Human Vaccines & Immunotherapeutics

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Active and passive immunization for cancer

David Baxter

To cite this article: David Baxter (2014) Active and passive immunization for cancer, Human
Vaccines & Immunotherapeutics, 10:7, 2123-2129, DOI: 10.4161/hv.29604

To link to this article: https://doi.org/10.4161/hv.29604

Published online: 11 Jul 2014.

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 Review Review
Human Vaccines & Immunotherapeutics 10:7, 2123–2129; July 2014; © 2014 Landes Bioscience

Active and passive immunization for cancer

David Baxter*
Manchester University Medical School; Manchester, UK; Stockport NHS Foundation Trust, Stepping Hill Hospital, Stockport UK

Keywords: Therapeutic cancer vaccines, active and passive immunization

Abbreviations: ADC, Antibody Drug Conjugate; ADCC, Antibody Dependent Cell Cytotoxicity; APC, Antigen Presenting Cell;
BCG, Bacille Calmette Guerin; CD, Cluster of Differentiation; CDC, Complement Dependent Cytotoxicity; CTL, Cytotoxic
T-Lymphocyte; CTLA4, Cytotoxic T Lymphocyte Antigen 4; DC, Dendritic Cell ; ERBB, Erythroblastic Leukemia Viral
Oncogene Homolog ; GM-CSF, Granulocyte Macrophage Colony Stimulating factor; HBV, Hepatitis B virus ; HER2, Human

©2014 Landes Bioscience. Do not distribute.

Epidermal Growth Receptor 2; HPV, Human Papilloma Virus ; ID, infectious disease; Ig, Immunoglobulin ; IL, Interleukin;
MBVs, Mixed Bacterial Vaccines ; MHC, Major Histocompatibility Complex; NK, Natural Killer Cell; TAA, Tumor Associated
Antigen; TH, T Helper Cell; TNF, Tumor Necrosis Factor

procedure, the administration of antibodies (passive immuniza-

Vaccination started around the 10th century AD as a means tion) started with diphtheria antibodies (antitoxin), first given
of preventing smallpox. By the end of the 19th century such successfully on Christmas Day, 1891. (Parrish 1968) The basis
therapeutic vaccines were well established with both active for such approaches is to make use of the same host mechanisms
and passive preparations being used in clinical practice.
that would normally eliminate infection.
Active immunization involved administering an immunogen
Concurrently, similar approaches began for the treatment of
that might be live/ attenuated, killed/ inactivated, toxoid or
subunit in origin. Passive immunization involved giving pre- cancer. As with IDs they were based on the principle of iden-
formed antibodies, usually to very recently exposed individu- tifying a difference(s) between tumor and normal cells and
als. At about the same time such approaches were also tried using these to facilitate host elimination of the tumor. Although
to treat a variety of cancers – proof of principle for the pro- work started in the 18th century, it wasn’t until the 20th cen-
tective role of the immune response against malignancy was tury that the use of either vaccines or antibody preparations, or
established by the observation that tumors transplanted into combinations, to treat certain cancers became more widespread.
syngeneic hosts were rejected by the host innate and adap- Therapeutic immunization anti-tumor approaches form the basis
tive responses. The impact of these therapeutic vaccination of this review - of considerable importance given that in high
has taken a considerable time to become established - in part income countries slightly more than 12% of all deaths are due to
because target antigens against which an adaptive response
lung, colorectal, breast and stomach cancers: with stomach and
can be directed do not appear to be uniquely expressed on
lung cancers causing just over 5% of deaths in middle income
malignant transformed cells; and also because tumor cells are
able to manipulate their environment to downregulate the countries.24
host immune response. Therapeutic cancer vaccines are also
divided into active and passive types – the latter being sub-
divided into specific and non-specific vaccines. Active immu- Therapeutic vaccines and cancer treatment
nization utilizes an immunogen to generate a host response
designed to eliminate the malignant cells, whereas in passive The concept that modulation of host response to the tumor
immunization preformed antibodies or cells are administered might be a potential approach to cancer treatment was recog-
to directly eliminate the transformed cells - examples of each nized at the end of the 19th century when Coley (USA) and
are considered in this review. Fehleisen (Germany) both independently reported some suc-
cess in the treatment of malignancy by injecting live or killed
bacteria, either into the patient or directly into the tumor.11,7,8
The approach was based on the clinical observation that some
Introduction patients post-surgery had an improved outcome if they devel-
oped an infection with associated fever. The results, however,
Active immunization (or vaccination) as we would recog- were not consistently reproducible and the approach was not
nize today, historically focused on the prevention of specific widely adopted. Nevertheless, the value of such Mixed Bacterial
infectious diseases (ID) starting with smallpox in the late 17th Vaccines (MBVs) or Coley’s Toxins as they were also known, was
/ early 18th centuries. Prophylactic vaccines have proved gen- the stimulus it provided for future research in the area.
erally highly effective and currently infants in the UK are pro- In 1884, Nuttall in collaboration with Flugge suggested that
tected against 25 different IDs by four months of age. A related protection against particular pathogens was due to chemicals
released by cells present in blood.2 These “antidotes” (synonym
*Correspondence to: David Baxter; Email: [email protected] opsonins or bacteriotropins) were identified and successfully
Published Online: 07/11/2014 used to treat a number of infections including diphtheria and
http://dx.doi.org/10.4161/hv.29604

