I. Introduction
The gliomas are the most common malignant tumors of the
brain, and extensive invasion into the surrounding normal brain tissue is often
seen because of their infiltrating nature. Despite surgical and technological
progress in the treatment of central nervous system (CNS) diseases, the
prognosis of patients with malignant gliomas still remains poor. With the
current treatment modalities for malignant gliomas, which consist of surgical
resection followed by radiation therapy and/or chemotherapy, the median
survival is still less than 1 year (Prados
et al, 1992). Thus, the
development of new therapeutic approaches for gliomas is essential.
Vaccination against cancer using either tumor cells or
tumor antigens is an active immunotherapeutic strategy that induces and/or
enhances anti-tumor immunity in the patientÕs body. This therapeutic strategy
differs from passive immunotherapy, in which immune cells having antitumor
activity, such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells,
are prepared in vitro and
administered to cancer patients. Furthermore, specific immune responses against
tumor antigens induced by cancer vaccines have been shown to be effective in
the treatment of cancer patients.
The concept of the CNS being an
Òimmune privileged siteÓ was developed from classical studies, which showed
that the brain is more permissive to transplantation of allografts than other
organs of the body. In fact, antigen-presenting cells (APCs), such as dendritic
cells (DCs), do not work efficiently within the CNS. Therefore, it would be
theoretically difficult to present antigens within the CNS to the immune
system. However, it was demonstrated in some studies that activated T cells can
migrate across the blood-brain barrier (BBB) and infiltrate the brain (Wekerle,
1993; Fabry et al, 1994).
Therefore, immunotherapy has been targeted at inducing specific immune responses
against brain tumors within the body outside the CNS. Recently, clinical trials
of a cancer vaccine containing DCs were performed in glioma patients and the
vaccine was reported to be effective in some patients (Yu
et al, 2001).
Although the effectiveness of this DC therapy still needs to be evaluated in
future clinical trials, including Phase II trials, it is considered significant
that no marked adverse effects were recognized and the safety of the vaccine
for the induction of tumor-specific immunity in glioma patients has been
proven. In this review, the recent advances in cancer vaccine therapy against
gliomas are described, followed by a discussion on the glioma antigens.
II. Cancer vaccines using tumor cells
One of the
rational strategies for the treatment of cancer is the stimulation of specific
immune responses against the tumor antigens in
vivo. Successful cancer vaccination to induce immunity against tumor
antigens could lead to tumor cell destruction and prolong the survival of
cancer patients. A variety of strategies have been used to enhance the
antigenicity of the tumor cells, including genetically modifying the cells to
secrete cytokines involved in antitumor immunity, and initiating a viral
infection for the ÔxenogenizationÕ of the tumor cells. A major advantage of
these methods is that identification of the tumor antigens is not required, and
theoretically, immunization with multiple tumor antigens, including tumor
antigens specific for individual tumors, is possible.
A.
Cancer vaccines using cytokines
Transduction of genes encoding cytokines into tumor
cells has been shown to result in augmentation of the immunogenic properties of
brain tumors. In a large preclinical study, irradiated B16 murine melanoma
cells producing murine IL-2, IL-3, IL-4, IL-6, IFN-g, or GM-CSF, were
administered subcutaneously as a cancer vaccine against tumors of the brain (Sampson et al, 1996). Of the cytokine-based vaccines examined, the
GM-CSF-producing cells were found to be the most effective for increasing the
survival of mice with established brain tumors. A major concern with
cytokine-based vaccines for CNS tumors is that they can potentially induce
cerebral edema, because a high dose of IL-2 administered systemically can cause
an increase in the vascular permeability, which in turn, could lead to cerebral
edema (Merchant et al, 1990). In fact, severe cerebral edema was reported in
animals injected intracranially with syngeneic cytokine-secreting cells (Tjuvajev et al, 1995). These findings indicate that subcutaneously
administered cancer vaccines containing cytokines can be safe and effective in
the treatment of CNS tumors.
While the promising
preclinical results mentioned above prompted several clinical trials, to date,
only isolated case reports have been published. In one case report, a patient
with malignant glioma received subcutaneous (s.c.) immunization with autologous
tumor cells and fibroblasts transduced with IL-2 (Sobol et al, 1995). Enhanced CD8+ CTL responses
against the autologous tumor in peripheral blood mononuclear cells (PBMCs) were
seen after the vaccination. The patient survived for 10 months after the first
vaccination. In another case report, a patient with metastatic melanoma with
brain metastasis received a vaccine of autologous melanoma cells transduced
with GM-CSF (Ellem et al, 1997). In this patient, both
increased anti-melanoma delayed-type hypersensitivity reactions and increased
CTL responses against the tumor were seen. After the vaccination, axillary
lymph node metastases regressed and an increase in cerebral edema surrounding
the brain metastasis was observed. These two reports showed the beneficial
clinical effects of cytokine-based vaccines against CNS tumors. However,
further study will be required to define the safety and efficacy of this
therapeutic strategy.
