The best way to prevent and remove infections is
through the natural 'sterilising' action of the
immune response that combines elements of
both innate and adaptive immunity to ward off foreign
pathogens without medical intervention. The immune
system 'remembers' the cleared foreign antigens to
speed up its response to re-infection. The immune
system in most cancer patients can still completely
destroy viruses and bacteria. The ferocity and
specificity of this response can be witnessed in the
way an inadequately suppressed immune system can
completely destroy a large transplanted organ, while
sparing one’s own (self) tissues. This destructive
effect would be beneficial for cancer therapy if it could
be directed at tumours.
The field of immunotherapy seeks methods to
harness, direct and control this immunity especially
against cancer. Therapeutic cancer vaccines are a form
of immunotherapy designed to educate the immune
system of patients with existing cancers to recognise
their tumour cells as foreign rather than self. If
successful, an immune response could theoretically
stimulate immune cells to destroy large tumours, and
also seek out and destroy metastatic tumour cells.
After immunotherapy, the ability of the immune
system to ‘remember’ tumour cells ought to eliminate
any recurrence without additional treatment in much
the same way as it protects against opportunistic
The immune system promises complete tumour elimination and durable remissions with properly designed cancer vaccines
Immunotherapy is a highly desirable alternative (or
complement) to current treatment strategies. Unlike
immune-mediated anti-tumour mechanisms, surgery,
radiation and chemotherapy have no anti-tumour
specificity at the single cell level. Therefore, it is not
technologically feasible for them to eliminate every
last tumour cell, without which cancer recurrence
commonly occurs. Furthermore, these modalities lead
to resistance rather than ‘memory’ of tumour.
The immune system promises complete tumour
elimination and durable remissions with properly
designed cancer vaccines. Its specificity in targeting
malignant cells and avoiding normal cells also
promises minimal toxicity. This is the only currently
feasible approach that has the technical possibility to
Current immunotherapy development status
The ability to educate the immune system to remove
all cancer cells has been successful in some animal
models. Mice can be immunised to reject syngeneic
transplanted tumours and protect against tumour
rechallenge without further treatment, whereas nonimmunised
mice invariably die. Protection is tumourspecific,
since immunised mice succumb to challenges
from different tumours. Tumour-specific CD8+
cytotoxic T-cells (CTL) are mainly responsible for
tumour elimination. Moreover, CTLs can specifically
recognise tumour cells and do not attack normal cells of the same tissue.
While these animal studies provide "proof-ofconcept"
for translating these methods to the clinic,
the promise of immunotherapy has been difficult to
realise. In the last two decades, immunological
strategies have been designed to stimulate antitumour
immunity in cancer patients, by vaccination
with peptide-pulsed or tumour lysate-pulsed dendritic
cells, cytokine-mediated immunotherapy, the
administration of large numbers of T cells generated
from tumour-infiltrating lymphocytes or engineered to
express receptors for specific tumour-associated
antigens (TAA), ‘naked DNA’, and recombinant virus.
Despite numerous attempts, the success rate of
clinical immunotherapy remains abysmally low.
However encouraging reports of successful trials using
novel cancer vaccines in prolonging survival in
prostate cancer illustrates the potential of this
approach, although the results fall far short of the
Despite the poor clinical results, dozens of cancer
vaccine clinical trials are currently being conducted by
both industrial and academic sponsors. One of the
reasons for continuing development and testing of
anti-cancer vaccines is the demand for alternatives to
the high morbidity associated with other modalities of
treatment, since immunotherapy has little toxicity.
While response rates to highly toxic chemotherapy
have improved over the last two decades, the modest
increase in 5-year survival  has come at a severe
price in terms of quality of life.
Flaws in cancer vaccine development
The failure of hundreds of immunotherapy clinical
trials to produce significant anti-tumour activity calls
for a re-examination of the underlying principles. For
over 200 years, vaccines have been used successfully
to prevent numerous infectious diseases by inducing a
humoral response (antibodies). The same concept is
being applied to develop cancer vaccines with the
intention of treating existing tumours, despite the fact
that vaccines giving protection against pathogenic
infection are incapable of curing existing infections
with the same pathogen. Hence, modeling of cancer
therapy on the basis of protective immunity is
fundamentally flawed as a strategy because protective
immunity does not provide therapeutic immunity.