www.landesbioscience.com Human Vaccines & Immunotherapeutics 2123

pneumococcal disease. The same approach was subsequently Effector T helper cells become either T H1 or T H2 cells, iden-
applied to cancer, with different animal species being immunized tifiable because of their CD4 + surface glycoprotein. The former
with malignant cells in the expectation that the resultant antisera are induced when the APC presents peptide associated with
could be used to treat human disease: the results, however, were MHC II molecules in the presence of IL-12, whereas the latter
uniformly unsuccessful. require MHC II peptide presentation in the presence of IL-4
Support for cancer treatment by vaccination did however and IL-2.
come from the later observation that tumor cells transplanted TH1 cells exhibit several functions – they activate macro-
into a different host do not multiply but are killed by host phages to kill pathogens they have internalized, they secrete cyto-
defenses. That this was not rejection of “foreign” tissue by kines that activate cytotoxic T cells, they induce B cells to change
cytotoxic T lymphocytes (CTL) cell activity due to major his- the type of immunoglobulin (Ig) G molecule they secrete (“class
tocompatibility complex (MHC) mismatching, but rather rec- switching”), and they assist the recruitment of leucocytes to the
ognition (and elimination) of the expressed cancer associated site of an inflammatory process. T H2 cells promote the differen-

©2014 Landes Bioscience. Do not distribute.

