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Indian Journal of Experimental Biology
Vol. 43, May 2005, pp. 389-406
Review Article
Tumor vaccine: Current trends in antigen specific immunotherapy
Rathindranath Baral
Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI),
37, S P Mookherjee Road, Kolkata 700 026, India
Effective cancer treatment to prevent the tumor growth as well as to stop its recurrence is the dream of oncologists.
Currently available therapeutic measures like, radiotherapy and chemotherapy, often suffer from severe toxicity and lack of
specificity of the drug towards tumor cells. Another promising approach is the 'immunotherapy', in which either the
immune system is activated by tumor vaccine to combat the tumor growth or antitumor antibodies can be used. Vaccination ·
can stimulate humoral, cellular and innate immune systems to generate various effector molecules, like antibody, cytotoxic
T cells, cytokines etc. In antigen specific immunotherapy, the immune system can be stimulated actively by antigen based
tumor vaccine to kill only those tumor cells, having expression of the particular tumor associated antigen. Different
experimental, preclinical and clinical studies have proved that generated immune responses are effective to restricnhe tumor
growth. Useful strategies of antigen specific immunotherapy and outcome of various laboratory and clinic based studies are
discussed.
Keywords: Antibody, Antigen, Immunotherapy, Tumor, Vaccine
Effective cancer therapy or prevention has been the
dream of clinicians and scientists for many years.
Although, the ultimate goal is yet to be achieved,
significant progress has already been made in terms of
our knowledge and understanding of the process of
carcinogenesis. Besides the conventional modes of
surgery, chemotherapy and radiotherapy, immunotherapeutic strategies are now accepted as more
effective in terms of the exquisite specificity that they
offer in targeting only tumor cells. On the other hand,
chemotherapy and radiotherapy are more general and
invasive with several side effects. There are several
immunotherapeutic strategies, which are currently
under investigation and some are in clinical practice
(Table 1). These strategies can be broadly categorized
into 'specific antigen based therapy' and 'nonspecific
therapy'. Again, specific therapy is either active or
passive. In active therapy, patient can be vaccinated
with an immunogen to generate an effective immune
response. On the contrary, passive therapy utilizes the
transfer of effector molecules (antibodies) or cells
(CTLs) to patients. In both active and passive
therapies, the developed immunity is specific for the
immunogen (antigen) only. As tumor cells generally
express one or more tumor associated antigen(s)
(TAAs) in significantly higher quantity, developed
antigen specific immunity can target tumor cell only,
*For correspondence:
Phone: 91-033-2476-5101/02/04, ext. 334
E-mail: [email protected]
without affecting antigen negative normal cells. Such
treatment modalities, in general, are termed as 'tumor
vaccine' . This review is aimed to discuss different
forms of 'tumor vaccine' for antigen specific cancer
immunotherapy. Emphasis will be on the principle
and results obtained during translation of basic
research into clinical set-up.
Antigen specific immunotherapy
Antigen specific immunotherapy holds promise as
a complementary approach to chemotherapy, radiotherapy and surgery, for the treatment of cancer
patients who are at high risk of relapse or progressive
disease. This mode of immunotherapy utilizes various
immunogens in the form of TAAs and an adjuvant or
Table I-Different forms of tumor vaccine
Specific
(Target tumor antigens)
• Tumor Vaccines
- Tumor Lysates
- Tumor cells
- Tumor cell membranes
- Purified tumor antigens
- Peptides
- Recombinant virus
coding tumor antigen
- Xenogenic tumor antigen
- Anti-idiotypic antibody
• DC Vaccines
- DC pulsed with above
preparations
DC =dendritic cell
Nonspecific
(Stimulates immune system)
• Cytokine Therapy
- Interleukin 2
- Interferon a2b
- Tumor necrosis factor a
• Adjuvant Therapy
- bacille Cal mette-Guerin
- Corynebacterium
parvum
- Detox
- Coley's Toxin
INDIAN J EXP BIOL, MAY 2005
390
carrier molecule to promote presentation of the
antigen to the immune effector cells. This therapy
stimulates the immune system actively, thus, it is also
designated as 'active specific immunotherapy'. Its
aim is to generate tumor specific antitumor responses
through stimulation of the host's immune system by
tumor vaccine. Tumor vaccines make use of tumor
antigens (Table 2) which in general, are derived from
proteins that are produced by tumor and aim to trigger
humoral and cellular immune responses. Treatment of
cancer patients with autologous tumor cell preparation
is considered as the first use of tumor vaccine in
human beings! . Animal studies were done earlier. In
subsequent times, a variety of antigen specific
immunostimulatory strategies have been applied with
some clinical success (Tables 3 & 4). The molecular
Table 2-Tumor associated antigens (TAAs) as vaccine target
Class of antigen
TAA*
Expression in cancer**
Overexpressed proteins
CEA
Her2/neu
MUCI
PSA
MART-l
gp-loo
PSMA
Tyrosinase
HPVI6 E7
p53
MAGEl
MAGE 3
Monosialoganglioside GM2
Disialoganglioside GD2
Disialoganglioside GD3
Telomerase
CA125
CA15-3
CA19-9
Colon, Breast, Lung, Bladder, Thyroid
Breast, Ovary
Breast, Ovary, Lung, Colon, Pancreas
Prostate
Melanoma
Melanoma
Prostate
Melanoma
Cervix, Oral
Colorectum, Breast, Oral, Liver
Testis
Testis, Melanoma, Gastrointestinal tract
Melanoma, Neuroblastoma, Sarcoma
Melanoma, Neuroblastoma, Sarcoma
Melanoma, Neuroblastoma, Sarcoma
Colon, Bladder, Oral, Lung, Prostate
Breast, Ovary, lung, Bladder
Breast, Colon,
Colon, Pancreas, Bladder
Differentiation antigens
Tumor virus
Mutated protein
Cancer testis antigens
Ganglioside antigenl>
Other antigens
*The list of T AAs in the Table is not complete. Several other antigens are available with potential to use in tumor
