Immunotherapy

Immunotherapy in Cancers
Prof. M.C.Bansal
MBBS,MS,MICOG,FICOG
Professor OBGY
Ex-Principal & Controller
Jhalawar Medical College & Hospital
Mahatma Gandhi Medical College, Jaipur.

Tumor cell proliferation and
immunotheray of cancers
 Professor M. C. Bansal
M.B.B.S. M.S. F.I.C.O.G M.I.C.O.G

Cell Cycle
 Information on growth patterns and doubling times
relates to the growth of the tumor mass as a whole.
The kinetic behavior of individual tumor cells has
been well described, and a classic cell cycle model has
been produced .
 M phase (mitotic phase) of the cell cycle is the phase
of cell division.
 G1 phase (postmitotic phase) is a period of variable
duration when cellular activities and protein and RNA
synthesis continue. These G1 cells can differentiate or
continue in the proliferative cycle.

 S phase (DNA synthetic phase) is the period in which
new DNA replication occurs.
 G2 phase (postsynthetic phase) is the period in which
the cell has a diploid number of chromosomes and
twice the DNA content of the normal cell. The cell
remains in this phase for a relatively short time and
then enters the mitotic phase again.
 G0 phase (the resting phase) is the time during which
cells do not divide. Cells may move in and out of the
G0 phase.

 The generation time is the duration of the cycle from
M phase to M phase. Variation occurs in all phases of
the cell cycle, but the variation is greatest during the
G1 period. The reasons for this variation are complex
and not completely understood.

 These cell cycle events have important implications for
the cancer therapist.
 Differential sensitivities to chemotherapy and
radiation therapy are associated with different
proliferative states.
 Dividing cancer cells that are actively traversing the
cell cycle are very sensitive to chemotherapeutic
agents.

 Cells in a resting state (G0) are relatively insensitive to
chemotherapeutic agents, although they occupy space
and contribute to the bulk of the tumor.

Cell Kinetics

 In cell kinetic studies performed on human
tumors, the duration of the S phase (DNA synthesis
phase) is relatively similar for most human
tumors, ranging from a low of 10 hours to a high of
approximately 31 hours.
 The length of the cell cycle in human tumors varies
from slightly more than half a day to perhaps 5 days.
 With cell cycle times in the range of 24 hours and
doubling times in the range of 10 to 1,000 days, it is
clear that only a small proportion of tumor cells are in
active cell division at any one time.

 Two major factors that affect the rate at which tumors
grow are the growth fraction and cell death.
 The growth fraction is the number of cells in the
tumor mass that are actively undergoing cell division.
 There is a marked variation in the growth fraction of
tumors in human beings, ranging from 25% to almost
95%.

 In the past, it was thought that human tumors
contained billions of cells, all growing slowly.
 In actuality, only a small fraction of cells in a tumor
mass are rapidly proliferating; the remainder are out of
the cell cycle and quiescent.
 Cancer “stem cells” are a very small population of cells
that appear to be relatively chemoresistant; these play
a major role in the development and progression of
cancers.

Tumor growth may be altered by the following:
 cytotoxic chemotherapy, which alters both the generation
time and the growth fraction of a tumor
 hormones, which appear to alter the growth fraction
without changing the generation time
 radiation therapy, which alters both the generation time
and the growth fraction
 alterations in oxygen tension and vascular supply, which
alter the growth fraction without altering generation time
 immunologic therapies, which seem to alter both
generation time and growth fraction

INTRODUCTION
 Cancer is caused by a series of events that include the
accumulation of successive molecular lesions and
alterations in the tumor microenvironment .
 Molecular lesions include overexpression, amplification, or
mutations of oncogenes; deletion of tumor suppressor
genes; and the inappropriate expression of growth factors
and their cellular receptors.
 In addition to these molecular changes, the formation of
new blood vessels (angiogenesis) and the lack of effective
host antitumor immune responses create a
microenvironment that supports the growth of cancer .