immunogens in the transplanted tumor cells, was due to the tiation of naïve T cells down the TH2 pathway, while inhibiting
transplantation being performed between genetically identical them entering the TH1 pathway: they also cause class switching
(syngeneic) animals. in B cells and are involved in IgE secretion.
CTLs, identifiable by their CD8 + surface molecule, are acti-
vated through their T cell receptor by APCs presenting peptide
Infectious disease immunity induced by active/ in conjunction with MHC I molecules – this is analogous to
passive immunization activation of T helper cells. Cells that recognize specific pep-
tides undergo clonal expansion and some will become long-
Active immunization involves administering the pathogen, lived memory cells. Any infected cell that subsequently presents
or a part of the pathogen (a Pathogen Associated Molecular the same peptide together with MHC I will then be induced to
Pattern - “an immunogen”), which is then recognized by an undergo programmed cell death (suicide, synonym apoptosis).
Antigen Presenting Cell (APC), usually a Dendritic Cell (DC) CTLs provide protection against intracellular infections (e.g.,
either through surface or endosome expressed receptors (Pattern viruses), tumor cells and mismatched transplanted tissues.
Recognition Receptors). Where the immunogen is recognized Thus the type of MHC molecule presenting the pathogen-
by surface receptors (for example Toll-like receptor 4) it is taken derived peptide determines the response – MHC I molecules
into the DC through receptor-mediated endocytosis; when it activate CTLs, whereas MHC II molecules activate B cells, T H1
is taken up by micropinocytosis, intracellular receptors (eg and T H2 cells. All nucleated cells in the body express MHC I
Nucleotide Oligomerisation Domain Proteins) are involved. By molecules but only APCs (macrophages, dendritic cells and B
whichever mechanism cell entry is affected, the immunogen is cells) have MHC II molecules.
then degraded into small peptidea fragments either in the pha- Passive immunization is based on administering pre-formed
golysosome or the cytosol – how the peptide fragments are then antibodies, which are obtained from a convalescent donor or
further processed depends on the site of degradation. in the case of respiratory syncytial virus, are commercially pre-
Peptide fragments generated in the phagolysosome are bound pared. The same process provides the basis for natural acquired
there to (MHC) II molecules and the MHC II-peptide complex immunity from mother to child either transplacentally or
then migrates through the cytoplasm to the cell surface: a simi- through breast milk.
lar process occurs with cytosolic processed peptide fragments Antibodies whether induced by active immunization or pas-
but here the peptide fragments are bound to MHC I molecules. sively acquired exert their prophylactic ID effects by blocking
Immunogen recognition and processing by either mecha- a pathogen attachment molecule or secreted toxin (neutralizing
nism meanwhile activates the APC causing it to migrate to local antibodies), activating complement through the classical path-
peripheral lymphoid organs (e.g., draining lymph nodes or gut way (Complement Dependent Cytotoxicity, CDC), or facili-
associated lymphoid tissue) where the MHC-peptide complex tating antibody dependent cell cytotoxicity (ADCC). ADCC
is presented to naïve T cells. This process is enhanced by the involves natural killer (NK) cells, macrophages, neutrophils
use of adjuvants, which may be based on depot adjuvants (for or eosinophils recognizing an Fc receptor on an infected cell
example alum), DC activators (for example MonoPhosphoryl bound with IgG molecule, for example FcγRIII, ligating to it
Lipid) or Proinflammatory molecules (for example MF59). and then inducing cell lysis. The downstream signaling effects
Simultaneous delivery of MHC II-peptide complex together of the antibody-receptor ligation are important.
with both co-stimulatory and cell-cell adhesion molecules by Cell mediated immunity involves either inducing apoptosis
the APC to the T cell receptor and the associated CD3 com- of infected cells by CTLs, upregulation of intracellular killing
plex of membrane proteins activates the naive T helper (T H) mechanisms by TH1 cells, or facilitating the activities of other T
cell, which then secretes Interleukin (IL) 2 causing the same cells (TH2 cells).
T helper cell to differentiate into an effector T helper cell and For both antibody and cell mediated immunity the immune
then undergo proliferation through clonal expansion with some response is specific to the immunogen(s).
cells also becoming memory cells.

2124 Human Vaccines & Immunotherapeutics Volume 10 Issue 7

Table 1. Therapeutic Cancer vaccines
Approach to
Target Subtype Example Comment
Immunization

Immunogen is irradiated autologous malignant

Whole (irradiated) cell GVAX prostate pancreatic cells: also contains GM-CSF
transfected gene and ipilimumab
Specific
Active Peptide, protein, tumor lysate
Component cell
and shed antigen vaccines Non licensed as of May 2014
vaccine
have been developed
Live, attenuated Local tumor instillation (eg bladder cancer)
Non-specific BCG vaccine
vaccine enhances immune response

©2014 Landes Bioscience. Do not distribute.

Antibody trastuzumab Blocks Human Epidermal Growth Receptor 2
Antibody Drug Antibody targets malignant cell releasing the
brentuximab vedotin
Conjugate fused antineoplastic drug
Specific
Tumor invading lymphocytes,
Passive Autologous or Termed adoptive T cell therapy – non licensed
CTLs, TH and T regs cell
allogeneic T cells (May, 2014)
vaccines developed
Antibody ipilimumab CTLA4 blocking antibody

Non-specific Tumor invading lymphocytes,

Autologous or Termed adoptive T cell therapy – non licensed
CTLs, TH and T regs cell
allogeneic T cells (May 2014)
vaccines developed
a
This discussion relates to a peptide immunogen only.

