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Tumor Immunology and Immunotherapy
1. Introduction
Cancer is a heterogeneous disease with over a 100 different types identified to date. The same
genetic mechanism that allows generation of polymorphism by mutations, a requisite for
evolution will inevitably introduce some deleterious changes into the DNA. With time these
changes may lead to cancer. Recently, cancer has become one of the most frequent cause of
death in the Western world. About 14 million new cancer cases are diagnosed worldwide each
year, with mortality approaching 50%. Although state of the art surgical procedures, chemoand radiotherapy protocols are available to extend life expectancy of cancer patients, a safe and
reliable cure is not available for most cancers. The following chapter aims to describe the
interaction between the tumor and the immune system including the tumor-specific immune
response and the diverse escape mechanisms the tumors develop to avoid immune recognition.
In the last part of this section we show how our knowledge in this field has increased to bring
cancer immunotherapy to life.
2. Cancer is a multistep process
As the incidence of cancer dramatically increases with age Carl O. Nordling and Alfred G.
Knudson proposed that tumor cells need to accumulate multiple mutations in the process of
transformation. Transformation involves dysregulation of growth-promoting cellular protooncogenes to become oncogenes that no longer respond to growth inhibitory signals (pathways)
and the inactivation of tumor-suppressor genes mediating growth inhibitory or apoptotic
signals. Over a hundred oncogenes and tumor-suppressor genes have been identified, many of
which are mutated in multiple type of tumors (Table 1.). In a few cancers, sequential activation
of oncogenes and inactivation of tumor suppressor genes have been identified, verifying the
Knudson hypothesis. (Figure 1.)
Table 1. Overexpression of oncogenes
and inactivation of tumor suppressor
genes associated with cancer (examples
only). Yellow light green shading is
used to highlight oncogenes and tumor
suppressors, respectively. The antiapoptotic bcl-2 gene is shaded blue.
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This illustration shows the development of
colorectal cancer by successive mutations
in different genes. The morphological
changes accompanying each change are
indicated. RAS is an oncogene; APC and
p53 are tumor suppressor genes. Both
copies of a tumor suppressor gene must be
mutated to contribute to malignant
transformation. These would typically be
accumulated over a period of 10–20 years
or more. After malignant transformation,
the tumor cells rapidly accumulate more
mutations. Some of these contribute to
making the cells more invasive, but others
are thought to be simply a consequence,
rather than a cause, of the cell’s becoming
cancerous. With further mutation the
tumor
cells
become
genetically
heterogeneous. Natural selection will then
favor those cells that divide faster and are
more invasive.
Figure 1. Steps of carcinogenesis in colorectal
cancer.
3. The hallmarks of cancer
Based on tissue origin, state of differentiation and response to therapy cancer is an extremely
heterogeneous disease. Well over a hundred different types of cancer are known to pathologist.
In addition, these cancers develop in an extremely heterogeneous human population, rendering
individual tumors unique, thus making the development of a “magic bullet” as a therapy for all
cancers very unlikely. Nevertheless, cancer cells share a few common features that distinguish
them from normal cells, referred to as the hallmarks of cancer (Figure 2).
Overexpression of oncogenes and inactivation of tumor suppressors in cancer cells provides
sustained proliferative signals and eliminates cell cycle checkpoints designed to allow time for
repair mechanisms which in normal cells correct the majority of mutations. Cells that
accumulate mutations, inactivate apoptotic pathways, induce the release of pro-angiogenic
factors and high level expression of the telomerase providing replicative immortality will
survive. Due to the lack of growth control and the defects in genetic repair mechanisms, cancer
cells ultimately develop genomic instability that leads the acquisition of an invasive phenotype
and survival at multiple sites of the body (Figure 2-3).
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Figure 2. The hallmarks of cancer. In
addition to the activation of oncogenes
sustaining proliferative signals and
inactivation of tumor suppressors
eliminating cell cycle checkpoints
several other safety mechanisms need
to be inactivated. These include
inactivation of apoptotic pathways,
induction of angiogenesis and induction
of telomerase enabling replicative
immortality. These changes allow
tumors to survive in their original site
and accumulate further mutations that
result in genomic instability and the
acquisition of an invasive phenotype
and survival at multiple sites of the
body (development of metastases).