vaccine. Except ganglioside antigens, most of these T AAs are protein/glycoprotein
** Apart from the organ names referred, expression may occur in other organs during carcinogenesis
Table 3---Milestones in the development of antigen specific immunotherapy
1800-1950
1950- 1970
1970-1990
I 990-present
1895
1957
1975
1991
First use of
heteroimmune sera in
patients
Start of tumor
immunization studies in
inbred mice
Development of
monoclonal antibody
technology
Discovery of first MHCrestricted tumor antigen
1902
1960
1975
1993
First therapeutic use of
autologous cancer cells
Transfer of antitumor
immunity with
lymphocytes
C. parvum potentiation of
antitumor responses
Definition of MHC
class II structure
1943
1963
1988
1995
Demonstration of
antitumor immunity
in mice
Initial clinical studies with
lymphocytes from cured
patients
TIL cell + JL-2 therapy
Peptide vaccine trial
1990
1996
Start of humanized
monoclonal antibody trials
Achievement of in vitro
growth of dendritic cells
1997
Dendritic cell tumor
antigen trials
BARAL: ANTIGEN SPECIFIC THERAPY OF TUMORS
391
Table 4-Examples of clinical trials targeting T AAs by antigen specific immunotherapy
Vaccine
Immunogen
Cancer
Phase of
trial
Clinical outcome
Autologous tumor
Cell vaccines
Allogenic
tumor
Cell vaccines
Autologous Tumor
Lysate
Vaccinia Virus
Oncolysate
Polyvalent Whole Cell
Vaccine
MAGE-3 Peptide
Colorectal Cancer
III
Melanoma
III
Melanoma
II
Melanoma
Pilot
Tyrosinase Peptide
Melanoma
II
gpl00 Peptide
Melanoma
II
PSM-PlIP2 pulsed DC
Prostate
II
Idiotype Protein
Pulsed DC
Myeloma
gpl00 & Tyrosinase
pulsed DC
Anti-HER2 MAb +
Chemotherapy
Melanoma
Metastatic Breast
Cancer
III
Anti-CD20 MAb
90Y-AntiCD20
NHL Relapsed
NHL Relapsed
II
IIII
MAb3Hl
(mimicking CEA)
+5-FU
MAb lA7
(mimicking GD2)
+5-FU
Colorectal Cancer
II
Melanoma
II
Reduced
Risk
of
Recurrence
Increase in Overall
Survival
Disease Free Survival
More Than 90 Months
Response
in
33%
patients
Stable Disease in 2
Patients among 7
Immune Response to
Peptides in 20 patients
among 24
Complete Response in
2 & Partial response in
7 patients among 33
Proliferative Response
to Idiotype protein in
5/6 patients
Response
in
50%
Patients
Response Rate 62%
with MAb & 36%
withoutMAb
Response Rate 48%
Response Rate 67%,
Complete
Response
26%
Relapse time delayed
in comparison to 5-FU
only
Complete Response in
1 patient & stable
disease in 12 patients
among 47 stageIIl
patients
Peptide Vaccines
Dendritic Cell (DC)
vaccines
Humanized MAb
Radiolabeled MAb
Anti-idiotypic MAb
characterization of novel human T AAs and increased
understanding of the immunological pathways
involved in tumor immunity have paved the way to
design a promising tumor immune vaccine 2 • TAAs are
readily available now and several ways to deliver
original or surrogate antigen have been developed 3• A
rigorous autotumorlytic immune response can be
induced in cancer patients by immunization with
T AAs. This immunization results in the generation of
antigen specific antibody response to mediate
antibody dependent cellular cytotoxicity and other
effector responses, including antigen specific T cell
responses and objective clinical responses on cancer
patients. The most important and widely used
approaches consist of whole tumor cell vaccine4 ,
purified TAA vaccine5 , peptide vaccine6 , anti-idiotype
7
vaccine , dendritic cell based vaccines etc. These
Pilot
Reference
Vermorken et al. l90
Wallack et al. 191
Morton & Barth
Marchand et al.
41
192
Scheibenbogen et al.
Weber et al.
194
Murphy et al.
195
Lim & Baileywood
Weber et al.
193
l96
197
Cobleigh et al. 198
McLaughlin et al. l99
200
Witzig et al. 2000
Foonet al. 1I2
Foon et al. 122
vaccine forms were evaluated in experimental system
as well as in clinical trials. Important work is
presently underway to correlate the antigen specific,
anti-tumor humoral and cellular immune responses
with the clinical response. Detected anti-tumor
immunity may not always be reflected in clinical
response and in most of the cases tumor load appears
to be a primary limiting factor. Beside antigen
specific immunotherapy, potential of nonspecific
immunotherapy was also examined.
Nonspecific immunotherapy
Immunostimulation by selective 'Biological
Response Modifiers' and various cytokines is also a
wide area of investigation. One of the earliest
experiences in immunotherapy arose from the
application of Coley's toxins, which stimulate
392
INDIAN J EXP BIOL, MAY 2005
nonspecifically the immune system, in patients with
unresectable sarcoma9 . Other bacterial agents such as
bacilli Calmette-Guerin (BCG), Staphylococcus
pyogenes and Corynebacterium parvum are believed
to function similarly. In 1992, the Federal Drug
Administration (FDA), USA approved IL-2, as first
immunotherapeutic agent in cancer treatment of
patients with metastatic renal cell carcinoma. Partial
clinical responses were reported in renal cell
carcinoma and metastatic melanoma10,II. Among
interferons, IFN-a2b has had the most significant
effect in human cancer immunotherapy. Several
clinical studies have already been conducted with
IFN-a2b and in a Phase III trial IFN-a2b has proved
to be effective in prolonging overall survival and
disease free survival in melanoma patients who are at
high risk of disease recurrence following surgeryl2.
Presently, IFN-a2b is a FDA approved immunotherapeutic agent being used in the adjuvant treatment
of cancer. Other cytokines, like, TNFa 13 , IL_414, IL12 15 and GMCSF I6, have some clinical significance in
the treatment of cancer. NK cells, LAK cells and
macrophages act as effectors in cytokine network of
nonspecific immunotherapy. However, this area is
beyond the scope of present review.
Tumor associated antigen, the key for vaccine
development
Process of tumorigenesis is associated with the
alteration in gene sequences and expression levels of
various protein antigens 17. These changes lead to the
expression of several tumor associated antigens
(TAAs), e.g., carcinoembryonic antigen (CEA)1 8,
prostate specific antigen (PSA)19, MAGE 20 ,
Her2/neu 21 , MUCI 22 , HPV16-E7 23 etc. (Table 2).