Therapeutic immunity to cancer requires a cellular
Cancer vaccination has followed classical
development strategies by focusing on finding unique
antigens on tumours not found on normal cells, i.e.
tumour-specific antigens (TSA), or by seeking tumourassociated
antigens (TAA) overexpressed by cancer
cells. TSAs have only been found in tumours induced
by infectious agents (e.g. EBNA-1 antigen from
Epstein Barr virus-induced Burkitt's lymphoma).
However, many TAAs have been identified, including CEA, MUC1, HER-2/neu and α-fetal protein, of which some are
expressed on many tumour types, but not on normal tissues, with the
exception of spermatogonia (e.g. MAGE family, GAGE family and NYESO-
1 antigens). TAAs are self antigens and thus do not mark
tumours as foreign, but nevertheless enable immunological
distinction between tumour and normal cells.
Cancer vaccines containing TAA can also contain agents that
augment the ability of these antigens to stimulate anti-tumour
immune responses. These have included mixture with immunological
adjuvants (such as MF59, incomplete Freund’s adjuvant, saponins
QS-21, and bacillus Calmette-Guerin [BCG]), synthesis of more
immunogenic derivatives, conjugation to immunogenic proteins, and
pulsing directly to dendritic cells, but without much success.
The perceived need for 'augmenting' TAA is based on the
assumption that, since TAAs are derived from self tissues, rather than
from foreign pathogens as in previous vaccines, they are relatively
weak. Methods that enhance the immunogenicity of TAA are thought
to be essential for eliciting stronger responses that can have a clinical
anti-tumour effect. The assumption is that cancer is a disease of a
weakened immune system and, therefore, methods are required to
'boost' the immune system to treat cancer. Traditional immunology
has taught us that the main purpose of the immune system is to
distinguish between "self" and "non-self", and since cancer is "self",
there should be no immune response against it, a concept which is
also fundamentally flawed.
Cancer: a disease of a weak immune system?
When a normal cell transforms into a tumour cell, changes occurring
in the surface expression of antigens give rise to TAAs that
theoretically can be detected by immune cells. Ehrlich first posited in
1909 that the immune system protects the host against cancer, a
concept modified in the 1950s by Lewis Thomas and later by Nobel
laureate Sir Macfarlane Burnet, who proposed that the immune
system has a “surveillance” mechanism for eliminating precancerous
and cancerous cells. The fundamental tenet of this hypothesis is that
tumours arise constantly in the body and the immune system must
recognise and eliminate cells that express TAAs. It predicts that in
circumstances where the immune system is weaken or suppressed,
surveillance is compromised, tumour cells take hold and clinical
disease results. This has been the basis on which the immune system
in cancer cases is seen as weak, and so the immune system must be
strengthened to mount an attack against cancer. However, there is
much evidence to the contrary.
While a few rare cancers occur in immunosuppressed individuals, most human cancers form in immunocompetent individuals.
Additionally, there is no doubt that many neoplasms, particularly
those of epithelial origin, have a significant inflammatory cell
component. This includes a diverse leukocyte infiltrate of
macrophages, neutrophils, eosinophils, and mast cells, often in
association with lymphocytes. Tumours are usually abundantly
infiltrated with immune cells, which argues against weak recognition
of their antigens. Further, many attempts to augment the immune
response enhance rather than suppress tumour growth [2,3]. In
mice, a newly induced in situ tumour, both of mesenchymal and
epithelial derivation, can be stimulated to grow faster if it engenders
an immune response. Even highly immunogenic tumours left
undisturbed in their original hosts can grow faster than tumours with
little or no immunogenicity. Therefore, the idea that tumours are
“invisible” to the immune system, which therefore needs to be
boosted, is misconceived. The problem may be that the immune
response to the tumour, while strong, may be of the wrong type. In
attempting to boost an immune response that has already failed to
protect against tumour formation, it is not surprising that tumour
growth may be enhanced rather than suppressed. This is another
flaw in the strategy of cancer vaccine development.
Right versus wrong immune response to cancer
Before designing a cancer vaccine of therapeutic potential, the type
of immunity that is required for tumour elimination needs to be
understood. Immune responses are generally described by two
polarised responses, the T-helper type 1 (Th1) and the T-helper type
2 (Th2). A Th1 response mediates cellular immunity and is critical
for immune-mediated tumour eradication; a Th2 response mediates
humoral immunity, the type of immunity that can protect against
some infectious diseases, but is the “wrong” or inappropriate
response to a tumour. Tumour-mediated deviation of T-helper cell
differentiation to Th2 is a tumour strategy for immunoavoidance
and survival. In fact, an ineffective Th2 response can be detected in
most patients with advanced cancer and metastatic disease. This
explains why simply boosting the immune response in cancer
patients fails, as this only serves to enhance a resident Th2 response
that has already failed to protect against tumour formation and is
incapable of eradicating cancer.