Tumor immunity induced by active/ passive as an adjunct to conventional treatments where disease outcome
immunization is poor or recurrence rates are high.
It is believed that similar mechanisms in part explain the
As the lifetime risk of developing a tumor in the UK is just anti-tumor effects of antibodies induced by therapeutic cancer
under 50%, presumably up to half the population may have an vaccines – that is blocking a receptor ligand interaction, CDC
immune response that can eliminate malignant cells. In the other or ADCC.20 However, additional effects of antibodies may be
half, some individuals with particular malignancies may have mediated through effects on tumor vasculature or stromal tis-
both lymphocytes and antibodies directed against tumor cells – sue, agonist effects on the receptor, and use of the antibody to
the former are able to activate cell-mediated immune responses, deliver a drug to the malignant cell: antibody preparations that
while the latter can bind to malignant cells; however, this doesn’t modulate the host’s immune response to the tumor have also
necessarily result in tumor eradication because either the tumor been developed.
suppresses the normal host adaptive immune response that would There appear to be at least four mechanisms to explain the
be expected to eradicate the “abnormal” malignant cells, or the effectiveness of active immunization with tumor vaccines – first
tumor cells are sufficiently indistinguishable from normal tissue antibody generation as with the passive immunization approach
that the host adaptive immune response to the abnormal cells is discussed above: second anti-tumor CTL activity: third using the
insufficient to eliminate the tumor. Such downregulation of the vaccine to deliver immunomodulatory molecules to the tumor
host response to malignancy is paralleled by ID pathogens, which environment (ADC as discussed previously) and finally a non-
are able to evade host innate and adaptive responses through a specific enhancement of the host immune response.
variety of mechanisms – Staphylococcus aureus for example The final step in the pathway, namely tumor cell lysis occurs
secretes Protein A that binds to IgG so preventing its action, through a cell mediated immune response that involves both
and the influenza virus attachment molecule, haemagglutinin, Natural Killer (NK) and CTLs – evidence for this is based on
undergoes antigenic drift. the increased incidence of malignancy in both immunodeficient
Two key functions of either the active or passive immuniza- and T cell deficient individuals.22
tion approach are to first present the tumor immunogen in such
a way that an appropriate adaptive immune response is generated,
and second to modulate the tumor cells’ ability to suppress the Prophylactic vaccines and cancer prevention
host response. While progress in these two areas is happening
as discussed below, it is slow and incomplete so that at present Although not used for cancer treatment it is important to
cancer vaccines (active) and/or antibodies (passive) are only used mention two prophylactic ID vaccines, which prevent infection

www.landesbioscience.com Human Vaccines & Immunotherapeutics 2125

and stop subsequent cancer development. The hepatitis B virus growth; preformed antibodies may therefore be administered
(HBV) vaccine has shown proven efficacy in the prevention of with the aim of modulating the tumor immune environment in
HBV associated hepatocellular cancer, and there are similar favor of the host. One example of such an approach relates to the
high expectations that the bivalent and quadrivalent first gen- process of APC antigen presentation to a T lymphocyte where
eration adjuvanted Human Papilloma Virus (HPV) vaccines activation of this latter cell requires that the MHC-TAA com-
(Cervarix and Gardasil respectively) will have a similar impact plex is presented with the co-stimulatory molecule CD28, which
on cervical cancer. It is believed that the effectiveness of both ligates with B7 facilitating activation of the T cell and initiating
HPV vaccines is based on their generating a B cell associated the adaptive host response – in the context of an infection, then
adaptive humoral response to the L1 immunodominant mol- after the pathogen had been eliminated, the activated clone of
ecule with HPV specific antibodies in cervical mucus prevent- T cells would secrete CTL Antigen 4 (CTLA4) which would be
ing virus cell entry through a neutralizing antibody response. transported to the APC-T cell synapse to bind with high affinity
This then prevents the subsequent changes to the cell replica- to the B7 molecule so limiting T cell activation and terminating

©2014 Landes Bioscience. Do not distribute.