Such T AAs could be useful in detecting cancer,
determining prognosis, monitoring disease progression or therapeutic response. Continuous efforts are
on to discover new T AAs by screening strategies such
as the SEREX programme, comparative proteome
analysis or gene expression profiling2. T AA, generally
a protein molecule, derived from tumors, can be either
tumor specific, expressed exclusively in tumor tissue,
.or tumor associated, highly overexpressed in tumors
but can also be found in normal tissues24 . Most
important tumor specific antigens are: cancer testis
antigens, e.g.; MAGE25 , protein variants that are
created by somatic mutations within tumor cells, e.g.,
CDK4, and proteins from tumor viruses, e.g.,
HPV16E7 26 . These are found only in tumor tissues
and therefore do not attract the risk of autoimmune
reactions during immunotherapy2. Some TAAs are,
differentiation . antigen, like, tyrosinase and overexpressed proteins, e.g., Her2/neu, CEA, PSA etc.
Some antigens are shared among different forms of
tumors and include telomerase27 and survivin28. On
the other hand, expression of some antigens is
restricted within a small percentage of tumors, such
as, the MAGE gene family . Altered genetic events
during or before carcinogenesis, like, gene mutation,
amplification, rearrangement, translocation etc, are
reflected by the overexpression of T AA. These
genetic events may be initiated by some unknown
factor(s), termed as etiological factor. T AAs, after
their expression on cancer cell surface, playa definite
role in favour of tumor cells, specifically by
decreasing the cellular adhesion and promoting
metastasis 29 ,3o. Based on the tumor specificity and
widespread expression, T AAs are being selected as a
candidate for vaccine development. Vaccination with
T AA, in its different form , may elicit antibody
response that is generally specific for the immunizing
antigen. Adequate amount of these antibodies with
high avidity are expected to bind the same antigen
present on tumor cell surface to induce cell lysis.
Tumor cell lysis may include antibody dependent
cellular cytotoxicity and complement mediated
cytotoxicity I. Most of these TAAs, except T
independent antigens like ganglioside antigens, can
elicit T cell response and promote cytotoxic T cell
(CTL) mediated tumor cell lysis.
Tumor vaccine in various forms
The first and most obvious type of vaccine is tumor
cell preparation or membrane preparation from tumor
cells, as a source of TAA. With the advancement of
molecular biologic approaches, gene modified tumor
cells expressing T AA have also been used. In
addition, purified antigen from tumor cell preparation,
recombinant tumor antigen, DNA-encoding protein
antigens and protein derived peptides have been
tested, and some of them are also evaluated in clinical
trials. Several investigators were successful in
obtaining some active antitumor immune responses
. h these lmmunot
.
h
'
wlt
erapeuttc
approac h es31-33 .
However, major problem using tumor material for
immunization is that T AAs are typically weakly
immunogenic due to tolerance 34 ,35. An effective
method to break the tolerance is to present the critical
epitope in a different molecular environment to the
BARAL: ANTIGEN SPECIFIC THERAPY OF TUMORS
tolerized host. While this can be done with welldefined antigens, it is impossible with most T AAs
because they are chemically ill-defined and difficult
to pUrif/ 6 . Another elegant approach for active
specific immunotherapy is anti-idiotypic approach
based on Ierne's network hypothesis 37 • Using this
approach, immunization can be done by anti-idiotypic
antibody (mirror image of TAA) instead of original
antigen, which is also effective to break the immune
tolerance 31 •
Tumor cell as a vaccine
The most straightforward means of immunization is
the use of whole tumor cell preparation (either
autologous or allogenic tumor cells). The advantage
to this approach is that all potential tumor antigens
can be presented to the immune system for processing
and presentations to the appropriate T-cell precursors.
In addition, steps involved in the purification of
antigen from tumor material can be avoided. The
difficulty with this approach lies :n the availability of
fresh autologous tumor material and in the scarcity of
well characterized long term tumor cell lines that are
HLA-typed and expressed high levels of MHC
antigens. This approach was examined in animal
models4 and also in clinics 3s •39 • In a randomized trial,
98 patients of colorectal cancer were treated by
resection alone or resection plus irradiated autologous
tumor cells. A significant improvement in overall and
disease free survival was seen in the patients received
active specific immunotherap/o.
Morton and Barth4 1 have performed an extensive
work on tumor cell vaccine on metastatic melanoma.
They conducted phase IIII trials of active
immunotherapy using an irradiated preparation of
whole cells f-om three allogenic human melanoma
cell lines that express at least 15 tumor associated
41
antigens • Fifteen to 20% of patients who received
this polyvalent melanoma cell vaccine (PMCV) for
treatment of stage IV melanoma had partial or
complete regression of distant metastases and
significantly longer survival than control patients42 , 43 . .
Interestingly, patients who received PMCV after
curative surgical resection had median survival
duration of 38 months, compared with the
postoperative median survival time of only 13 to 18
months44-46.
Purified T AA as a tumor vaccine
Purified antigen can be used as an immunogen in
vaccine with an objective to induce an antibody
393
response against a T AA and to generate antigen
specific cytotoxic T cells (CTLs)5. Human TAAs are
non-self in animal system and highly immunogenic.
Thus, results obtained from experimental system have
shown a strong antigen-specific immune response
against the tumor. However, these antigens are poorly
immunogenic in human system as most of these
tumor antigens are self-antigen. As a consequence,
positive results from animal system may not be
always applicable in humans. Transgenic animal
model, which expresses human T AA and, thereby,
reflects the human situation would help to understand
the fate of T AA vaccine and to find out the ways to
overcome the problem of tolerance47 ,48.
Irrespective of its limitations, this approach is
tested in human system, specifically in melanoma
using different ganglioside preparations. An altered
pattern of cell surface ganglioside (GD3, GD2, GM2
etc) expression was observed in malignant melanoma
and other cancers of neuroectodermal origin 49 ,5o.