 Our improved understanding of these mechanisms
presents an opportunity for the development of novel
therapeutic approaches .
 This presentation provides an overview of
biologic, targeted, and immunotherapeutic strategies
for gynecologic cancers.

Biologic and Targeted Therapies
 The growth of cancer cells is crucially dependent on
oncogenic signal transduction pathways.
 Extracellular signals are transmitted to the cancer cell via
transmembrane receptors.
 Activation of the epidermal growth factor receptors
(EGFR, HER2, HER3, and HER4), for example, stimulates a
cascade of intracellular proteins that ultimately lead to
changes in gene expression.
 Novel therapeutics are targeted to modulate these signal
transduction pathways by blocking the extracellular
transmembrane receptors or interfering with intracellular
proteins such as tyrosine kinases further downstream.

 This novel therapeutic approach is also termed
molecular targeting .
 It is accomplished by either monoclonal antibodies
that bind to transmembrane receptors and serum
proteins such as vascular endothelial growth factor
(VEGF) or chemical, small-molecule inhibitors that
prevent activation of signal transduction proteins.
 Targeting the signaling cascade inhibits the
proliferation of cancer cells, induces apoptosis, and
blocks metastasis.

 The specificity of these molecules is based on the
assumption that cancer cells are overexpressing
various proteins in the signal transduction
pathways, therefore presenting a preferred target
compared to normal cells.
 Conceptually, this should result in more cancer cell-
specific therapy and less clinical side effects because of
sparing of normal tissue

Angiogenesis

 The formation of new blood vessels (neoangiogenesis) is a
normal process during embryonic development, tissue
remodeling, and wound healing .
 Malignant tumors are able to induce angiogenesis by
secreting paracrine factors that promote the formation of
new blood vessels.
 Angiogenesis is a complex process that is influenced by
various pro-and antiangiogenic factors, including
VEGF, interleukin 8, platelet-derived endothelial cell
growth factor, and angiopoietins.
 Overexpression of these angiogenic factors leads to
neovascularization and increased supply of nutrients and
oxygen to the tumor.

 Three main therapeutic strategies that target
angiogenesis are currently being explored for the
treatment of cancer patients .
 One group of agents targets VEGF
(e.g., bevacizumab, VEGF-Trap), the second group
prevents VEGF from binding to its receptor
(pertuzumab), and a third group of agents inhibits
tyrosine kinase activation and downstream signaling
in the angiogenesis signaling cascade
(valatanib, sunitenib).

Vascular Endothelial Growth Factor

 VEGF is overexpressed in gynecologic
malignancies, therefore presenting an excellent target
for therapy .
 Inhibition of VEGF-induced angiogenic signaling
decreases tumor microvascular density and causes
death of solid tumors in various preclinical models.
 Several agents are now available for clinical use; all
target the VEGF signaling pathway.
 The most widely used agent at this time is
bevacizumab, a humanized, recombinant monoclonal
antibody that binds to all isoforms of VEGF-A.

 In ovarian carcinoma, various clinical trials have
demonstrated the efficacy of bevacizumab treatment.
 In a study by the Gynecologic Oncology Group, 62
patients received single agent bevacizumab 15 mg/kg
intravenously every 21 days .
 Thirteen patients (21%) showed clinical responses
with two complete and 11 partial responses.
 The median response duration was 10 months, and 25
patients (41.3%) survived progression free for at least 6
months.

 Bevacizumab has also been used in combination with other
agents.
 In a phase II study of 13 patients with recurrent ovarian or
primary peritoneal carcinoma, combination treatment with
bevacizumab (15 mg/kg i.v. every 21 days) and erlotinib (150
mg/day orally) resulted in one complete response and one
partial response for a total response rate of 15% .
 Seven patients had stable disease.
 Another trial investigated the combination of bevacizumab
(10 mg/kg every 14 days) and oral cyclophosphamide (50
mg/day orally) in 70 patients with recurrent ovarian cancer.