tion cycle induced by the virus that lead to cervical or other the infectious response.
ano-genital malignancies.6,5,4 The use of an aluminum adjuvant The survival mechanism for certain tumors is to promote
with Gardasil and a DC activator adjuvant with Cervarix is key their growth and metastasis by encouraging CTLA4 production
to their effectiveness. and so downregulating the T cell activity, that would normally
be directed against the malignant cells.(Quezada 2013) A pas-
sively administered antibody that blocked CTLA4 would there-
Therapeutic vaccines and cancer treatment fore be expected to maintain T cell activation against tumor cells,
and clinical trials with the anti CTLA4 monoclonal antibody,
Both active and passive immunization approaches have been ipilimumab have demonstrated the benefit in terms of extended
applied to cancer treatment. Passive immunization involves the survival in for example patients with metastatic malignant mela-
administration of either an antibody against a defined antigen noma.15 One particular problem with this approach, however,
(s), or a reactive lymphocyte that recognizes the malignant tumor is that the generalized T cell activation caused by ipilimumab
cell. Furthermore, passive immunization may be non-specific may lead to immune adverse events particularly in the skin and
where the aim is to activate a generalized host adaptive immune gastro-intestinal tract.
response, or specific when the objective is a targeted response Antibody based: specific
against a particular malignant cell. Passive immunisation can Despite the earlier treatment failures with antibodies raised in
also be used to deliver a drug to a defined (malignant) cell animal models as previously discussed, technological advances
whereby antibodies against a cell antigen are used for targeting in the late 20th century led to the recognition of the complexity
and delivering the drug. See Table 1. and large number of molecules expressed on cell surfaces, gen-
Active immunization similarly can be non-specific or specific erating renewed interest in developing antibody directed cancer
with the same expected outcomes as for passive immunization treatments that might block specific tumor molecules or facili-
i.e., a non-specific vaccine is administered in the expectation that tate antibody dependent cell cytotoxicity (ADCC). Cell surface
the resulting generalized activation of the host adaptive immune molecules may be categorised as somatic tissue derived (ie those
response will eliminate the malignant cells. In contrast a specific antigens expressed on normal adult tissues), developmentally
vaccine is based on administering an antigen (or more accurately derived (ie those expressed on fetal cells), and in the case of
an immunogen) to an individual with a malignancy in the expec- tumors, neoplastic tissue derived (ie those expressed on cells that
tation that they will develop an antibody, a CTL, or combina- have undergone malignant transformation – these vary with the
tion response, which will then target a defined tumor associated tumor type).19
antigen(s) (TAA) and eliminate the malignant cell - an active The objective of the specific passive immunization approach
cancer vaccine may be constructed from a component(s) of the is to administer an antibody, usually IgG, that is specific to a sur-
cell or the whole cell, rather like the subunit and whole cell ID face molecule(s) expressed uniquely on a tumor cell (TAAs), and
vaccines respectively. More complex vaccines that use both spe- not on other cell lineage lines, and which in addition does not
cific and non-specific components have also been developed – for cross-react/ recognize surface molecules on “normal, non-cancer-
example GVAX Prostate, see below. ous” cells. Furthermore, both the antibody pharmacodynamics
and pharmacokinetics are important to a successful product – for
example a cell surface expressed TAA that is also secreted into
Passive immunization and cancer treatment plasma would be expected to reduce treatment efficacy due to a
reduction in available antibody concentration at the cell surface
Passive immunization for cancer involves administering either level.
antibodies or CTLs; for antibodies they can act in a non-specific The identification of such unique TAAs has so far proved
or specific manner as discussed below. elusive largely because the expressed tumor surface antigens are
Antibody based: non-specific also found on normal cells. However, in particular tumors these
Many tumors have the ability to downregulate the host TAAs, while not unique, are overexpressed, and (specific) mono-
immune response and enable their survival and continuing clonal antibody vaccines have been developed and licensed with

2126 Human Vaccines & Immunotherapeutics Volume 10 Issue 7

their effectiveness being largely explained on the basis of their See Table 1. The immunological basis for T cell therapy is evident
preferential activity against these overexpressed TAAs. from the significantly improved survival in patients with colorec-
An example of this approach is the monoclonal antibody tal cancer whose tumors show high levels of TILs compared with
trastuzumab, directed against the Human Epidermal Growth those patients with low level TIL infiltration. Although there are
Receptor 2 (HER2), which is overexpressed in 25–30% of a large number of TAAs against which T cell activity might be
females with metastatic breast cancer. Studies have shown that directed, the process, also termed adoptive T cell transfer, has not
breast cancer patients whose tumors overexpress HER2 have a yet resulted in any licensed (passive) vaccines. Proof of principle
shortened disease-free survival compared with patients whose of the antitumor effects of administered CTLs has, for example,
tumors do not overexpress HER2. Blocking this receptor by anti- been demonstrated in patients with malignant melanoma where
body retards malignant cell proliferation and as part of a multi- T cell infiltration of tumor occurred although its clinical impact
modality treatment approach has been shown to delay disease was limited. The use of TILs isolated from patient tumor speci-
progression.21 That the action of trastuzumab is, however, more mens has also been generally unsuccessful.14 Of concern has been

©2014 Landes Bioscience. Do not distribute.