Overexpression of gangliosides on the surfaces of
these cancer cells, makes them attractive target for
immunotherapy. GM2 vaccination with BCG in
melanoma patients have been reported to induce IgM
antibodies to GM2 in most patients and disease free
survival was extended in patients producing high titer
of anti-GM2 antibodies s" s2. These antibodies are
principally IgM, but inconsistent IgG titer was also
detected. GD3 and GD2 vaccines were also tested S3 ,
but overall results are not very much promising. To
improve the clinical outcome, these gangliosides were
conjugated with keyhole limpet hemocyanin (KLH)
and injected in combination with various adjuvant
preparations s4 , resulting in increased immunogenicity
and better tolerance to patients ss .
A tumor associated protein, GA-733, has also been
used as a vaccine for the treatment of colon cancer.
This vaccine can reduce the tumor growth by a
specific cell and antibody mediated immune
responseS6 . Recently, Biomira, Inc. (Edmonton,
Alberta, Canada) introduced a tumor vaccine using a
mucin type carbohydrate antigen (Sialyl-Tn). In this
vaccine, Sialyl-Tn was conjugated to the carrier
molecule, KLH. This Sialyl-Tn-KLH vaccine has
been developed for immunizing patients with mucinexpressing tumors. In murine and human studies, the
vaccine has been shown to stimulate anti-Sialyl-Tn
antibodies and mucin-specific T-cell responses S7 . The
immune response was reported to be augmented by
pretreatment with intravenous cyclophosphamide that
394
INDIAN J EXP BIOL, MAY 2005
serves to inhibit suppressor T-cells. Survival benefit
was reported for breast cancer patients who
received the Theratope vaccine after intravenous
cyclophosphamide58. A multinational phase III study
tested this vaccine in patients with metastatic breast
cancer. Better clinical response or stability of the
disease was observed in this trial. Other malignancies
for which the vaccine may be applicable include
ovarian and gastrointestinal cancers58 .
Peptide vaccine as a substitute of whole TAA
vaccine
Instead of whole T AA vaccine, peptides generated
from the sequence information of a T AA were also
tested as vaccine. These peptides can produce
antibody response and cellular immune response
directed against the active epitope of TAA. An
advantage of peptide vaccine is that they can be
synthetically generated in a reproducible fashion 59.60 .
In a study, 63 patients were vaccinated with a 105amino acid polypeptide that included 5 repetitions of
the entire conserved tandem repeat of the MUC 1
peptide 61. In these patients, delayed type hypersensitivity (DTH) reactions were evaluated at 48 hr and
intense T-cell infiltration was reported in majority of
patients. A limited number of patients had a 2-4 fold
increase in mucin specific CTL precursors in the
peripheral blood after vaccination. A 9-mer peptide
spanning the MUCl tandem repeat with an HLA-All
MHC class I restriction was identified. CTLs specific
for this peptide were also identified from peripheral
blood62. Anti Her2/neu antibody response was
generated using a peptide, but not by whole Her2/neu
molecule 63 . In prostate cancer, Kiessling et al. defined
two immunogenic peptides of prostate stem cell
antigen, which were observed to be recognized by
circulating CD8 + T cells from prostate cancer
64
patients and were able to activate CTLs in vitro ,
thus, may serve as a candidate vaccine. A number of
peptides were synthesized based on the sequence
homology of an anti-idiotypic antibody 3Hl and
CEA65. Two of these peptides would stimulate the
proliferation of T lymphocytes from 3HI treated
colon cancer patients and induce the secretion of
IFNy. Further research is in progress to test the
efficacy of these peptides as a vaccine.
Recombinant vaccinia virus in tumor vaccine
The ability to engineer recombinant viruses
encoding T AAs, coupled with the intrinsic
immunogenicity of viruses, has engendered broad
interest in recombinant viral vaccines 66 • Currently,
members of the pox-, retro-, herpes-, and adenoassociated viruses have been used as vehicles in
recombinant viral vaccine construction . Adenovirus,
encoding MART-I , gplOO and tyrosinase, induced
both humoral and cellular immune responses when
used to vaccinate melanoma patients. Schlom
66 68
et aL. • at National Cancer Institute, Bethesda, MD,
tested this approach. Vaccinia virus has been safely
and successfully used as a live vaccine for the
prevention and eradication of smallpox. These viruses
are highly immunogenic and stimulate both humoral
and cell mediated responses 67 . A recombinant
vaccinia virus expressing human CEA (rV -CEA) was
reported to stimulate the T-cell response and strong
anti-CEA antibody response in animal species,
. Iud'mg non h uman pnmates
.
6668
. .
mc
' . V accmatlOn
0f
mice with rV -CEA rendered them resistant to the
growth of subcutaneously tran splanted CEAexpressing tumors 69. In addition to CEA, this model
was also effective for melanoma antigen p97 . Upon
immunization, mice were found to be protected from
the challenge with melanoma cells, which was
mediated by the generation of strong immune
response69 . Recombinant vaccinia virus constructs
with other candidate human T AAs have also been
developed and tested in animal models 7o . To improve
this vaccinia-virus based immunotherapy, low dose
IL-2 or GMCSF was administrated in a murine tumor
model with rV -CEA71. Recently, Greiner et al.72
reported that combination of rV -CEA with
costimulatory molecules (B7 .I , ICAM-I, LFA-3)
along with biological adjuvant GMCSF reduced the
number of intestinal tumors in CEA-transgenic mouse
model.
Tumor cells engineered with
immunostimulatory molecules
genes
of
Another important strategy in active specific
immunotherapy is the development of engineered
tumor cells, where gene or protein of different
immunostimulatory molecules are transferred into the
cells, expressing TAAs73. Tumor escape from immune
effectors is most often caused by weak
immunogenecity of T AAs, antigen masking or overall
immunosuppression. To compensate these problems,
cytokine genes, foreign HLA genes, T AA genes and
genes of co-stimulatory molecules were introduced
into tumor cells to make these as an efficient
vaccine 74 . In a study, IL-2 gene was introduced to
BARAL: ANTIGEN SPECIFIC THERAPY OF TUMORS
lympoma and melanoma using diptheria toxin. When
these engineered cells were injected into mice, an
active immune response was reported to prevent the
tumor growth 75 . Vaccination with membranes
modified
by
protein
transfer
to
express
glycosylphosphatidylinositol
(GPI)-linked
B7.1
(CD80), induces protective immunity in mice and
allogenic antitumor T-cell proliferation in humans
in vitro76 . GPI was also used to express IL-12 on
tumor cell surface, which prevented tumor growth in
mice in a highly tumorigenic murine mastocytoma
model 77 . B7 -transfected melanoma cells stimulate
directly CD8 + T cells for tumor rejection 78 . In some
cases, after transfection with the B7 -1 and B7-2
genes, poorly immunogenic tumors fail to elicit an
effective immune response. However, such tumor was
reported to be immunogenic after transfection of the
genes encoding murine B7-1 together with CD48 79 .