B.
Cancer vaccines using viruses
When a tumor was infected with a leukemia virus and
transplanted into syngeneic rats, the tumor grew for a while but regressed
subsequently (Pelner et al, 1958). Furthermore, when native tumor cells were
transplanted into rats that had rejected the tumor, these tumor cells were
eliminated. Based on this experimental evidence, the concept of tumor
xenogenization by viruses was proposed. In fact, a number of clinical trials
were performed between the 1950s and 1970s, in which patients with advanced
malignancies were treated with lytic viruses (Moore, 1960; Asada, 1974). However, these trials were not well controlled and
the results were highly variable. One critical problem that was observed in
some cases was viral toxicity. In an attempt to overcome this problem,
replication-conditional mutant viruses, such as the herpes simplex virus type-1
(HSV-1) mutant G207 (Mineta et al, 1995; Markert et al, 2000), and the adenovirus mutant ONYX-015 (Bischoff et al, 1996; Khuri et al, 2000; Nemunaitis et
al, 2000),
were developed. These viruses could replicate within the tumor and selectively
destroy only the tumor cells, and had no local or systemic toxicity, because
they failed to grow within normal tissues.
Using the conditionally replicating HSV-1 mutant G207,
we developed an approach for the treatment of metastatic brain tumors using a
combination of viral therapy with immunotherapy. G207 replicates selectively
within tumor cells and causes tumor cell destruction without local or systemic
toxicity (Toda et al, 1998). Furthermore, inoculation with G207 into tumors
outside the CNS induces systemic immune responses against not only HSV, but
also against the tumor antigens (Toda et al, 1999). However, the antitumor effect of inoculation with
G207 into s.c. tumors as a cancer vaccine has been shown to be less effective
against brain tumors than against liver or skin tumors, even though systemic
immune responses to the tumor antigen were induced (Endo et al, 2002). Similarly, it has been reported that immunization
with CT26 cells expressing the hemagglutination antigen of influenza virus produces
systemic antitumor immunity in various tissues, but not in the brain (Schackert et al, 1989). These observations suggest that modification of the
brain tumor and/or the immunological environment in the CNS is needed for
effective immunotherapy of brain tumors. Thus, we developed an approach for the
treatment of metastatic brain tumors using a combination of oncolytic viral
therapy and a cancer vaccine using G207 (Toda, 2002, 2003).
An experimental model of brain metastasis was developed
using immunocompetent mice harboring both intracranial (i.c.) and s.c.
syngeneic tumors (Toda et al, 2002). Intratumoral injections of G207 into both the i.c.
and s.c. tumors was associated with a significant antitumor effect on the
metastatic brain tumors. This therapeutic effect was absent in athymic mice,
indicating that it was mediated by T cells. CTL responses against HSV as well
as the tumor antigen were seen in mice given the combined treatment. These results suggest that with our
strategy, in which both the metastatic brain tumor and the primary tumor
outside the CNS are inoculated with G207, HSV-infected brain tumors may be
eliminated by the combined effects of the direct oncolysis and the induced
anti-HSV and anti-tumor T cells.
For the clinical application of this therapeutic approach, various
host-virus interactions, particularly immune responses, need to first be
considered. By adulthood, 60-90% of the human population is seropositive for
HSV-1. Pre-existing and therapeutically elicited immune responses to the virus
may cooperate to enhance the efficacy of the combined treatment. G207 is
currently being used in a clinical trial for the treatment of recurrent glioma,
and its safety has been proven (Martuza, 2000). This reassurance opens up the
possibility of using G207 for the treatment of metastatic brain tumors.
C.
Cancer vaccines using dendritic cells
DCs are the most potent APCs and are the only cells
capable of priming na•ve T-cells. Cancer vaccines containing DCs can be applied
to cases in which specific tumor antigens are not used, such as tumor cell
lysate, acid-eluted peptides from tumor cells, tumor cell-derived RNA, or fused
DCs and tumor cells (Gong et al, 1997), as well as to those in which identified tumor
antigens are used. Since single large-scale isolation and expansion of DCs in
culture has become feasible, DC-based therapy has been successfully employed in
several clinical trials for cancer, including melanoma (Thurner et al, 1999), renal cell carcinoma (Kugler et al, 2000), and prostate cancer (Lodge et al, 2000).