 The Gynecologic Oncology Group has initiated a
clinical trial that will evaluate the addition of
bevacizumab to first-line chemotherapy after primary
tumor debulking.
 A similar trial by the Gynecologic Cancer InterGroup is
designed to evaluate the safety and efficacy of adding
bevacizumab to standard chemotherapy (carboplatin
and paclitaxel) in patients with advanced epithelial
ovarian or primary peritoneal cancer .

Epidermal Growth Factor Receptor
Inhibitors
 The epidermal growth factor receptor family consists
of four members including EGFR
(HER1), HER2, HER3, and HER4 .
 EGFR overexpression has been reported in 35% to
70% of patients with epithelial ovarian cancer .
 In endometrial cancer, EGFR is overexpressed in 43%
to 67% of tumors and is associated with shortened
disease-free and overall survival .
 In addition, amplification of the HER2 gene is
commonly found in endometrial carcinoma.

 Various agents directed against epidermal growth
factor receptors are available .
 Trastuzumab is a humanized monoclonal antibody
that binds to the extracellular domain of HER2 .
 Blockade of HER2 affects various molecules that
ultimately decreases cell proliferation.
 Pertuzumab is another humanized monoclonal
antibody that binds to a different epitope of HER2
compared to trastuzumab.
 Binding to HER2 prevents dimerization of the
receptor, which is required for its function .

Epidermal Growth Factor Receptor
 Inhibition of EGFR signaling is accomplished by using
either monoclonal antibodies against the extracellular
receptor or small-molecule inhibitors against the
intracellular kinase domain.
 Both strategies results in inhibition of
phosphorylation or receptor activation.
 Erlotinib is a potent reversible inhibitor of EGFR
tyrosine kinase that blocks receptor
autophosphorylation and has been used for the
treatment of ovarian carcinoma.

 Erlotinib has been used in combination with docetaxel and
carboplatin as first-line treatment after surgical
cytoreduction in patients with ovarian, fallopian tube, and
primary peritoneal cancers .
 Cetuximab (C225, Erbitux) is a chimerized monoclonal
antibody against EGFR.
 Cetuximab in combination with carboplatin resulted in
three complete (10.7%) and six partial (21.4%) responses in
28 patients with recurrent ovarian cancer.
 Twenty-six of these 28 patients (92.8%) had EGFR-positive
tumors.


 The combination of paclitaxel, carboplatin, and
cetuximab for first-line chemotherapy of stage III
ovarian cancer patients resulted in progression-free
survival of 14.4 months and was therefore not
significantly prolonged compared to historical data.

 Gefitinib (ZD1839 Iressa) is a low molecular weight
quinazoline derivative that inhibits the activation of EGFR
tyrosine kinase via competitive binding of the ATP-binding
domain of the receptor.
 Treatment of patients with recurrent ovarian cancer using
the combination of gefitinib, carboplatin, and paxitaxel
resulted in a high overall response rate of 63% .
 Interestingly, antitumor responses were observed in 35% of
patients with platinum-resistant disease compared to a
73% response rate in patients with platinum-sensitive
disease.

 Gefitinib has also been used in combination with
tamoxifen.
 In squamous and adenocarcinoma of the cervix, gefitinib
(500 mg/day) treatment resulted in disease stabilization in
six of 28 patients (20%) but no clinical responses .
 Lapatinib is a small-molecule inhibitor of both the HER2
and EGFR tyrosine kinase receptor.
 The rationale for using lapatinib in endometrial carcinoma
is supported mainly by studies in human cancer cell lines.
Its efficacy in endometrial cancer is being investigated
currently in clinical trials .

HER-2/neu
 The HER-2/neu receptor is activated by homo- or
heterodimerization, resulting in tyrosine phosphorylation
and subsequent activation of various downstream signals
that among other functions control cellular proliferation,
migration, and invasion.
 Trastuzumab is a recombinant, humanized IgG1
monoclonal antibody that is specific for the extracellular
domain of HER-2/neu.
 Binding of the antibody to HER-2/neu prevents activation
of the receptor with a subsequent increase of apoptosis in
vitro and in vivo, impaired DNA damage repair, and
inhibition of tumor neovascularization.