Recently, other characteristics of cancer have been recognized (Figure 3). Importantly, tumors
need to develop under the constant surveillance of the immune system. Cancer cells must avoid
detection and destruction by the cells of the immune system. Unexpectedly, in the light of recent
findings it is clear that tumor-induced inflammation acts as a tumor-promoting factor. How
tumor cells and the tumor-supporting tumor-associated stroma (TAS) manage to suppress
tumor-specific immune responses is perhaps the most important question of tumor
immunology.
Figure 3. Recently recognized hallmarks of
cancer. To survive, cancer cells must avoid
recognition and destruction by the immune system.
Chronic inflammation induced by pathogens or
other stimuli promote the development of tumors.
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4. Interactions between the tumor and the immune system
Tumor cells derive from normal cells of the body, therefore they are very similar in their
antigenic profile to healthy cells of the body. In fact, it is a relevant question what evidence we
have supporting specific recognition of tumors by the immune system. In the late 19th century
Dr. William Cooley observed that in some cancer patients getting an infection following surgery
had sometimes resulted in tumor remission suggesting that strong activation of the immune
system by an infection may help to clear tumors. In animal models it has been shown that strong
T-cell activation signals e.g. an allogeneic MHC present on the tumor cell is sufficient for tumor
clearance. As shown in figure 4., transplantation of tumors into an MHC-incompatible strain of
mice results in tumor rejection. (The mechanism is remarkably similar to the rejection of
allografts.)
It is also known that patients with congenital immunodeficiencies or after treatment with
immunosuppressive drugs have an increased risk of developing cancer. With the development
of the methods in molecular and cell-biology, today we have direct evidence for the recognition
of tumors by the immune system.
1. Immune cells including lymphocytes, macrophages and granulocytes infiltrate tumors.
2. Lymphocytes proliferate in the regional (draining) lymph nodes closest to the tumor
sites.
3. Tumor-specific CD4+, CD8+ T-cells and antibodies are readily detected in cancer
patients.
Despite the solid evidence of immune recognition, clearance of tumors fails, suggesting that
tumors acquire resistance to tumor-specific immune effector mechanisms.
Figure 4. MHC-dependent rejection of tumors. When
tumors are transplanted between MHC incompatible
mice they are rejected by the alloreactive immune
response in response to the allogeneic MHC. The left
panels depict transplantation of a tumor between two
mice of the same MHC type. The tumor grows in the
recipient. In the right panels, the tumor is transplanted to
a mouse of a different MHC type and is rejected.
(Experiments of precisely this type led to the discovery
of the MHC, although their intent was to discover tumorspecific antigens.)
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4.1. Recognition of tumor cells; tumor antigens
Specific recognition of tumor cells by conventional T-cells requires the presence of tumorderived peptides in complex with MHC. When oncogenic viruses transform a somatic cell
virus-specific antigens (and altered self-proteins) are synthesized thus cancer cells induced by
oncogenic viruses are very different from healthy cells. Such cancer cells should be readily
recognized by the immune system. When tumorigenesis is induced by random point mutations
in a few oncogenes and tumor suppressor genes the tumors should be more difficult to
recognize. Despite this, practically all cancer patients have CD8+ T-cells and antibodyproducing plasma cells reactive to their tumors. These T-cells and antibodies are specific to the
more than 1000 different tumor antigens identified to date. Antigens expressed exclusively by
the tumor cells, but not by any other cells of the body are called tumor-specific antigens (TSA)
(Figure 5.). Tumor-specific antigens derive from cellular proteins mutated during the process
of multistep carcinogenesis. Many of the peptides generated from mutated tumor antigens are
known, moreover the MHC molecules by which these peptides are presented have also been
determined. Some examples are
shown in Table 2. Note that different
peptides are preferentially presented
by certain types of the polymorphic
HLA-A HLA-B and HLA-DR
molecules! Antigens expressed on
both tumor cells and some normal
cells however at a much lower level
are called tumor-associated antigens
(TAA) (Figure 5.). Many tumorassociated antigens correspond to
human proteins normally expressed
only by immature sperm cells in the
testis or by the trophoblast. This subset
of tumor-associated antigens is called
Figure 5. Tumor-specific and tumor-associated
the cancer/testis antigens or CTantigens.
antigens. The functions of these genes
are normally restricted to reproduction
and fetal development. They are normally not expressed in differentiated cells but in cancer
cells they are re-activated. As these proteins are normally made in immunologically privileged
sites, the immune system is not tolerant to them thus they may be immunogenic when expressed
by the tumor. Because of their potential immunogenicity and restricted expression in specific
tumors CT antigens are promising targets of immunotherapy. In addition, they may serve as
markers to identify certain types of cancers, monitor the efficacy of therapy and are suitable for
the early diagnosis of potential relapses following therapy. A small number of the best
characterized cancer-testis (CT)-antigens are depicted in Table 3.