The first clinical trial using a DC-based cancer vaccine
for glioma patients was reported by Yu et al, (2001). DCs pulsed with
acid-eluted peptides from cultured autologous tumor cells were injected
intradermally into the deltoid region three times biweekly. The DC vaccination
was associated with significantly increased survival, and no significant side
effects or autoimmune toxicity was observed. A clinical trial using fused DC
and glioma cells also showed partial responses and no serious adverse effects (Kikuchi et al, 2001). To enhance the therapeutic efficacy, another
clinical trial using these fused DC cells with recombinant human IL-12 is
currently under way. So far, DC-based cancer vaccines have proved to be safe.
However, it is difficult to precisely determine the efficacy of the DC
vaccines, because of differences in the protocol design among studies. The
efficacy of the vaccines, therefore, remains to be further evaluated in
randomized and controlled clinical trials.
III. Cancer vaccines using identified
tumor antigens
Since human tumor antigens recognized by T cells were
identified, manipulation of immune responses against a tumor target became
possible. Furthermore, T cells, which are capable of antigen-specific
propagation and have a memory mechanism, have been shown to be important in
tumor rejection in not only mouse tumor models, but also in human cancer
patients. Thus, T cells are considered to play a central role in cancer vaccine
therapies. So far, mainly the major histocompatibility complex (MHC)-class I
binding peptides that can activate CD8-positive CTLs have been identified as
tumor antigens. However, it is also necessary to identify MHC-class II binding
antigen peptides that activate helper T cells for the enhancement of antitumor
immune responses.
For cancer vaccines using identified tumor antigens,
various forms of antigens are available, including peptides, proteins, and
genes, which are concurrently used with various adjuvants. The advantage of
antigen peptides is the ease with which they can be synthesized and used.
However, identification of peptides binding to a variety of MHCs is necessary.
Although immunization with recombinant antigenic proteins has also been
considered, quality control for clinical applications is not easy. In addition,
clinical trials of cancer vaccines containing virus vectors expressing
antigenic genes have been performed, based on the potential for their
preparation in large quantities and induction of strong antitumor immune
responses. However, the results of clinical trials have revealed certain
problems, including the finding that repeated administration induces anti-virus
neutralizing antibodies, which attenuates the immune response to tumor
antigens. Thus, it is necessary to further evaluate which forms of tumor
antigens would be appropriate for the induction of antitumor immune responses
for successful treatment of cancer patients.
Since the identification, for the first time, of the
MAGE-1 gene as a human tumor antigen recognized by CTLs (van der Bruggen et al, 1991), numerous human melanoma antigen genes have been
identified. These antigens can be grossly classified into the following
categories.
1. Cancer-testis (CT) antigens:
Cancer-testis (CT) antigens are a group of antigens
that are expressed in various cancer tissues, but not in normal tissues except
for the testis. The most representative of these antigens is the MAGE gene
family (Boon et al, 1994). Expression of MHC molecules is extremely limited in
cells of the reproductive system. Therefore, CTLs against CT antigens do not
attack reproductive system cells and instead selectively attack cancer cells.
Their expression patterns make them an ideal target, and in fact, a number of
clinical trials are in progress.
2. Differentiation antigens
Differentiation antigens, whose expression is enhanced
in tumors, although they are also expressed in the normal tissue of origin of
the tumor, are recognized by CTLs. Such antigens as tyrosinase, MART-1, and
gp100 that are expressed in both normal melanocytes and melanomas have been
identified (Kawakami and Rosenberg, 1997). Because they are autoantigens, normal tissue can also
be a target for the CTLs. These antigens are used in tumor vaccine therapies
for the treatment of melanomas, and their potential usefulness has been
reported (Rosenberg, 1999).
3. Mutated antigens:
A multitude of gene mutations are accumulated within
tumor cells. Mutant peptides derived from tumor-specific genetic mutations are
recognized by CTLs as tumor antigens. The mutated peptides of CDK4 and b-catenin have been identified as CTL-recognized
antigens (Kawakami and Rosenberg, 1997).