 The HER-2/neu oncogene is overexpressed in several
gynecologic malignancies, including 20% to 30% of
ovarian cancers.
 HER2/neu overexpression is infrequent in cervical
cancer.
 In uterine papillary serous carcinoma, 12 of 68 (18%)
tumors showed HER2/neu overexpression; this was
associated with a worse overall prognosis .

 Mitogen-Activated Protein Kinase Pathways
 The mitogen-activated protein (MAP) kinase cascades
are activated by various cofactors, inflammatory
cytokines, and stress.
 Sorafenib is among the first of the agents with
clinically proven efficacy. Sorafenib is a competitive
inhibitor of raf that has been approved for treatment
of renal cell carcinoma and hepatocellular carcinoma.
 Besides targeting raf, sorafenib also inhibits VEGFR2
and VEGFR3, FT3, c-kit, and PDGFR-β.

The PI3-kinase/Akt/mTOR Pathway
 The phosphoinositide3-kinase (PI3-kinase)/Akt/mTOR
pathway is a major oncogenic signaling pathway in various
cancers.
 Activation of this pathway can be demonstrated in more
than 80% of endometrial cancers, 50% to 70% of epithelial
ovarian cancers, and approximately 50% of cervical
cancers.
 Several inhibitors of PI3-kinase/Akt/mTOR signaling are
currently in clinical trials.
 Rapamycin or rapamycin analogues, for example, block the
activity of mTOR, a protein complex responsible for
increasing protein synthesis and cellular proliferation.

 Several mTOR inhibitors, including RAD001 and
CCI779, and specific PI3-kinase inhibitors are
currently under development in preclinical models
and clinical trials. PI3-kinase/Akt/mTOR inhibitors
have been used in endometrial cancer with limited
benefit.

Immunotherapy
 Failure of functional immunity contributes to the
genesis of virus-associated cancers, such as those
caused by human papilloma virus (HPV) or Epstein-
Barr virus.
 The greatest success story involving the enhancement
of immunity to combat gynecologic cancer is the
development of vaccines against HPV, which are highly
effective for the prevention of cervical dysplasia and
cancer .

 Some researchers suggest that immune responses are
mainly involved in protection from virus-associated
cancers but not other forms of cancer .
 Cancer is a common disease, and overt immune
deficiency certainly is not necessary for its
development.
 However, recent studies have shown that many
cancers, including those that are not known to have a
viral etiology, are seen with increased frequency in
patients who have dysfunctional immunity.

 In a recent metaanalysis of cancer incidence in
populations known to be immune deficient (e.g.,
organ-transplant recipients, patients with HIV
infection), Grulich and co-workers found an increased
incidence of several common cancers, suggesting that
impaired immunity can contribute to the development
of cancer.

Components of the Immune System
Involved in Antitumor Responses
 Various types of human immune responses can target
tumor cells.
 Immune responses can be categorized as humoral or
cellular, a distinction based on the observation in
experimental systems that some immune responses could
be transferred by serum (humoral) and others by cells
(cellular).
 In general, humoral responses refer to antibody responses;
antibodies are antigen-reactive, soluble, bifunctional
molecules composed of specific antigen-binding sites
associated with a constant region that directs the biologic
activities of the antibody molecule, such as binding to
effector cells or complement activation .

 Cellular immune responses generally refer to cytotoxic
responses mediated directly by activated immune cells
rather than by the production of antibodies .
 Nearly all immune responses involve both humoral
and cellular components and require the coordinated
activities of populations of lymphocytes operating in
concert with each other and with antigen-presenting
cells.
 These activities result in various effector functions
such as antibody production, cytokine secretion, and
the stimulation and expansion of cytotoxic T cells.