Th1 and Th2 responses are counter-regulatory, increased Th1
responses downregulate Th2 responses and vice versa. Therefore, we propose that one function of a successful cancer vaccine candidate
would be to avoid enhancing an existing “wrong” Th2 response, and
to create de novo an excessive Th1 “right” response to the tumour
sufficient to downregulate the Th2 response. The challenge will be
to create this Th1 response against an overwhelming tumourmediated
resident Th2 response and natural mechanisms that
suppress autoimmune destruction of normal tissues.
However, deviation of the anti-tumour immune response from a
Th2 to a Th1 response can only be a part of a possible strategy for
therapeutic anti-tumour immunity. While Th1 immunity is essential
for tumour eradication, in some patients who develop a potentially
effective Th1 response against tumours (or can be immunised to
develop one), their tumours continued to grow. This shows that
tumours can successfully suppress or avoid a protective Th1
response. Accordingly, a successful immunotherapy strategy will not
only need to enhance Th1 immunity and suppress Th2 immunity, but
must disable immunoavoidance of the Th1 response and counter
natural tolerance circuits preventing immune destruction of normal
Tumours have numerous active mechanisms to suppress host Th1
immunity, including altering the function of APCs, fostering
dysfunctional T-cell co-signaling, generating an immune-subversive
Th2 cytokine milieu, downregulating HLA molecules, and recruiting
tolerogenic DCs and myeloid suppressor cells. Many of the
mechanisms that impede anti-tumour immunity result in the
development of T regulatory (Treg) cells. These Treg cells are the
dominant immune escape mechanism in early tumour progression.
In addition, most human tumour cells produce high levels of
transforming growth factor (TGF)-β that can directly convert naïve T
cells to Treg cells. TGF-β also suppresses the transcription of genes
encoding multiple key proteins of CD8+ cytotoxic T-cells (CTL), such
as the cytolytic molecules perforin and granzymes.
Tumour-mediated immunoavoidance shifts and promotes the
immune system to an ineffective Th2 response which renders it
tolerant, permitting tumours to grow unimpeded by the surveillance
mechanisms. Establishment of self-tolerance is a part of a natural
immune regulatory mechanism that prevents autoimmune reactions
to organ-specific self-antigens. Many such tolerance mechanisms are
the same as those employed by tumours to prevent immune
Therefore, an additional feature of a successful therapeutic cancer
vaccine is the ability to overcome cancer immunoavoidance
mechanisms and natural tolerance mechanisms.
Strategy to overcome cancer immunoavoidance
Since the immune system is programmed to respond aggressively to
foreign antigens, it has perplexed immunologists as to how a
successful pregnancy is possible. The fetus is foreign to the mother
(50% match) and mother’s immune cells regularly encounter foreign
cells of the fetus, yet they do not respond these cells. The interaction
between the tumour and the immune system has been likened to
pregnancy where an allogeneic graft (the fetus) rapidly develops
without rejection by an immunologically competent host. The ability
of the fetus to evade the maternal immune response is not due to
anatomical barriers, since maternal immune cells cross the placenta
and can enter the fetus. The mechanisms by which tumours escape
immune attack are similar to the escape of the allogeneic
fetoplacental unit, which include loss or downregulation of HLA
molecules, Th2 cytokine activity shift, secretion of
immunosuppressive factors (including TGF-β), Treg activation, and suppression of Th1 immunity.
Tolerance to a fetus is lost in some women experiencing
spontaneous abortion. The mechanism of breakdown of natural
immune protection may, therefore, be instructive to cancer vaccine
design. There is a unique cytokine network at the materno-fetal
interface that plays a key role in the maintenance of pregnancy.
Successful pregnancy is correlated with a Th2 bias both at the
materno-fetal interface and in the periphery. However, in an abortionprone
pregnancy, a Th1 bias occurs systemically and at the maternofetal
interface. Like the materno-fetal interface, ongoing inflammatory
responses within the stroma of tumours are also dominated by Th2
cytokines that not only promote tumour growth, but profoundly
suppress the host’s ability to mount an effective Th1 anti-tumour
immune response. This suggests that conversion of the systemic and
intratumour microenvironment to Th1 may break immune tolerance
to the tumour.
