Tumor Biology for the Clinician:
Melanoma Peptide Vaccines
Craig L. Slingluff, Jr, MD
Department of Surgery,
University of Virginia Health Sciences Center
Introduction
Vaccines against viral disease
are effective in preventing human infections. They are administered to prevent
infections for which effective treatments are not available, especially when
active infection is associated with high mortality. Human cancers, like some
viral infections, are highly lethal, and existing treatments are largely inadequate.
However, cancers differ from viral infections in numerous ways. Cancers have
long latency periods, while viral infections typically have short incubation
periods. Cancers in different individuals are not identical, whereas viruses
in different individuals generally are identical or closely related. In most
cases, cancer antigens are encoded by normal host genes, whereas viral antigens
are foreign to the host.
To vaccinate successfully
against melanoma, an antigen or a series of antigens expressed on melanomas
from different individuals (shared antigens) is required. Protective or cytotoxic
immune responses must be generated against these shared antigens, and side effects
must be tolerable or absent. These requirements imply that the antigens must
be immunogenic in humans and that patients being immunized must not be tolerant
or anergic to them. Furthermore, the concern for a nontoxic regimen requires
that cross-reactivity on normal tissues not be a significant side effect.
In murine tumor systems,
a naive animal can be protected against subsequent tumor challenge by vaccination
with irradiated syngeneic tumor cells,[1] and metastatic tumor deposits can
be eradicated by adoptive transfer of immune lymphocytes.[2] Following these
principles, patients with metastatic cancer have been treated with tumor vaccines
and with adoptive transfer of tumor-specific cytotoxic T lymphocytes (CTLs).
Complete regressions of metastatic tumor deposits have been observed in some
of these patients.[3-6] These results with adoptive transfer of lymphocytes
provide compelling evidence that antigens recognized by tumor-directed CTLs
are relevant targets for immune rejection of human tumors. Results with immunotherapy
in human trials, however, have not been as successful as those in murine tumor
systems. Unlike murine subjects, human cancer patients are not immunologically
naive subjects being vaccinated with autologous (syngeneic) tumor with the goal
of preventing the establishment of a tumor challenge. Potential barriers to
equivalent success in humans are the gradual growth of tumors over years, which
could be tolerizing, and the difficulty of immunizing against antigens to which
some degree of tolerance exists.
Experience With Tumor Vaccines
Despite these barriers,
melanoma vaccines have been administered to patients for several decades in
hopes of boosting immunity to the patient's melanoma, usually as an adjuvant
to surgery. However, convincing therapeutic efficacy has not yet been demonstrated
in prospective randomized trials.[7] Early efforts to evaluate responses to
tumor vaccines focused on humoral responses. The result was the identification
of many antigens that could be defined serologically on melanoma cells, including
glycoproteins and gangliosides.[8-11] Adoptive therapies directed against these
antigens have been disappointing, but there is renewed interest in humoral immune
responses and in tumor vaccines directed against gangliosides,[12] with phase
II studies suggesting some protective effect.
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Table 1. Cell-Based Tumor
Vaccines
Whole cell
allogeneic
single cell line
pooled cell lines
autologous
cytokine gene-transduced
hapten-modified
Membrane preparation
vaccinia oncolysate
Shed antigens
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Despite the long-term interest
in humoral immune responses, the dominant thrust of current research in melanoma
immunobiology has focused on defining antigens recognized by human T cells and
on augmenting the cellular immune response to melanoma. The fact that T cells
infiltrate many primary and metastatic melanoma deposits suggests the presence
of a cellular immune response in vivo. However, the response appears to be inadequate,
because tumors grow despite the infiltrate. One explanation for this may be
the lack of costimulatory molecules (such as B7) on human melanoma cells.[13-15]
Evidence from adoptive cellular
therapy trials[16] demonstrates that melanoma- specific CTLs expanded in vitro
from metastatic tumor sites can eradicate metastatic melanoma deposits in some
patients after adoptive transfer. Though not optimized, the response rates from
this therapy suggest that tumor-specific CTLs can be an effective therapeutic
agent against malignant disease. Ex vivo culture of human lymphocytes and subsequent
reinfusion is labor-intensive, costly, and requires expertise that generally
is not available at most medical centers. The stimulation of effective cellular
immune responses in vivo would be preferable, which would take advantage of
the host's immune system. The question then is how to achieve that goal with
tumor vaccines.