 Cellular interactions involved in immune responses
include direct cell-cell contact, as well as cellular
interactions mediated by the secretion of, and
response to, cytokines.
 The latter are biologic messenger molecules that play
important roles in the genesis, amplification, and
effector functions of immune responses.
 T lymphocytes play a pivotal role by acting as helper
cells in the generation of humoral and cellular
immune responses and by acting as effector cells in
cellular responses.

 Cytotoxic T cells are effector T cells that can directly
interact with, and kill, target cells by the release of
cytotoxic molecules and the induction of target cell
apoptosis.
 T-lymphocyte precursors mature into functional T
lymphocytes in the thymus, where they learn to recognize
antigen in the context of the major histocompatibility
complex (MHC) molecules of the individual.
 Most T lymphocytes with the capability of responding to
self-antigens are removed during thymic development.

 T lymphocytes are distinguished from other types of
lymphocytes by their biologic activities and by the
expression of distinctive cell surface
molecules, including the T-cell antigen receptor and
the CD3 molecular complex.
 T lymphocytes recognize specific antigens by
interactions that involve the T-cell antigen receptor .

 There are two major subsets of T lymphocytes: T helper/inducer
cells, which express the CD4 cell surface marker; and T
suppressor/cytotoxic cells, which express the CD8 marker.
 CD4 T lymphocytes can provide help to B lymphocytes, resulting
in antibody production, and also can act as helper cells for other
T lymphocytes.
 Much of the helper activity of T lymphocytes is mediated by the
production of cytokines.
 CD4 T cells have been further subdivided into TH1 (cellular
immunity/proinflammatory) and TH2 (antibody response-
promoting) subsets, based on the pattern of cytokine production
and the biological properties of these cells.

 Recent studies have identified a subset of T cells that
inhibit autoreactive cells, perhaps acting to prevent
autoimmune responses .
 This subset of T cells has been called regulatory T cells.
Other recently described T-cell subsets include TH17
cells, which are important in driving immune responses to
bacteria and fungi .
 The CD8 T-lymphocyte subset includes cells that are
cytotoxic and can directly kill target cells.
 A major biologic role of such cytotoxic T lymphocytes is the
lysis of virus-infected cells. However, cytotoxic T
lymphocytes can directly mediate the lysis of tumor cells.

 Effector T cells also can contribute to antitumor immune
responses by producing cytokines, such as tumor necrosis
factor (TNF), that induce tumor cell lysis and can enhance
other antitumor cell effector responses.
 Both CD4 and CD8 T cells respond to antigen only when it
is presented in the context of MHC molecules on antigen-
presenting cells or target cells or both.
 The T-cell receptor on CD4 T cells is restricted to
responding to antigen plus MHC class II molecules; the
receptor on CD8 T-cells is restricted to responding to
antigen plus MHC class I molecules.

 Therefore, provision of effective costimulatory signals
is necessary for the induction of effective antitumor
responses by activated T cells.
 B lymphocytes are the cells that produce and secrete
antibodies, which are antigenbinding molecules .
 B lymphocytes develop from pre-B cells and, after
exposure to antigen and appropriate activation
signals, differentiate to become plasma cells—cells
that produce large quantities of antibodies.
 Mature B lymphocytes use cell-surface
immunoglobulin molecules as antigen receptors.

 In addition to producing antibodies, B lymphocytes
play another important role: They can serve as efficient
antigen-presenting cells for T lymphocytes.
 Although the production of antitumor antibodies does
not appear to play a central role in host antitumor
immune responses, monoclonal antibodies reactive
with tumor-associated antigens have proved to be very
useful in antitumor therapy, as well as in the detection
of tumors or of tumor-associated molecules.

 Macrophages and dendritic cells also play key roles in
the generation of adaptive, lymphocyte-mediated
immune responses by acting as antigen-presenting
cells.
 Helper/inducer (CD4) T lymphocytes, bearing a T-cell
receptor of appropriate antigen and self-specificity, are
activated by antigen-presenting cells that display
processed antigen combined with self-MHC
molecules.