Vaccines for human papilloma virus (HPV)
associated tumors
Human papilloma virus (HPV) has been found to
be closely associated with several forms of cancer,
particularly with cervical carcinoma. More than 100
HPV types have been characterized until now, among
them 11 have been considered as high risk types and
detected in tumor tissue. In recognition of the
association of cervical cancer with this viral infection,
substantial interest has arisen to develop effective
prophylactic and therapeutic vaccines. Prophylactic
strategies currently under investigation focus on the
induction of effective humoral and cellular immune
responses, which are potentially protective against
subsequent HPV infection. Papillomavirus-like
particles have been synthesized to induce neutralizing
antibody respo .. ses, and impressive immunoprophylactic effects have been demonstrated in both
animals and humans 8o • The therapeutic vaccines were
constructed utilizing two non structural early proteins
coded by HPV (products of their E6 and £.7
oncogenes). These E6 and E7 proteins are very much
essential for the pathogenesis of HPV associated
tumors and, thus, several attempts have been made to
target these oncoproteins 8 1• Active immunotherapy
with E7 protein along with CpG oligonucleotide in a
HPV associated murine tumor model, resulted in a
very promising outcome in relation to the slower
tumor growth and extended survival. This vaccination
protocol was able to induce significant humoral and T
cell response to combat the tumor growth 82 •
395
Immunization with xenogenic T AA
Priming adaptive immunity against self-antigens is
potentially a difficult task. Presentation of altered self
to the immune system is a strategy to elicit immunity
against poorly immunogenic antigens. Immunization
with conserved paralogues of T AA can induce
adaptive immunity against self-antigens expressed by
cancer. Cancer immunity induced by xenogenic
immunization follows multiple and alternative
pathways. The effector phase of tumor immunity can
be mediated by cytotoxic T cells or macrophages and
perhaps natural killer cells for antibody-dependent
immunity . Helper CD4+ T cells are also required to
generate such immunity. Using this strategy, rats were
immunized with human Her2/neu protein and
developed significant antibody and T-cell responses
that were specific for both human and rat Her2/neu 83 .
Immunization with human glioma protein causes
tumor growth inhibition in rat glioma model 84 . This
tumor inhibitory effect is due to the antigen specific
IgG immune response and CTL response. GuevaraPatino et ai. have shown that xenogenic DNA vaccination can elicit tumor immunity through T cell and
antibody-dependent effector mechanisms 85 . They
have tested xenogenic DNA vaccines for melanoma
differentiation antigens, tyrosinase-related protein 2
and gplOO and prostate-specific membrane antigen in
association with CTLA-4 blockade86 •
Anti-idiotypic antibody as a vaccine
The idiotype network hypothesis of Lindenmann 87
and Jerne 37 offers an elegant approach to transform
epitope structures into idiotypic determinants .
According to this concept, immunization with an
antibody (Abl) against an antigen (TAA) can
generate several types of anti-Id antibodies (Ab2) in
the injected host. One set of these anti-Id antibodies,
designated Ab2B, acts as 'internal image' of the
antigen and mimics its molecular features . Thus,
injection of Ab2~ to the new host will elicit a new set
of antibodies, which, besides binding to the Ab2~
(Ab3 response), will also bind to the nominal antigen
(Abl' response). The efficacy of anti-Id antibodies as
cancer vaccine has been demonstrated in a number of
preclinical and clinical studies 7,88-92.
Anti-Id vaccine and conventional TAA vaccine
both stimulate the adaptive immune system in an
active specific manner through T- and B-cell
receptors. Priming adaptive immunity against selfantigens is potentially a difficult task. To overcome
396
INDIAN J EXP BIOL, MAY 2005
this particular problem, anti-Id vaccine has
advantages over conventional antigen vaccine. Firstly,
TAAs are often a part of "self' and usually evoke a
very poor immune response in tumor bearing hosts
due to tolerance to the antigen . Following
immunization with a TAA, generation of immune
response may be obstructed by either central or
peripheral tolerance. In central tolerance, no antiT AA antibody is generated after injection of T AA due
to absence of responsible immunocytes (clonal
deletion). Another possibility is that the antibody
generating immune cells remain silenced following
challenge with TAA (clonal anergy). In peripheral
tolerance, some antibody is initially produced, but
then, because of the expression of suppressive
mechanisms (suppressor T cells, antibodies, immune
complexes etc.), antibody production diminishes or
ceases entirely. For example, cancer patients are
immunologically tolerant to CEA, which is likely to
be related to its oncofetel origin. An effective method
to break the tolerance is to present the critical epitope
in a different molecular environment to the tolerized
host93 . Anti-Id antibody is the mirror image of the
nominal antigen and behaves as a foreign molecule in
patients due to its heterologous nature. Mirror image
anti-Ids mimic the three-dimensional structures of
antigens and, thus are genetically unrestricted and
effective across the species barrier because
heterologous antigens are better immunogens. Anti-Id
vaccines are proteins, hence, will have to be MHC
restricted theoretically. Anti-Ids can generate a
significant amount of antibody (Ab3) response, which
has ability to recognize the TAA after breaking the
tolerance imparted by self-TAA vaccine. Anti-Id
vaccine, 3Hl, is reported to induce helper CD4+ T
cell response instead of suppressor T cells 65 . This may
be another way to avoid the self tolerance. Secondly,
most of the T AA~ are poorly characterized and
difficult to purify. On the other hand, using
hybridoma technology anti-Id MAb can be produced
in large quantity, which will be more economical.
Anti-Id vaccine also excludes the possibility of some
undesired side effects which are sometime associated
with conventional antigen vaccine. As a biological
molecule, it has no toxic effect except causing little
fever or swelling at the site of injection. Moreover,
anti-Id vaccine is nothing but an immunoglobulin, it
can be manipulated at protein or gene level.