Cell-Based Vaccines
The classic approach has
been to immunize patients with viable, whole melanoma cells, either autologous
or irradiated. This approach is based on the assumptions that human melanoma
cells express antigens to which an immune response can be generated, that such
a response protects against tumor recurrence, and that administration of melanoma
cells after ex vivo preparation results in an appropriate immunologic milieu
to induce protective immunity. Potential problems with cell-based melanoma vaccines
include the following: The dosage of antigen is not quantified or reproducible.
Intact tumor cells may be immunosuppressive due to lack of costimulation or
secretion of certain cytokines. The risk of viral disease exists when allogeneic
vaccines are used The use of autologous vaccines is limited to patients with
measurable advanced disease. Specificity of response is difficult to evaluate.
Several cell-based tumor
vaccines that have been or are being used are listed in Table 1. Autologous
tumor cell vaccines have the advantage of expressing all the antigens relevant
to autologous tumor rejection in the immunized patient. Allogeneic melanoma
cells may not express all the antigens that are present on autologous tumor
cells, but melanoma cells from different individuals who share major histocompatibility
complex (MHC) molecules express shared antigens recognized by melanoma-specific
CTLs.[17,18] Thus, allogeneic melanoma cells may express relevant antigens for
stimulation of an effective immune response against autologous melanoma. One
argument for using autologous cells in whole-cell vaccines is that the autologous
tumor cells will present antigenic peptides in the context of self-MHC molecules;
however, this model does not conform with some current beliefs. The majority
of human melanoma cells fail to express the costimulatory molecules B7.1 and
B7.2,[15] without which these melanoma cells may not be adequate antigen-presenting
cells (APCs). Thus, it may be hypothesized that those peptides must be presented
to the immune system by professional APCs that process cellular proteins derived
from the immunizing melanoma cells. This is a hypothesis for which some evidence
exists.[19] If accurate, the HLA type of the immunizing cell line may not have
any significant impact on the immunogenicity in a host. Instead, the ability
for immunogenic peptides to be presented on appropriate MHC molecules of potent
antigen-presenting cells may be more important.
Cell-Free Tumor Vaccines
Vaccination with purified
peptides or purified proteins becomes a possible consideration as the identity
of some of the immunogenic MHC-associated peptides present on human melanoma
cells, as well as the proteins from which they originate, become known. This
prospect of cell-free tumor vaccines has several attractive features, including
the ability to immunize with known, large quantities of specific antigens, the
absence of risk of transferring infectious agents, the ability to evaluate immunologic
responses in terms of known specific epitopes, and the opportunity to evaluate
immunologic toxicity in terms of specific autoimmunity. In addition, any success
with individual peptides could be multiplied by creating a cocktail of immunogenic
peptides. Also, the reproducibility of this sort of cell-free vaccine and its
anticipated safety would eventually lead to the possibility of immunizing patients
at risk, such as those with family histories of melanoma and dysplastic nevi
or those with multiple melanoma primaries.
During the past decade,
tumor-specific CTLs have been generated in vitro from peripheral blood, draining
lymph nodes, or metastatic tumor deposits of human cancer patients. These are
mostly CD8+ cells whose target cell recognition is restricted by class I MHC
molecules.[20,21] The existence of tumor-specific CTLs in cancer patients is
evidence for an ongoing, though insufficient, immune response to these tumors.
Although tumor cells may
"escape" from recognition by such CTLs by down- regulating expression
of MHC[22-25] or accessory/costimulatory molecules,[14] by selection of antigen-loss
variants,[26,27] or by alterations in antigen-processing pathways,[28] such
observations do not explain the isolation of CTLs that can recognize and lyse
the fresh autologous tumor from patients with growing cancers. Presumably, either
this cellular immune response is too weak to be effective or specific tolerance
or immune suppression has overcome specific immunity in vivo. To explain this
phenomenon, it is necessary to obtain a better understanding of the antigens
recognized by these CTLs.
Most antigens recognized
by cytotoxic T cells are short peptides that are bound to class I MHC molecules,
those peptides having been produced by the degradation of proteins that are
produced inside the cell.[29] A major focus of tumor immunologists, therefore,
is the identification of the subset of MHC-associated peptides that are selectively
expressed on tumor cells and that act as epitopes for tumor-specific CTLs.