Evidence in support of this concept can be found by analyzing the
potent anti-tumour immune effect that occurs in allogeneic bone
marrow/stem cell transplantation (BMT) setting. The graft versus
tumour (GVT) response is arguably the most potent form of cancer
immunotherapy in clinical use. In fact, the GVT effect that occurs on
infusion of donor lymphocytes in CML patients with a tumour
recurrence after allogeneic BMT is the only way to cure the disease.
Clinical application of GVT is limited, however, due to graft versus
host disease (GVHD), a life-threatening complication of allogeneic
BMT. T-cells in the donor graft are critical in the induction of both
GVHD and GVT because depletion of T-cells from the bone marrow
graft not only effectively prevents GVHD, but results in more frequent
cancer relapse. Both GVT and GVHD are mediated by production of
Th1 cytokines, making it difficult to separate the beneficial GVT
effects from the harmful GVHD effects.
The anti-tumour GVT effect provides long-term remission when it
occurs through the development of Th1 tumour-specific immunity.
This suggests that GVT is not simply the result of tumour eradication
by allogeneic recognition. Immunity that protects against tumour
recurrence without further treatment suggests development of
tumour-specific adaptive immunity. Indeed, donor-derived tumourspecific
CTL develops in the host and contributes to the GVT effect.
Thus the sustained Th1 cytokine release that occurs in allogeneic
BMT due to GVHD acts as an adjuvant in creating anti-Th1 immunity,
breaking immune tolerance, and disabling tumour immune
suppression that can result in durable remission from disease.
Understanding human immune mechanisms involved in normal pregnancy and spontaneous abortion provides a model for designing vaccine immune responses to overcome self-tolerance
In the past, immunotherapy methods have been translated from
animal models to the clinic, but without significant anti-tumour
efficacy. Understanding human immune mechanisms involved in
normal pregnancy and spontaneous abortion provides a model for
designing vaccine immune responses to overcome self-tolerance. The
GVT effect of allogeneic BMT shows how Th1 anti-tumour immunity
might develop in a cancer patient de novo and possibly overcome
New ideas on the development of cancer vaccines
This discussion provides a working hypothesis that can explain the
failures of immunotherapy in the clinic. Past immunotherapy
approaches have relied upon proof-of-concept from animal data that
has not translated well to the clinic; classic methods of vaccine
development which provide protective rather than therapeutic
immunity, and which either acted to stimulate a resident ineffective
Th2 response or promoted a Th1 anti-tumour response without
disabling tumour immunoavoidance and natural tolerance
Successful immunotherapy will require the conversion of a resident Th2 immune response into a Th1 response. De novo
development of a Th1 response that overwhelms and disables the
resident Th2 response is feasible if antigens are introduced in the
presence of Th1 cytokines, as occurs in the curative GVT effect after
allogeneic BMT. The presence of Th1 cytokines can drive
uncommitted T-cells to develop a Th1 cytokine profile, while
simultaneously inhibiting cells with the reciprocal phenotype; e.g.
IFN-γ, a Th1 cytokine, can selectively expand Th1 cells and inhibit
proliferation of Th2 cells. Further, breaking of tolerance to
autologous tissues is also feasible in a sustained Th1 inflammatory
environment, as evidenced by Th1-mediated spontaneous abortion
and Th1-mediated GVHD, which acts as an adjuvant to the curative
Th1 anti-tumour effect in allogeneic BMT procedures.
These mechanisms are consistent with the new concept called the
“danger theory", which proposes that the regulation of immunity and
tolerance is not determined by recognition of self versus foreign
antigens as previously thought, but by the context in which the
antigens are presented to the immune system [4,5]. Thus antigen
encounter by dendritic cells (DC) in an inflammatory or ‘dangerous’
environmental context prompts a strong Th1 immune response
regardless of whether the antigens are self- or foreign-derived. In
contrast, antigen capture by DC in a non-inflammatory context leads
ultimately to immunotolerance. A tumour “conditions” the
microenvironment for the tolerant response, but where normal cells
are being destroyed as in GVHD, an active Th1 response is favoured.
A new experimental cancer vaccine protocol
To elicit anti-tumour immunity, it is necessary to engineer the
microenvironment where DCs are processing tumour antigens to
contain sufficient inflammatory “danger signals” potent enough to
downregulate tumour-mediated immunosuppressive cytokine
production and related tolerogenic mechanisms. This should enable
the development of a Th1 immune response against the tumour,
whose magnitude and duration will also control whether it is
sufficient to downregulate tumour immunoavoidance mechanisms.