 Antigen-presenting cells also provide costimulatory
signals that are important for the induction of T-
lymphocyte activation.
 In addition to serving as antigen-presenting
cells, macrophages can ingest .and kill
microorganisms and act as cytotoxic antitumor killer
cells.
 These cells also produce various cytokines, including
IL-1, IL-6, chemokines, IL-10, and TNF, which are
involved in many immune responses

 These monocyte-produced cytokines can have direct
effects on tumor cell growth and development, both as
growth-inducing and growth-inhibiting factors.
 Natural killer (NK) cells are cells that have large granular
lymphocytic morphology, do not express the CD3 T-cell
receptor complex, and do not respond to specific antigens.
NK cells can lyse target cells, including tumor
cells, unrestricted by the expression of antigen or self-MHC
molecules on the target cell.
 Therefore, NK cells are effector cells in an innate (non-
antigen-restricted) immune response and may play a vital
role in immune responses to tumor cells. The cells that can
effect antibody-dependent cellular cytotoxicity (ADCC) are
NKlike cells.

 Cytokines are soluble mediator molecules that
induce, enhance, or effect immune responses.
 Cytokines are produced by various types of cells and play
critical roles not only in immune responses but also in
biologic responses outside of the immune response, such
as hematopoiesis or the acute-phase response.
 T helper 1(TH1) and TH2 cells, which control the nature of
an immune response by secreting characteristic and
mutually antagonistic sets of cytokines (9,10,11), are defined
by the cytokines they produce.

 TH1 clones produce IL-2 and IFN-, whereas TH2
clones produce IL-4, IL-5, IL-6, and IL-10.
 TH1 cytokines promote cellmediated and
inflammatory responses, whereas TH2 cytokines
enhance antibody production.
 Most immune responses involve both TH1 and TH2
components.
 Research has identified CD4-positive T cells that
participate in the maintenance of immunologic self-
tolerance by actively suppressing the activation and
expansion of self-reactive lymphocytes.

 These cells are called regulatory T cells, or Treg cells. Treg
cells are characterized by the expression of CD25 (the IL-2
receptor-chain) and the transcription factor FoxP3.
 Treg cell activity is thought to be important in preventing
the development of autoimmune diseases.
 Removal of Treg also may enhance immune responses
against infectious agents or cancer.
 Although much remains to be learned about the role of
Treg activity in antitumor immunity, it is clear that such
cells may play a role in modulating host responses to
cancer.

Therapeutic Strategies
 There is great interest in developing effective biologic
and immune therapies for gynecologic malignancies.
 For example, patients with small-volume or
microscopic residual peritoneal ovarian cancer are
attractive candidates for immunotherapy or biologic
therapy, especially approaches based on regional
peritoneal immunotherapy or biotherapy.
 Also, many patients with advanced disease are
immunocompromised, suggesting a role for
immuneenhancing therapeutic approaches.

 Dysplastic and cancerous cervical epithelial cells
infected with HPV, an oncogenic virus, also present an
attractive target for immune enhancement-based
therapeutic strategies, including the development of
therapeutic vaccines for HPV.
 Advances in molecular
biology, biotechnology, immunology, and cytokine
biology have resulted in the availability of many
new, promising immunotherapeutic approaches for
gynecologic cancers.

Monoclonal Antibodies and
Antibody-Based Immunotherapy
 Monoclonal antibodies have played an important role in both the
development of immunotherapeutic agents and tumor markers.
 Monoclonal antibodies also have been used for radioimmunodetection
and are being used for treatment.
 Monoclonal antibodies can potentially induce antitumor responses in
various ways:
(i) by complement activation and subsequent tumor cell lysis;
(ii) by directly inducing antiproliferative effects, perhaps by
interaction with tumor cell surface signaling molecules;
(iii) by enhancing the activity of phagocytic cells, which can
interact with immune complexes containing monoclonal
antibodies; and
(iv) by mediating ADCC via interactions of the Fc portion of
monoclonal antibodies with Fc receptors on cells that
mediate ADCC .

