trials of a monovalent HPV-16 L1
VLP vaccine and HPV-16/18 VLP vaccine, conferred
close to complete protection against persistent infection
and cervical disease attributable to the HPV type(s)
targeted by the vaccine.
Gardasil has been approved for the immunisation of girls
and young women(9- 26 years)for use in the US and 80
other countries, while cervarix has been approved for
use in females (10-45 years) in Europe and Australia.

58. Infection with H. pylori is associated with a variable
proportion of several disorders, including duodenal
ulcers, gastric ulcer, gastric carcinoma, which is the
second most common cancer worldwide, and the much
less common gastric mucosa associated lymphoid
tissue lymphomas. Responses in pre-clinical vaccine
studies have been obtained with animal models. Thus
far clinical trials with single antigens have been
disappointing, and efforts are underway to test
vaccines consisting of several antigen

59. Conclusion
Over last 2 decades, the elucidation of molecular biology,
ie. signal transduction pathways involved in the
regulation of tumour growth, cell death in human
cancers or molecular markers of cancer progression
have provided the fundamental basis for the
development of molecular targeted therapies.
Since such strategies are specifically directed against key
components that are crucial for the cancer cell’s
survival and function, they may be more selective and
effective in killing malignant over non- malignant cells.

60. While several approaches have already been translated
into medical application, many concepts have still to be
evaluated.
There is not only need to learn to measure the benefits in
newer ways rather than standard fashion but also to
select the appropriate patient population with the
specific markers.
Eventually, these efforts are expected to yield more
effective - yet less toxic - treatment options for the
sake of patients suffering from cancer.

61. THANK YOU