complex than receptor blockade is evident from the observation the emergence during treatment of tumor escape variants pre-
that ADCC is more likely to occur in malignant breast cells over- sumably indicating the need for CTLs, and hence TAAs, to com-
expressing HER2 than in cells that do not overexpress HER2. prise a broad range of epitopes, this would appear to be similar
HER2 is a member of the Erythroblastic Leukemia Viral to the postulated emergence of a mumps vaccine escape variant
Oncogene Homolog (ERBB) family of growth factors, and a against which the current Jeryl Lynn strain is not effective.
group of monoclonal antibodies (including Cetuximab) directed
against the highly related Epidermal Growth Factor Receptor
(EGFR) have been approved in the US for treatment of a number Active immunization with cancer vaccines
of solid tumors including lung and colorectal cancers.25,17
Currently 12 therapeutic monoclonal antibody preparations Active immunization for cancer involves administering a cell
have been licensed by the US Federal Drug Agency as adjunctive component (s) or whole cell, which can act in a non-specific or
therapies in the treatment of certain hematological malignancies specific manner as discussed below. See Table 1. ID vaccines
and solid tumors.20 Such monoclonal antibodies were first devel- generally contain a number of different excipients that either
oped in the mouse model, but cross reactivity between mouse enhance the host immune response or maintain vaccine effective-
proteins and human proteins led to the development initially of ness in a range of environmental conditions – the former include
chimeric mouse-human monoclonal antibodies where the con- adjuvants that are included in many cancer vaccine preparations.
stant part of the Ig molecule was human and the variable part Non-specific
mouse-derived, and subsequently to a fully humanized monoclo- A non-specific vaccine is used to generate a host cell response
nal Ig molecule. that eliminates the cancer through a generalized, non-specific
The final passive antibody approach uses specific antibody as a immune stimulant effect, rather like the MBVs/ Coley’s tox-
vehicle to deliver drugs to tumor cells – termed an antibody drug ins described previously. These vaccines may use additional
conjugate (ADC). This approach developed as a mechanism to approaches – for example they can also be used as a vehicle to
reduce drug toxicity by directing drug activity to tumor cells and deliver immunomodulatory molecules to the tumor environment.
avoiding bystander effects on normal tissue. Proof of principle The first vaccine used in this way was Bacille Calmette Guerin
was demonstrated by enclosing doxorubicin in liposomes coated (BCG) that traditionally was developed to protect against hema-
with specific antibody against mouse squamous cell carcinoma togenous Tuberculosis. In 1976 Morales et al. reported on the use
cells, and then administering them to affected mice with result- of intravesical BCG to successfully treat superficial bladder can-
ing tumor eradication/ reduction in tumor mass.1 Doxorubicin cer and prevent disease recurrence. The response involves both a
conjugates, however, had very limited clinical efficacy in humans cell mediated and humoral response to the vaccine. The former
and more potent ADCs were subsequently developed with two on the basis of granulocyte infiltration of the tumor, followed by
currently licensed for use in the US. One example is brentux- macrophages and TH lymphocytes, and the latter because of the
imab vedotin, which has a chimeric antibody directed against observed cytokines identified in urine of patients administered
CD30 (expressed on both Hodgkin’s and large cell lymphomas, intravesical BCG, which Bohle et al. suggested represented a pre-
and embryonal carcinomas) conjugated with the antineoplastic dominant TH1 response – TNF-α, IL-1, IL-2, IL-6, IL-8, IL-12
compound monomethylauristatin E – when administered to and IL-18. The TH2 cytokines IL-5 and IL-10 were also detected,
patients with resistant/ refractory Hodgkin’s lymphoma, effica- as were GM-CSF, IFN-γ and IL8 which are neither TH1 or TH2
cies in excess of 85% have been reported.13,12 cytokines – the authors did, however, acknowledge some con-
siderable variability in cytokine excretion by patient.3 This non-
specific effect of BCG has previously been used to treat leukemia,
T Cell-based specific/ non-specific melanoma and prostate cancer where a small but non-significant
improvement in outcome was observed.9
Various approaches to administering different T cell types Specific
(CTLs, tumor infiltrating lymphocytes [TILs], TH and Tregs) for This approach uses a TAAs-based vaccine to generate an adap-
cancer treatment have been trialled since the mid-20th century. tive anti-tumor response that subsequently eliminates the cancer