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Table 2. Examples of tumor-specific mutations identified in
tumor-specific antigens (data serve as illustration only)
Table 3. Cancer-testes antigens.
(for illustration only)
4.3. The tumor-specific immune response
Tumor-specific antigens are novel to the immune system therefore they can be recognized by
T and B lymphocytes. Although tumor-associated antigens can be present in the cells of some
normal tissues they are expressed at a much lower level usually insufficient for the induction
of a T-cell response. However when these antigens are highly expressed in tumors an antigenspecific immune response may be induced. Some tumor-associated antigens as the above
described CT-antigens are expressed in immunologically privileged sites thus the immune
system is not tolerized against them, so they can induce an antigen-specific immune response.
The mechanisms involved in the immune response to tumor cells are identical to that of against
pathogens. For cancers induced by tumorigenic viruses (EBV, HTLV-I, HPV) the mechanisms
are identical to those discussed for other viruses. Most tumor cells are not derived from antigenpresenting cells, thus they are unable to provide the necessary co-stimulatory signals required
for the activation of naive CD4+ and CD8+ cells (CD8+ T-cells require even stronger costimulation than CD4+ T-cells). Death of cancer cells or antigen shedding in all cancers
releases tumor antigens that are ingested by the host’s dendritic cells. Moreover, DC-s can
internalize parts of or an entire tumor cell, process them and present to tumor-specific T-cells
in the form of MHC/peptide complexes (Figure 6.). Presentation of tumor antigens to CD4+
T-cells occurs via the standard exogenous pathway while presentation for CD8+ T-cells
requires cross-presentation. CD4+ helper T-cells activated by DCs secrete cytokines (e.g. IFNγ, IL-2) and induce expression of stimulatory co-receptors by DCs both of which are essential
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for the induction of the activation of tumor-specific naive CD8+ T-cells. The activated (socalled „licensed”) CTLs leave the lymph node and are re-activated by the antigen/MHCI
complexes presented on the surface of the tumor cells. CTLs then kill tumor cells without
additional co-stimulation or T-cell help.
Figure 6. Activation of tumor-specific CD8+ T-cells by dendritic cells.
4.4. Non-specific eliminations of tumor cells
Tumor cells are recognized by the cells of both the innate and adaptive immune response. NKcells and γδ T-cells recognize the MIC glikoprotein, expressed by cells undergoing stress. The
lectin-type NKG2D activating receptor is expressed on both cell types and after binding to MIC
induces degranulation followed by the killing of the tumor cell.
4.5. Cancer „immunoediting”
Having discussed that transformed cells are recognized by the cells of the immune system and
that they induce specific anti-tumor responses it is conceivable that tumors develop in the
presence of constant immunosurveillance and under strong immunoselection. This immunoselection drives the process called immunoediting, which on one hand removes tumor cells
detected by the immune system and on the other hand induces the tumor cells to change their
phenotype into one that is resistant to the anti-tumor response launched by the host (Figure 7.).
Immunoediting has three phases: elimination, equilibrium and escape. When normal cells get
transformed by a combination of carcinogens and inherited genetic factors they express ligands
for NK-receptors (NKR), tumor antigens recognized by T-cells and release danger signals,
which together may result in the elimination of the vast majority of tumor cells (Elimination).
The elimination phase dominates the early phase of tumor development. If the elimination phase
is completed, the host remains tumor free. However sometimes cells escape
immunosurveillence and remain in a dormant state in which growth and elimination by the
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immune cells are in equilibrium (equilibrium stage). T-cells, IL-12, and IFN-γ are required to
maintain tumor cells in a state of functional dormancy, whereas NK cells and molecules that
participate in the recognition or effector function of innate cells are not required; this indicates
that equilibrium is a function of adaptive immunity only. Equilibrium may also represent an
end stage of the cancer immunoediting process and may restrain outgrowth of occult cancers
for the lifetime of the host. However, as a consequence of constant immunoselection pressure
placed on genetically unstable tumor cells held in equilibrium, tumor cells may accumulate
mutations that allow cell variants emerge that:
1. are no longer recognized by adaptive immunity (by losing expression of tumor
antigens or develop defects in antigen processing and presentation).