T-Cell-Defined Epitopes
Expressed on Melanoma Cells
The first peptide epitope
defined for a human tumor was identified by a cDNA library transfection strategy.
It is restricted by HLA-A1 and encoded by a gene called MAGE-1.[30] CTLs from
the same patient used to identify this epitope also recognize a distinct MAGE-1
peptide in association with HLA-C region antigen.[31] However, it has not been
possible to demonstrate recognition of MAGE-1 epitopes restricted by these or
other MHC molecules using tumor-directed CTLs from other patients.[6,32] MAGE-1
is expressed in approximately 20% to 40% of cancers of several different tissue
types, including melanomas, breast cancers, non-small cell lung cancers, head
and neck squamous cell cancers, and bladder cancers. Among normal tissues, it
has been identified only in the testis.[32,33] Twelve members of the MAGE gene
family have now been identified.[34] Although their expression patterns are
all similar, their functions remain unknown. MAGE-3 also encodes a peptide epitope
for HLA-A1-restricted CTLs (EVDPIGHLY),[35] and it has been possible to stimulate
CTL responses to this peptide using lymphocytes from normal individuals.[36]
This peptide is highly homologous to the HLA-A1-restricted peptide epitope from
MAGE-1 (EADPTGHSY).
Other peptide epitopes defined
on human melanoma cells are derived from molecules that are expressed in a tissue-specific,
rather than tumor-specific, manner. CTLs from two patients were shown to recognize
two different peptides derived from tyrosinase in association with HLA-A2.1
- YMNGTMSQV and MLLAVLYCL.[37,38] Tyrosinase is an enzyme involved in the enzymatic
conversion of tyrosine as a step in melanin synthesis, and it is consequently
expressed in normal melanocytes as well as most melanomas. Attempts to identify
reactivity to these peptides in other HLA-A2+ patients have been largely unrewarding.[6,39]
However, HLA-A24 has been shown to present tyrosinase-derived epitopes to tumor-specific
CTLs,[40] and tyrosinase has been identified as the source protein for peptide
epitopes for class II MHC-restricted, melanoma-specific CD4+ T-helper cells.[41]
Another tissue-specific
protein, called gp100 or Pmel-17, has been identified as a source for HLA-A2.1-restricted
CTL epitopes. The relevance of this protein has been independently identified
by three different experimental approaches.[6,39,42] This protein is the target
of the antibody HMB45, which is specific for melanoma and melanocytes and has
been in clinical use by pathologists for several years.[43-46] Based on the
correlation between HMB45 reactivity and recognition by a single tumor-infiltrating
lymphocyte-derived CTL line, one group established that transfection of cells
with the gene for gp100/Pmel-17 reconstituted the epitope recognized by this
T cell.[42] A second study using this same T-cell line to screen transfected
cDNA libraries identified not only the gp100/Pmel-17 gene as the source of the
epitope, but also a minimal peptide from the sequence that reconstituted activity
(LLDGTATLRL).[6,47] Independently, using tandem mass spectrometry to study naturally
occurring HLA-A2.1-associated peptides on human melanoma, the nonamer peptide
YLEPGPVTA was shown to reconstitute the epitope recognized by CTLs from all
five melanoma patients tested.[39] This peptide is encoded by a portion of the
gene for gp100 and is distinct from that recognized by the single CTL clone
used in the other two studies. Gp100[46] and Pmel-17[48,49] are highly homologous
but nonidentical sequences, and they probably represent allelic variants of
the same protein. The expression of the protein is correlated with melanin biosynthesis,
but its exact function is unclear.[49] Patients whose tumor-infiltrating lymphocytes
(TILs) recognize gp100-derived epitopes had responses to adoptive therapy with
those TILs.[47]
Another gene encoding an
HLA-A2.1-restricted epitope on melanoma cells was identified independently by
two different laboratories using cDNA library transfection methods.[47,50,51]
The function of the encoded protein, called MART-1[47,50] or Melan-A,[51] is
unknown. However, its tissue distribution is limited to cells of melanocytic
origin, and it is expressed in both normal melanocytes and most human melanomas.