This depends on the extent and quality of the local inflammatory
response and the maintenance of a systemic inflammatory response
over a long duration to disable immunoavoidance.
Based on concepts derived from actual human immune
mechanisms leading to curative anti-tumour immunity and the
breaking of natural immunotolerance, we propose a novel approach
to cancer vaccine development, proof-of-concept having been shown
in animal tumour models [6,7]. The protocol has three separate
phases, the first designed to increase the circulating numbers of Th1
immune cells in cancer patients, shifting the balance from Th2 to
Th1. The second elicits anti-tumour specific Th1 immunity. The
third relies on activating components of the innate and adaptive
immune responses to generate a sustained Th1 cytokine environment
that downregulates immunoavoidance (protocol NCT00861107;
The key component is an experimental drug, AlloStimTM, which
consists of in vitro differentiated and expanded Th1 immune cells
derived from normal blood donors. These cells, used in an
intentionally mismatched setting, are activated at the time of
injection with anti-CD3/anti-CD28 monoclonal antibody conjugated
microbeads, and produce large amounts of inflammatory cytokines
while expressing effector molecules on the cell surface, e.g. CD40L
and FasL, that promote the Th1 immunity.
To enhance the number of circulating Th1 cells circulating in
cancer patients, AlloStimTM cells will be injected intradermally each
week. The alloantigens expressed on foreign cells should stimulate a
potent immune rejection response. In addition, the expression of Th1
cytokines by the AlloStimTM will provide an inflammatory adjuvant
environment that steers the immune response to the alloantigens on
AlloStimTM cells to Th1 memory immunity. Multiple injections are
expected to act as booster shots, increasing the number of circulating
memory Th1 cells specific for the alloantigens.
To educate the immune system of the threat posed by the tumour,
and to respond by developing tumour-specific Th1 immunity,
combination of AlloStimTM with tumour cryoablation is proposed. By
combining pathological tumour death8 by cryoablation with
intratumoural AlloStimTM that produces inflammatory danger signals, the conditions are set for creating Th1 tumour-specific immunity.
Normally cells in the body die by apoptosis, a continuous part of cell
turnover. The immune system does not respond to apoptotic cells,
thereby avoiding autoimmunity. Most chemotherapy agents induce
tumour cell death by this same apoptotic process . Cryoablation of
tumour causes death by necrosis, and releases the internal contents
of many cells simultaneously into the microenvironment which
provide “eat me” signals to immune cells recruited into the site.
According to the danger theory, DCs in the microenvironment can be
programmed to mature, which promotes the development of Th1
immunity specific for the engulfed antigens.
With increased Th1 memory cells in circulation and tumourspecific
CTLs, the final step is to give AlloStimTM by intravenous
infusion. The intentionally mismatched allogeneic cells in
immunocompetent hosts primed for the alloantigens should elicit
potent rejection. This would create an immunological environment
similar to the GVHD environment in allogeneic transplants .
However, rejection of allogeneic cells is not expected to be toxic.
CD40L (CD154) expressed on the surface of AlloStimTM should
interact with CD40 constitutively expressed on host hematopoietic
progenitors, epithelial and endothelial cells, and all APC, DC,
activated monocytes, activated B lymphocytes, follicular DCs and NK
cells. CD40L is a strong inducer of Th1 responses and its stimulation
abrogates the suppressive effect of Treg cells. It also activates innate
NK cells and DCs. CD40-CD40L activation of DCs leads to maturation
and upregulation of co-stimulatory molecules, producing large
amounts of IL-12 that has potent anti-tumour and Th1 directing
properties. CD40L also has direct anti-tumour effects by suppressing
growth and inducing extensive cell death [11-13]; its activation
additionally enhances CTL-mediated lysis of tumours.
Th1 cytokines produced by AlloStimTM and CD40L expression also
activate circulating allospecific Th1 cells created in the first phase of
the protocol, thereby sustaining the necessary inflammatory
environment for downregulating immunoavoidance and enabling the
tumour-specific CTL created in the second phase of the protocol to
mediate anti-tumour effects.
This protocol incorporating these new concepts for the
development of cancer vaccines is about to be tested in the clinic The
results might in due course bring us closer to realizing the promise
of immunotherapy in cancer.
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• Richmond Prehn has discussed this problem in an earlier issue of Oncology news (Prehn RT. A cancer vaccine or just wishful thinking? Oncology News 2006;1:8-10).