 In addition, monoclonal antibodies can be labeled
with either radioactive particles or antitumor drugs
and used to focus these agents onto tumor cells .
 In fact, some monoclonal antibody-based drugs are
currently approved and being used for the treatment
of cancer with great success.

 Several clinical trials have utilized monoclonal antibodies
directed against ovarian cancer antigens, including
CA125, folate receptor, MUC1 antigen, and tumor-
associated glycoprotein 72 .
 Evidence that CA125 can act as a tumor antigen that
stimulates humoral and cellular immune responses is
derived from various in vitro studies and clinical trials.
 Oregovomab (B43.13) is a murine monoclonal antibody to
CA125 that has been used for the treatment of ovarian
cancer. The antibody binds to circulating CA125, resulting
in the formation of immune complexes (antibody-antigen
complexes).

 These immune complexes are recognized as
foreign, mainly because of the murine component.
 They are taken up by antigen-presenting
cells, allowing the processing of the autologous CA125
antigen, ultimately leading to induction of CA125-
specific antibodies, helper T cells, and cytolytic T cells.

 the velocity of the rise in CA125 levels at relapse was found
to be a highly significant predictor of postrelapse outcome.
 Another antibody network-based strategy has employed
anti-idiotype vaccines in patients with relapsed ovarian
cancer.
 ACA125 is a murine anti-idiotypic antibody that mimics an
antigenic epitope on CA125.
 Therefore, antibodies generated to ACA125 have the
potential to react with antigenic epitopes on CA125, with
ACA125 serving as an antiidiotype vaccine that would
enhance immune responses to CA125 .

 Treatment with ACA125 resulted in both humoral and
cellular responses, and those patients who had
detectable anti-ACA125 responses showed a longer
mean survival time than those who did not develop
responses .
 Abagovomab is an anti-idiotypic antibody that mimics
the CA125 antigen.
 The initial results of abagovomab treatment in
patients with ovarian cancer were reported by
Sabbatini et al. and showed that all patients developed
an anti-idiotypic antibody response (Ab3).

 In addition, the generation of T-cell immunity to
CA125 was demonstrated in five patients. While
patients had measurable serum CA125 levels in both
trials, neither trial analyzed CA125 expression in tumor
tissue.
 A large international, multicenter trial is underway to
investigate the effect of abagovomab as consolidation
treatment in patients with ovarian cancer.

Adoptive lmmunotherapy
 Adoptive immunotherapy involves the ex vivo
expansion of antitumor immune cells followed by the
administration of such effector cells. It has provided
another immune system-based approach for
antitumor therapy.
 Adoptive immunotherapy, involving the infusion of
large numbers of autologous ex vivo-activated immune
effector cells, has been shown to produce tumor
regression in various animal and human tumors.

 Early approaches used peripheral blood mononuclear
cells exposed to IL-2 ex vivo to lead to the generation
of lymphokine-activated killer (LAK) cells that are
cytotoxic for a variety of tumor cells .
 adoptive immunotherapy with LAK cells does not
appear to be a practical option for the treatment of
ovarian cancer.
 The use of immunotherapy based on ex vivo-
stimulated tumor-infiltrating lymphocytes or tumor-
associated lymphocytes from ascites, with or without
added IL-2, also has been examined in ovarian cancer .

Dendritic Cell and Tumor Vaccine
Therapy
 Various tumor-associated antigens are potential
immunogens for tumor vaccines, including (i)
differentiation antigens, (ii) new antigens created by
mutation of genes encoding host cell proteins, (iii)
molecules that are overexpressed on tumor cells
(i.e., HER2, NY-ESO-1, CA125), and (iv) viral antigens from
oncogenic viruses (i.e., HPV-encoded antigens) .
 Experimental tumor vaccine therapy in ovarian cancer has
been carried out using the NY-ESO-1 antigen. Nearly half
of epithelial ovarian cancers are NY-ESO-1 positive .