IV. Glioma antigens
Only a few reports have been published so far
concerning glioma antigens that are recognized by the immune system. Until
recently, cloning of tumor antigens was mainly performed using tumor-specific
CTLs. However, an attempt has been made to identify glioma antigens by SEREX
(serological identification of antigens by recombinant expression cloning) (Sahin et al, 1995, 1997, 2000; Fischer et al, 2001;
Okada et al, 2001; Struss et al, 2001; Behrends et al, 2003; Ueda et al, 2004).
A. Human glioma antigens
identified by the SEREX method
The TEGT gene was the first gene to be identified as a
human glioma antigen by the SEREX method (Sahin et al, 1995). The expression level of the TEGT gene, which is
controlled during the process of sperm development, has been found to be high
in gliomas. Although the number of analyzed cases is small, IgG responses in
the serum against the TEGT antigen have been detected only in glioma patients,
and not in patients with other cancers or healthy donors. Another report showed
positive IgG responses in the serum to PHD finger protein 3 (PHF3) in 24 of 39
glioma patients, but not in 14 healthy donors (Struss et al, 2001). However, the reasons for the more frequent positive
IgG responses to the PHF3 antigen in glioma patients than in healthy donors
still remain to be clarified, because neither expression specificity nor
genetic mutations have been recognized in relation to the PHF3 antigen.
The SEREX method fundamentally uses a combination of a
cDNA library constructed from tumor tissue and the serum of the same patient
(autoserum). However, in order to identify CT antigens, we performed a modified
SEREX method using a testis cDNA library and the sera of multiple glioma
patients (allosera) (Figure 1) and
identified a glioma antigen, SOX6 (Ueda et al, 2004).
SOX6, a Sry-related HMG (high mobility group)
box-containing gene, is specifically expressed in the developing central
nervous system and in the early stages of chondrogenesis in
mouse embryos. Our study revealed that IgG antibodies against SOX6
were present in the sera of 12 out of 36 glioma patients (33.3%), 0 out of 14
patients with other brain disease (0%), and 1 out of 54 patients with other cancer
(1.9%). No IgG responses to SOX6 were identified in the sera of any of 37
healthy individuals, except in one
elderly female. RT-PCR and Northern blot analysis showed that the SOX6 gene was
more highly expressed in glioma tissues than in normal adult tissues, except
the testis. Furthermore, immunohistochemical analysis with anti-SOX6 antibody showed that
SOX6-positive cells were detected in all the glioma tissues analyzed, but only
a few positive cells were detected in nonneoplastic tissue samples from the
cerebral cortex. These results indicate that the
developmentally regulated transcription factor SOX6 is aberrantly expressed in
gliomas and is specifically recognized by the IgGs in the sera of glioma
patients.
The fact that glioma antigens recognized by IgG were
identified in the patientsÕ sera suggests antigen-specific activation of T
cells. To apply them to tumor vaccine therapies in the future, it would be
necessary to first determine whether these identified antigens can induce or
enhance glioma-specific immunity.
B. Glioma antigens recognized by T
lymphocytes
So far, no glioma-specific antigen recognized by T
lymphocytes has been identified. However, it has been reported that SART1 and
SART3, tumor rejection antigens against epithelial cancers, are expressed in
gliomas, and that CTLs specific for the SART1 and SART3 antigens destroyed
glioma cells (Imaizumi et al, 1999; Murayama et al, 2000).
We have tried to identify glioma
antigens recognized by T lymphocytes by a method of induction of tumor-specific
immune responses using HSV (Iizuka et al, 2004). We transplanted a mouse glioma cell
line in syngeneic mice and administered HSV into the tumor tissue to induce
CTLs specific for the mouse glioma cells. We then screened for antigenic genes
using the established CTLs that specifically destroy gliomas in a
MHC-restrictive fashion and identified a new mouse glioma antigen (unpublished
data). The function of this molecule is not yet known, but sequence analysis
revealed that genetic mutations exist in the gene isolated from the mouse
glioma. A mutated peptide including one of these gene mutations has been shown
to be recognized by the CTLs as a T cell epitope of a glioma antigen. We
propose to analyze whether this antigen peptide can induce specific immune
responses useful for the treatment of gliomas.
V. Conclusion
The encouraging results from
preclinical studies of immunotherapy against brain tumors have led to clinical
trials of cancer vaccines for the treatment of malignant gliomas. So far,
cancer vaccine strategies appear to be safe for the treatment of brain tumors
and no severe side effects have been reported. Although further feasibility
studies are required, the immunotherapeutic approach is a potent strategy for
specifically targeting invasive malignant gliomas within normal brain tissue.
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