Apart from these beneficial effects, anti-Idvaccines
also have some potential complications. It is unknown
how long anti-Id immunity will last. After vaccination
with murine anti-Id antibodies, an individual may
generate a human anti mouse antibody (HAMA)
response
that
can
neutralize
the
vaccine.
Humanization of the anti-Id antibodies may be
necessary to overcome the problem. Moreover, care
must be taken in choosing the antibody for the
vaccination, since different anti-Id antibodies
generated against the same idiotope can have different
or even opposite physiological effects. However,
several clinical evidences suggest that these
limitations could have never been a major problem to
restrict their clinical use 94 .
Progress in the field of anti-idiotypic vaccine
Basic information on B- and T- cell induced
responses using the anti-Id approach was obtained
from studies in a mouse leukemia model (LI21O). A
number of anti-Id hybridomas against MAb to the
LI210 tumor were generated. These anti-Id MAbs
have been reported to inhibit the tumor growth by the
induction of tumor specific DTH, CTL, antibodies
and T helper cells in the system95,96. In the same
system, 100% cure of established tumors was reported
by combining anti-Id vaccine with cyclophosphamide,
whereas, 50% cure rate was obtained with anti-Id
therapy alone97 • Using an anti-Id vaccine mimicking
CEA, significant tumor growth restriction and
survival benefit were noted in C57BLl6 mice
challenged with lethal dose of CEA positive murine
tumor35 . This anti-Id vaccine was also effective in
CEA-transgenic mouse model bearing murine colon
tumor. This model is closer to the human system, as
gastrointestinal tract of these transgenic mice
expresses human CEA 98 . Potential of anti-idiotypic
antibodies for the regression of murine tumor growth
was reported by several groups99- IOI. Based on
promIsmg results
from
animal
experiments,
preclinical and clinical studies have already been
performed with anti-Id antibodies.
An Ab2~ anti-Id antibody to a murine MAb was
generated36 that identifies a highly restricted T-cell
antigen designated gp37. This antigen is present in
70% of acute T-cell lymphoblastic leukemia and 30%
of T-cell lymphoma lO2 • Following administration of
this anti-Id antibody, 3 of 4 patients developed
humoral and idiotypic cell mediated response. One
among 4 patients had complete remission of the
tumor. Another T AA is human milk fat globule
membrane antigen expressed in breast cancer. An
BARAL: ANTIGEN SPECIFIC THERAPY OF TUMORS
anti-Id MAb targeting this TAA was developed that
can induce specific antitumor immune responses in
mice, rabbit and monkeys 103. In human, this antibody
can generate high titer of antibody response and Tcell response, but clinical response is not always
correlated with the immune response lO4 . This antibody
was also evaluated in breast cancer patients with bone
marrow transplantation lO5 . Among several TAAs,
CEA has received prime importance in cancer
immunotherapy. A number of investigators have
generated anti-Id antibodies in rats, mice, baboons
and humans that mimic CEAI06.108. An anti-Id MAb,
designated as 3Rl, that mimics a specific epitope of
CEA has been developed and characterized l09. In a
Phase I clinical trial with 3Rl, development of antiCEA immunity causing ADCC of CEA positive cells
was reported I10,1II. In another study, this anti-Id
therapy was combined with standard chemotherapy,
where no adverse effect of 5-fluorouracil on 3Rlinduced immune response was observed ll2 . Moreover,
this vaccine increases overall survival of treated
patients. In addition to anti-CEA antibody response,
3Rl may stimulate Th 1 type helper T cells to secrete
cytokines, like, IFN-y and IL-2, which in tum, induce
cytotoxic T cells. cDNA encoding the variable heavy
and light chain of 3Rl has been cloned and
sequenced 65 . Sequence information was utilized to
develop anti-idiotypic single chain vaccine l13 and to
design peptide vaccine to obtain an anti-CEA
antibody response.
The human anti-Id antibody mimicking GA733-2
antigen, induced long lasting antigen specific T-cell
immunity and specific IgG antibody response against
target antigen I14. Similarly, monoclonal anti-Id
antibodies have been developed that mimic the gp72
antigen 115. Administration of aluminium hydroxide
precipitated antibody in 13 patients with advanced
colorectal cancer produced blastogenic responses to
gp72 antigen in 9 patients 116. Cryopreserved
lymphocytes from this anti-Id immunized patient
could kill autologous tumor cells 117.
Ganglioside antigens are generally overexpressed
in cancers of neuroectodermal origin. Several
attempts have been made to target these antigens
using anti-Id approach. An anti-Id antibody (BEC-2),
which mimics disialoganglioside GD3, was examined
in a Phase III triaI I18 ,119. Another promising anti-Id
antibody is lA 7 that mimics T cell independent
antigen GDi 20 • Excellent anti-GD2 humoral response
was detected using this lA 7 vaccine, which was
397
observed to be reflected in the increment of overall
survival of patients I21 .122 • An additional survival
benefit was observed after combination of high dose
IFN-a2b with this vaccine (unpublished data). Anti-Id
antibody mimicking different epitopes of human
Rer2/neu was reported 123. This antibody may have
therapeutic efficacy for Rer2/neu positive cancer
patients, which is yet to be tested in clinical trials.
Adjuvants
immunity
to
enhance
the
antigen
specific
Modem vaccines are increasingly reliant upon
administration with additional substances, termed
adjuvant I24 .125 , in order to stimulate effective immune
responses against an antigen. An adjuvant can
stimulate humoral or cellular or both wings of the
immune system l26 by activating B cells, T cells, NK
cells, monocytes/macrophages or dendritic cellsI27.128.