 Vaccination with a peptide from NY-ESO-1 resulted in
the generation of both cellular and humoral immunity
to this antigen, in most vaccinated patients .
 Vaccines based on HER2 also have been tested in
ovarian cancer patients, with such treatment resulting
in the induction of specific T-cell responses in most
patients .
 Human papilloma virus—specifically, HPV subtypes
16, 18, 31, and 45—has been implicated as the major
etiologic agent in cervical cancer.

 HPV-infected dysplastic and cancerous cervical
epithelial cells consistently retain and express two of
the viral genes, E6 and E7, that respectively interact
with and disrupt the function of the p53 and
retinoblastoma tumorsuppressor gene products.
 Factors other than infection with HPV, such as cellular
immune function, play an important role in
determining whether the infection of cervical
epithelial cells regresses or progresses to cancer.

 This has led to the development of prophylactic and
therapeutic vaccines to HPV, as well as treatment
approaches based on the enhancement of host immune
function.
 Human papilloma virus vaccines have been shown to have
an exceptional level of efficacy , clearly reducing the
incidence of both HPV-16 and -18 infections and HPV-16
and -18-related cervical intraepithelial neoplasia.
 The HPV vaccines Gardasil and Cerverix use HPV-like
particles as immunogens to generate neutralizing
antibodies for HPV.

 These findings suggest that HPV-based therapeutic
cancer vaccines may also be effective for the control of
cervical cancer .
 HPV E6 and E7 are attractive antigens for use in
therapeutic vaccines because these HPV-encoded
proteins are involved in cellular transformation and
therefore are consistently expressed in HPV-positive
tumor cells.

 Dendritic cells are highly effective antigen-presenting
cells and play a central role in the induction of both
CD4 and CD8 T-cell responses.
 Dendritic cells can be pulsed with tumor antigen
peptides or bioengineered to express tumor
antigens, allowing them to be used in experimental
therapies that aim to enhance antitumor immunity.
 Exposure of T cells to dendritic cells pulsed with
ovarian cancer-derived antigenic preparations resulted
in the generation of cytolytic effector T cells that could
kill autologous tumor cells in vitro .

 In a phase I clinical trial, Hernando and co-workers
showed that patients with advanced gynecological
malignancies could be effectively vaccinated with
dendritic cells pulsed with a nontumor test
antigen, keyhole limpet hemocyanin (KLH), and
autologous tumor antigens.
 Lymphoproliferative responses to KLH and to tumor
lysate stimulation were noted. The treatment was
safe, well tolerated, immunologically active, and
generally devoid of significant adverse effects.

Biologic Response Modifier and
Cytokine Therapy: Modulation of Host
Immunity
 Most early experimental biologic therapies for
metastatic ovarian cancer involved biologic response
modifiers such as Corynebacterium parvum (a heat-
killed, gram-negative anaerobic bacillus), bacillus
Calmette-Guérin (BCG), or modifications of these
agents .
 Exposure to C. parvum resulted in the nonspecific
enhancement of host immune responses, including
the induction of an acute inflammatory response .

 Biologic response modifier therapy for ovarian
cancer, including treatment with C. parvum and BCG, was
examined in several studies.
 IP treatment with IL-12 in patients with carcinomatosis
from mesotheliomas, müllerian or gastrointestinal
carcinomas, showed a 10% complete response rate and
disease stabilization in nearly half of the treated patients .
 In a recent phase II trial, treatment with subcutaneously
administered IL-2 and oral retinoic acid was reported to
improve survival in patients who had ovarian cancer
responding to chemotherapy .

 The recent identification of T-cell subpopulations that
have potent immunoregulatory properties, such as
Treg cells and TH17 cells, provides new opportunities
for the design of host immune system-modulating
therapies with the aim of enhancing immune
responses to cancer.
 TH17 cells are another recently identified regulatory T-
cell subpopulation, characterized by the secretion of
IL-17. They have the ability to modulate Treg activity .

Immunotherapy

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