www.landesbioscience.com Human Vaccines & Immunotherapeutics 2127

cell. The vaccine may be based on single or multiple antigens or a Two vaccine programmes to prevent cancer have been suc-
whole cell preparation can be used – for the latter the cells may be cessfully developed and implemented for HBV-associated
either autologous (same host) or allogeneic (same species different Hepatocellular and HPV-associated cervical cancer. Given that
host). The former are more difficult to obtain and prepare, and both HBV and HPV immunology is relatively simple with dis-
as a consequence established allogeneic cell lines have been fre- ease prevention associated with a neutralizing antibody response,
quently used to develop vaccines (see GVAX below) – although the traditional approach to immunization used for many vaccine
usually MHC matched prior to use it is possible that a “graft preventable infections has been applied for these two infections
versus host response” may explain some of the observed anti- – namely a simple peptide antigen (s), an adjuvant and various
tumor activity. Furthermore, transfection of the allogeneic cell excipients including preservatives, buffers and diluents.
line with proinflammatory cytokines (for example Granulocyte In contrast the progress in developing therapeutic vaccines to
Macrophage Colony Stimulating Factor [GM-CSF]) has been treat malignant disease has been much slower and reflects the
used to enhance the response. Intradermal vaccine administra- complexity of the host/ tumor interaction, with the need to gen-

©2014 Landes Bioscience. Do not distribute.

tion with multiple dose protocols appears to be the preferred erate a cell mediated response apparently more important than
option.9 the simple antibody response that is so effective for a number
The single or multiple antigen cancer vaccine is equivalent to of vaccine preventable infections. This necessary understanding
the subunit ID vaccine. Various approaches to developing these informs the selection of tumor vaccine antigen/ immunogen, the
vaccines have been utilized – peptide, protein, tumor lysate and mechanism (s) for involving DCs in uptake, processing and pre-
shed antigen vaccines – but none has successfully passed clini- sentation of these tumor components, and delivery approaches
cal studies to licensing. Given the postulated importance of a that involve route of vaccine administration and schedule, mak-
cell mediated immune response in eliminating malignant cells, it ing the construction of therapeutic cancer vaccines inevitably far
would not be expected that such antigen vaccines on their own, more complex than their ID equivalent.
that generate a primarily B cell response, would be clinically As knowledge of tumor host interaction has expanded so the
effective. These have been reviewed elsewhere.10 use of such preparations has accelerated over recent years; like ID
GVAX Prostate is an example of the whole cell vaccine vaccines they can be divided into active and passive types, with
approach – this uses an irradiated prostate allogeneic tumor cell both being subdivided into specific and non-specific vaccines
line as the “immunogen” combined with GM-CSF in individu- based on their mode of action. Passive types are based on the
als with hormone resistant prostate cancer. The use of the whole administration of preformed antibody or T lymphocytes: active
cell as the vaccine immunogen results in multiple tumor anti- immunization may be designed to eliminate the malignant cell,
gens being presented to host dendritic cells, irradiated cells are or enhance the host immune response in a more general manner.
unable to replicate and therefore do not constitute a tumor risk It is evident, however, that future effective cancer vaccines
to the host. The fact that the vaccine also expresses GM-CSF is will not be as easily categorised as active/ passive and specific/
believed to optimize immune cell recruitment at the injection non-specific but will contain a number of separate components
site. Clinical trials have been successfully undertaken to demon- based on an in-depth understanding of tumor host immunol-
strate safety and toxicity, clinical trials to determine clinical ben- ogy. Thus the immunogen is likely to have multiple epitopes, in
efit need to now be performed.23 There is also a similar GVAX part to prevent the emergence of escape variant malignant cells
irradiated pancreas tumor cell line vaccine. – specific active immunization. A means of enhancing the host
response may be included for example, a transfected proinflam-
matory cytokine gene (s) – non-specific active immunization.
Summary Incorporating a means of overcoming tumor downregulation of
the host response may also be a necessary feature, for example
Malignancies are an important cause of morbidity and pre- blocking T cell suppression – non-specific passive immunization.
mature mortality in middle and high income countries where as And finally the vaccine may directly target transformed cells
many as 10% of deaths result from lung, breast or gastro-intesti- using monoclonal antibodies – specific passive immunization.
nal malignancies. Vaccines to treat these cancers effectively would For the foreseeable future, these vaccines will not be used for
therefore be of considerable importance, but require an in-depth treatment alone but will be part of a therapeutic approach that
understanding of the interaction between the tumor and the host involves traditional modalities. It would be expected, however,
immune response, including how individual tumors are able to that as tumor immunology understanding increases their impact
modulate this host response to enhance their survival chances. will become increasingly more effective.

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