The HLA-A2.1-restricted epitope(s) derived from this protein are recognized
by CTLs from approximately 90% of patients studied.47
In addition to these peptide
epitopes, others are being identified at a rapidly increasing pace. The extensive
and growing experience with melanoma-specific CTLs has permitted identification
of multiple CTL epitopes on melanoma cells, some of which are widely recognized
and some of which may be recognizable with appropriate stimulation or vaccination.
The two major types of antigens for melanoma-specific CTLs are (1) melanocyte
differentiation antigens and (2) normal genes expressed only in tumor cells
and in the testis. It has been observed anecdotally that spontaneous regression
of melanoma or responses to immunotherapy may be accompanied by vitiligo (loss
of melanin pigment), which may be associated with improved prognosis.[6,52,53]
These findings are consistent with the earlier report of Anichini et al[54]
that HLA-A2-restricted melanoma-specific CTL clones also recognize HLA-A2+ cultured
melanocytes. The association between tumor immunity and autoimmunity is an area
of intense interest.
It has been postulated that
tumor immunity is weak or ineffective because the antigens are recognized by
low-affinity T cells. With the recent identification of several CTL epitopes
derived from normal gene products, it is evident that a component of tumor immunity
is autoimmunity. For CTL recognition of these antigens to occur, tolerance to
these antigens either must never occur or must be overcome in vivo or in vitro.
In the case of MAGE antigens, expression in normal tissues is limited to the
testis. The patient from whom MAGE-specific CTLs were generated is a woman.[55]
In the absence of testicular tissue, tolerance to MAGE antigens may be absent.
It also is possible that MAGE antigens are expressed in testicular cells lacking
MHC expression, in which case tolerance also may be absent. In the case of tissue
differentiation antigens, tyrosinase, Melan-A/MART-1, and gp100/Pmel-17, it
is possible that tolerance has developed for these molecules expressed in melanocytes.
Melanoma-specific CTLs recognize and lyse cultured melanocytes,[54] confirming
the expression of some differentiation antigens by cultured melanocytes and
suggesting that peripheral tolerance to these antigens can be overcome.
The concentration of tyrosinase
peptides required to reconstitute epitopes for CTL recognition is much higher
than that required for other defined peptide epitopes.[38] The affinity of these
peptides for the HLA-A2 molecule is comparable to that of other high affinity
peptides. Therefore, it has been postulated that the CTLs that recognize them
are low-affinity CTLs. Their low affinity may permit them to escape intrathymic
clonal deletion, while high- affinity CTLs against autoantigens are deleted.[38,56]
Conversely, the peptide 946, from gp100 (YLEPGPVTA) reconstitutes an epitope
with 50% maximal lysis at 1 to 10 pM (seven to eight orders of magnitude lower
than the tyrosinase peptides and several orders of magnitude less than some
viral peptides). This peptide has intermediate to low affinity for the HLA-A2
molecule; therefore, the CTLs that recognize it are believed to have high affinity
for the epitope.[39] It is possible that clonal anergy is not induced on normal
melanocytes if the epitope is presented in low quantity on normal cells or if
appropriate costimulatory molecules or T-cell help is not available. To answer
questions about host tolerance to the differentiation antigens and autoimmunity
directed against them, it will be important to define more accurately the expression
and recognition of these antigens in normal humans, as well as the expression
of MHC molecules and costimulatory molecules on melanocytes. As peptide-based
vaccine strategies are initiated, using these and other antigens, evaluations
of cross-reactive immune responses against normal tissues will be critical.
In melanoma patients experiencing regressions of metastatic tumor, vitiligo
has been observed, but no clinically significant changes in other tissues of
melanocytic origin have been observed.[6] However, if immune responses to solid
tumors of other tissues also involve destruction of normal tissues sharing those
antigens, the consequences may be more serious.