Potentiation of the active immune response by an
adjuvant also involves the production of various
cytokines that work in an integrated fashion both
locally and systemically 129.130. The use of the same
::mtigen with different adjuvants has been shown to
elicit significantly different responses from the
immune system 13l . For example, comparison of
immunization of mice with killed Schistosomula from
Schistosoma mansoni with the adjuvant BCG,
pertussis, bacterium parvum, tetanus toxoid, LPS,
yeast glucan, aluminium hydroxide and saponin
showed that only the animals immunized with BCG
or saponin were protected from live S. mansoni
challenge l31 . In addition to the efficacy of the
adjuvant for eliciting an antigen specific protective
immune response, the issue of toxicity of the adjuvant
needs further consideration. Freund' s adjuvant,
considered as a gold standard among all adjuvants,
helps to produce excellent humoral and cell mediated
immunity, but this water-in-oil emulsion is unsuitable
for the human and veterinary uses because of the
imparted local and systemic toxicity 125,132. Similarly
lipopolysaccharide, which is also a strong adjuvant, is
highly . toxic 133 • At present, aluminium hydroxide
(Alugel) precipitated vaccines are approved by Food
and Drug Administration, USA for use in tumor
immunotherapy 104. Beside Alugel, some other
adjuvants, like, QS_21122.134, are currently being used
in clinical trials. An immunostimulatory molecule
CpG oligodeoxynucleotide (CpGODN) is also useful
as
immune
adjuvant
in
tumor
antigen
immunization 137. This adjuvant enhances the immune
398
INDIAN J EXP BIOL, MAY 2005
response to vaccine strategies involving Tindependent antigen by using CpGODN encapsulated
in liposomesl 36 . In Trypanosoma cruzi immunization
model, this CpG adjuvant is proved as a Thl
promoting adjuvant 137 . This adjuvant is also useful in
passive therapy · with a MAb in lymphoma 138 • This
CpGODN was also used as an adjuvant during
vaccination with anti-Id MAb 3H1, mimicking CEA.
This vaccination significantly increases overall
survival of tumor bearing mice, possibly by induction
of ADCC and cytotoxic T lymphocytes 139.
Recombinant cytokines also play a certain role as
adjuvantI40.141. In multiple myeloma, therapeutic
efficacy of idiotype vaccine is disappointing. Use of
GM-CSF and IL-2 along with vaccine can increase
the antitumor activit/ 41 . These cytokines enhance the
antitumoral response possibly by enhancing the NK
and CD8+ T cell activity. An antigen specific immune
response and increase in the secretion of IFN-y, GMCSF and TNF-a were observed to be elevated in
resected melanoma patients when peptide vaccine
(derived from tumor antigen gplOO and tyrosinase)
42
was combined with GM-CSF as an adjuvane . A
suitable adjuvant that can induce activation of various
T cell subsets and production of various cytokines is
thought to be more effective and less toxic than
immunization with external cytokine as adjuvant. In a
recent study, liposomes containing monophosphoryl
lipid A coated. with alum is proved to be effective to
enhance immune response directed against 30KDa
secretory protein of Mycobacterium tuberculosis
H37Ra. Interestingly, this vaccine formulation along
with this neoadjuvant exhibited a Th 1 shift in terms of
higher IgG2a response over IgGl 143 . Neem leaf
preparation was used as an effective immune adjuvant
to increase the immunogenecity of B 16melanoma
antigen and breast tumor associated antigen
(unpublished data). This neem preparation induces the
secretion of IL-12 and IFN-y in vitro (unpublished
data). Studies are in progress to define the m0de of
action of this promising adjuvant.
Dendritic cells in tumor vaccine
Dendritic cells (DCs) constitute a family of antigen
presenting cells defined by their morphology and their
unique capacity to initiate a primary immune
responseI44.145. They originate from bone marrow and
are present as immature antigen presenting cells in
nonlymphoid tissues. On activation by antigenic
challenge and/or inflammation, the DCs mature and
migrate to the secondary lymphoid tissues where they
present the 'processed antigen to T cells 146. As DC has
unique T cell stimulatory property, small numbers of
DCs are sufficient to induce an effective T cell
response l44 . In addition to the activating T cells, DCs
may directly modulate growth and differentiation of B
cells 147, and, thus, regulate humoral responses 146,148.
Because of this unique immunostimulatory properties,
several attempts have been made to enhance active
specific immunity by using DCs pulsed with vaccine.
Different investigators have proved that antigenpulsed DCs are more effective than general antigen
vaccine l49 . As a consequence, DCsare pulsed with
TAAs in their different forms, e.g., tumor cell
l52
lysate l5o, peptide l51 , proteins
etc. and excellent
antitumor effects are reported in vitro and
experimental tumor models. Recently , Saha et al. 153
reported that dendritic cells pulsed with 3Hl (an antiidiotype antibody mimicking CEA) can induce
antigen specific protective immunity. Based on the
accumulated evidence, it is suggested that DCs can be
considered as a good candidate in designing antigen
specific tumor vaccines.
Mechanism of action of tumor vaccine - Role of
T cells
In active specific immunotherapy immunization
with tumor vaccine results in the generation of antiTAA antibodies. This antibody may interact with
T AA, present on tumor cell surface, to induce ADCC
and CDC. Secondly, tumor vaccine is endocytosed by
antigen presenting cells, like, dendritic cells and
degraded to 14-25 mer peptides to be presented by
MHC class II antigens to activate CD4+ helper T
cells. Activated CD4+ T cells, secretes Th2 cytokines,
like IL-4 and . stimulates B cells for antibody
production. CD4+ T cells also secrete Th 1 cytokines
like IL-2 and IFN-y that activate CD8+ T cells, NK
cells and macrophages. On the other hand,
endocytosed tumor vaccine (T AA) may be degraded
into 9-10 mer peptides to be presented in the context
of MHC class I antigen to activate CD8+ cytotoxic T
cells I. These cells can directly kill tumor cells by
different mechanism, e.g. , perforin mediated lysis,
. . 0 f F as l'Igan d etc. 154 ' 155 .
activatIOn
On the basis of recognition of antigens by T cells,
antigens can be divided into two groups, e.g., T
dependent and T independent. Most of the protein
antigens are T dependent antigen and vaccination with
this type of antigen receives T cell help for the tumor
BARAL: ANTIGEN SPECIFJC THERAPY OF TUMORS
growth restriction. On the other hand, T independent
antigens, ·like, carbohydrate antigens, mediate their
antitumor effect generally through humoral immune
system31 • Livingstone and his group have used
several T independent carbohydrate antigens as a
tumor vaccine after forming various antigenconjugates 156,157 . Use of adjuvant also helps to
increase the potency of such antigens l5S •
Progress in tumor vaccine research in India
Several research groups from India have studied
various aspects of TAA biology, however, tumor
vaccine research is still in infancy in India. Success in
designing and application of tumor vaccine partly
depends on the acquired knowledge on T AAs or
tumors. Expression of T AAs, particularly on different
etiologically distinct cancers (oral cancer, cervical
cancer etc.), from Indian patient population has prime
importance to make a good platform for tumor
vaccine research in India. A good database helps to
select an antigen for targeting by tumor vaccine.