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Table 2. Investigational
Aspects of Cell-Free Tumor Vaccines
Assess efficacy of individual peptides, whole proteins, or subunits
Evaluate dose-response relationships
Characterize antigen presentation pathways
Determine optimal adjuvants
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Table 3. Approaches for
the Development of Tumor Vaccines From Peptide Epitopes for Melanoma-Specific
Cytotoxic T Lymphocytes
Purified peptide plus adjuvant
Peptide conjugated to cytokine
Peptide-lipid conjugate
Vaccinia construct with minigene encoding peptide
Peptide-pulsed dendritic cells
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Development of Novel Tumor
Vaccines for Melanoma
Many questions about how
to vaccinate against melanoma (Table 2) need to be answered in terms of human
immune systems and in the context of human MHC molecules. Though transgenic
mouse models may function as reasonable models for some purposes, many of the
questions about peptide vaccines need to be addressed in human clinical trials.
A number of these trials are planned or are underway, and they include approaches
ranging from using purified synthetic peptides plus adjuvant to introducing
gene sequences encoding MHC-associated epitopes into APCs via viral vectors
(Table 3). One aspect of these and related tumor vaccines under investigation
is the choice of adjuvants.
While alum and other traditional
adjuvants are effective at increasing immunogenicity of proteins and protein
subunits for the purpose of generating serologic (antibody) responses, newer
adjuvants are needed to assist in the generation of tumor-specific cell-mediated
immunity. Alum is a poor choice for this purpose. While bacille Calmette-Guerin
and other bacterial cell wall extracts have some efficacy at inducing cell-mediated
immunity, they are fairly toxic. Attention currently is focusing on minimizing
toxicity from bacterial cell wall products (eg, Detox by Ribi ImmunoChem Research,
Inc, Hamilton, Mont) and studying alternate vaccine adjuvants including forms
of oil emulsions related to incomplete Freund's adjuvant (eg, Montanide ISA-51
by Seppic, Inc., Paris, France) and saponins (eg, QS21 by Cambridge Biotech,
Worcester, Mass).
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Table 4. Potential Causes
of Vaccine Failure
Protective response not induced Inadequate dose of vaccine
Weak/inappropriate adjuvant
CD4 helper arm not activated
Peptide presentation incorrect
Tolerance exists
Autoimmunity induced Vitiligo
Ocular manifestations
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Table 5. Evaluation of Cellular
Immune Responses to Tumor Vaccines
Delayed-type hypersensitivity response to peptide and to tumor cells
Cellular infiltrate at immunization site and distant tumor sites
Mixed lymphocyte tumor cell cultures/cytotoxic T lymphocytes
generated in vitro
Precursor frequency analysis
Clinical tumor regression
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Phase I trials of peptide
vaccine may need to be assessed in a different light than phase I trials of
pharmacologic agents. In the latter, dose escalation is performed to determine
a maximum tolerated dose. For peptide vaccines, it is difficult to imagine a
major dose-related toxicity at any reasonable dose, and the optimal dose may
not be the maximum tolerated dose. Immunologic effects and autoimmunity, if
they occur, may appear at similar doses and may be much less dependent on dose
than on the immunologic milieu in which the vaccine is administered. Evaluation
of novel tumor vaccines depends on the need to evaluate those aspects of the
immune response that are believed to be affected by the vaccine and to evaluate
cross-reactivities and toxicities. Several potential causes of vaccine failure
are listed in Table 4, and methods used in the evaluation of tumor vaccines
are listed in Table 5.
If tumor vaccines derived
from peptide epitopes for melanoma-specific CTLs can be used effectively to
generate protective immunity against the immunizing peptide, then consideration
of how to optimize the effective immune response will follow. Many mechanisms
for tumor escape from immune recognition have been observed and proposed. An
approach that almost certainly will be needed is the creation of cocktails of
peptides or protein subunits, which would be administered with an effective
adjuvant or a set of minigenes incorporated in a single viral vector.
Conclusions
During the past two years,
the number of identified CTL epitopes for human melanoma has increased rapidly.
Though mutated self-proteins might have been suspected as the predominant form
of these epitopes, those that have been identified appear to be the result of
the expression of normal genes. These genes include tissue differentiation antigens
and latent genes expressed only in malignancy and in the testis. As we develop
a better understanding of the relationship among tumor immunity, autoimmunity,
and tolerance, then it also should be possible to identify failures of tumor
immunity. The successful immunization against cancer may then become feasible,
and methods for quantifying the status of the immune response - and for augmenting
that response - may be developed. During the next decade, a better understanding
of the immune response to human solid tumors is certain to emerge.
This work was supported
by United States Public Health Service Grant CA57653.
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