Studies on T AA, also called tumor marker, can be
divided into two groups. Firstly, search for a new
antigen and its characterization. Secondly, screening
of an establish~d marker in different regions of India.
In relation to the search of new T AA, Chattopadhyay
and co-workers made significant contribution. A
tumor antigen with mol. wt. 83 kDa (MTAA) was
isolated from murine mammary tumor virus
(MuMTV) induced tumors in mammary gland of
C3H/Jax mice 159 and circulating antibody against
MTAA was detected in the serum of breast cancer
patients 160. Another glycoprotein antigen (mol. wt. 85
kDa) was also isolated and characterized from breast
tumor. Diagnostic significance of this antigen is also
..
.,
.
reporte d 161 '162 . I nvestIgatlOn
on antigenIc
ch anges In
cervical
epithelium
either
from
normal
(premenopausal and postmenopausal) or cancer
bearing women 163 demonstrated a 67 kDa antigen
from cervical cancerous tissues, which was observed
to be cross reactive with serum from cancer cervix
and other gynecological patients 164. Diagnostic
potential of these three antigens was evaluated in a
panel of patients, suffering from various types of
cancer 167 and these are reported to be potential
diagnostic tool for breast and cervical cancer I61 ,165.
Some efforts have been made to assess the status of
various established antigens among Indian patient
population. Bhatnagar et al. compared the level of
CEA ' in tissue and serum of colon cancer patients.
399
They concluded that determination of tumor CEA
could be a useful adjunct for the clinical management
of colon carcinoma l66 . Another group assessed the
level of prolactin, CA15 .3 and TPA in breast
carcinomas 167. Muthuswamy and Raste measured
CA15.3 in association with CEA. Based on the
experimental results, they concluded that CA15.3
reflects tumor burden in a better way than CEA I6S .
Alpha-fetoprotein was found to be increased in
hepatoma patients from South India l69 . A high
prevalence of circulating p53 antibodies was observed
in 60% esophageal squamous cell carcinoma patients,
indicating its potential as a marker in the screening of
high risk population 170. P53 was also studied in oral
premalignant and malignant lesions in association
with p-glycoprotein 171. Das et al. studied extensively
p53 gene in various forms of cancer having high
incidence in Eastern India 172- 177 • A 62-64 kDa protein
T AA was identified in human oral carcinomas
xenografted in nude mice 178. This TAA was targeted
to lyse oral cancer cells by antibody (3F8E3)
dependent cellular cytotoxicity after modulation with
'.:ytokines 179. Shedding of this TAA limits its use as a
vaccine target, however, modulation by rHu-IFN
alpha increases firm anchorage of T AA on the cancer
cells, thereby, increasing its potential as vaccine
target 1so. Abdulkader et al. studied several TAAs and
tumor associated viral antigens in oral and cervical
cancer patients lSl , e.g., hepatitis B surface antigen lS2 ,
herpes simplex virus type 1 antigen IS3, adenoviral
antigen lS4 and p53 1S5 • These studies will help to
design the immunotherapeutic strategy in our country.
However, further elaborate study on other markers
expressed in various forms of cancer in different
geographical regions of India is essential.
Little is known on tumor vaccine research from
India. Talwar et al developed two vaccines against
hCG and GnRH for fertility control lS6 • In addition to
their effect in fertility control, these vaccines were
also utilized in cancer lS6 . A particular type of lung
cancer secretes hCG as a growth factor. Anti-hCG
vaccine was reported to be effective to combat this
particular type of cancer lS7 • On the other hand, antiGnRH ' vaccine was used for hormone dependent
prostate carcinoma patients 187, which may act by
inhibiting blood testosterone level.
In 1970s, Ray et al. 1SS used neuraminidase treated
tumor cells as 'tumor vaccine' arid encouraging
results were reported. They observed that
neuraminidase treated 3-methy1cholanthrene induced
400
INDIAN J EXP BIOL, MAY 2005
fibrosarcoma grew less well in C3H mice compared
with the untreated tumor. In DBDN induced
fibrosarcoma model reduced transplantability was
noted if tumor cells were pretreated with
neuraminidase. Several studies in this direction on
various tumor models proved the efficacy of
neuraminidase treated tumor cells as a 'tumor
vaccine' 188. They hypothesized that target cells may
be killed directly by immune lymphocyte and
macrophages and neuraminidases may alter certain
cellular contacts.
Baral et al. in their studies, have vaccinated mice
with different tumor antigens to examine antibody as
well as T cell responses. In these studies, a neem leaf
preparation was observed to be effective as an
immune adjuvant to enhance the antigen specific
immunity (unpublished data). This neem preparation
stimulated the murine immune system and activated
immune system is able to restrict the in vivo growth of
murine carcinoma and melanoma l89 .
Conclusions and future prospects
Active specific immunotherapy is a new hope in
cancer treatment to avoid the toxicities imparted by
chemotherapy and radiotherapy. This approach is
effective to kill tumor cells in a specific manner, thus
normal cells remain unaffected. Identification of
antigen expressed on tumor cells, preferably in early
stage, is the primary criteria to design an
immunotherapeutic strategy. After getting idea on
antigenic status, the antigen in its suitable form is
presented in vivo to initiate optimum antibody and Tcell responses. The journey on tumor vaccine research
was initiated from whole tumor cell lysate vaccine
and in subsequent time, several developments have
been made including DC based vaccine. Some of
these vaccines were tested in ~Iinical trials with some
encouraging results (Table 4). This mode of therapy is
particularly effective to prevent recurrences after
surgical removal of primary tumor and is proved to be
safe. Unlike vaccines used for the prevention of
different diseases, scope of prophylactic vaccine in
cancer is limited, due to unavailability of a universal
T AA, till date. This field is still open to find out a
solution. Describing new developments of tumor
vaccine research, hundreds of papers are published in
each year with promising views. The day is not too far
when the outcome of extensive tumor vaccine
research will be utilized in clinic for the benefit of
cancer patients along with conventional therapies. To
utilize the full benefit of this treatment, particularly in
our country, early detection programme and screening
of patients for the appearance of T AA (marker) need
to be strengthen in the meantime.
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