2. become insensitive to immune effector mechanisms (loss of immunogenicity).
3. induce an immunosuppressive state within the tumor microenvironment.
These tumor variants may enter the
escape phase, in which their growth is
no longer blocked by the immune
system. These tumor cells proliferate,
invade other tissues and eventually
form metastases. Finally, they
emerge to cause clinically apparent
disease. Apparently, if transition
between the equilibrium and escape
state could be blocked, large tumors
and devastating metastases would not
develop. Therefore, it is of
fundamental
importance
to
understand how tumors gain
resistance to immunosurveillance
mechanisms.
Existence of the equilibrium state in the
process of tumor progression is supported by
Figure 7. Cancer „immunoediting.
multiple
murine
tumor
models.
Immunocompetent mice treated with lowdose carcinogen [3′-methylcholanthrene
(MCA)] harbor cancer cells for an extended time period even when the mice did not develop any tumors. When
the immune system of these animals was ablated [by injection of T-cell-specific monoclonal antibodies (mAbs)
that deplete T cells and IFN-γ], tumors rapidly appeared at the original MCA injection site in about 50% of the
mice.
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4.6. Evasion of tumor-specific immune response, tumor escape mechanisms
Tumors detected in the clinic have completed the process of immunoediting and have developed
escape mechanisms that allow their survival and continuous growth under the surveillance of
the host’s immune system. This is usually achieved by a combination of three mechanisms
(Figure 8.):
1. loss of antigenicity
2. loss of immunogenicity
3. orchestrating a tolerogenic microenvironment in the vicinity of the tumor
Figure 8. Mechanisms of tumor escape.
4.6.1. Loss of antigenicity
Antigenicity of a tumor means “visibility” of the tumor for the cells of the adaptive immune
system (e.g. tumor-specific CTLs). This can be achieved by the tumors in multiple ways.
Tumors often lose expression of tumor-specific and tumor-associated antigens by either
suppressing of genes encoding these proteins or by the activation of proteases that remove TAA
and TSA from the surface of tumor cells. In addition, tumor cells often lose their HLA class I
expression which renders them invisible for tumor-specific cytotoxic T-cells (Figure 9.).
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Figure 9. Loss of HLA class I expression in
prostate cancer. On a section of a human prostate
cancer biopsy specimen class I molecules are
stained brown with a specific monoclonal antibody.
Brown staining (HLA class I molecules) is
restricted to tissue stromal cells and lymphocytes
infiltrating the tumor. Tumor cells remain
unstained indicating the lack of HLA class I
expression.
Fortunately, not all lymphocytes require MHC/peptide complexes for activation. Natural killer
cells and γδ T-cells are not controlled by MHC-restriction. Instead of MHC-peptide complexes
NK-cells and γδ T-cells recognize cells that are undergoing cellular stress. The NKG2D
activating receptor expressed on both cell types recognizes the MIC protein expressed by tumor
cells. Moreover the lack of Class I MHC expression removes an inhibitory signal triggered by
the interaction of HLA proteins with the inhibitory (KIR) receptors of NK-cells. In the absence
of these inhibitory signals the tumor-killing capacity of NK cells is increased. Unfortunately,
many tumors manage to survive by the secretion of a protease that cleaves MIC from the cell
surface, removing the ligand for NKG2D and blocking the receptor (Figure 10.).
Figure 10. Human epithelial tumors survive by removing MIC the ligand for the NKG2D receptor.
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4.6.2. Loss of Immunogenicity
Even when tumor cells are recognized by multiple components of the immune system the tumor
may survive if it is able to induce concomitant inhibitory signaling that override activation
signals generated by TSA- or TAA-induced T-cell receptor signaling. PD-L1, the ligand of PD1
(programmed cell death-1, an inhibitory receptor of the B7/CD28 receptor family) is frequently
expressed on tumor cells. Interaction of PD-L1 with PD1 expressed on tumor-specific
activated T-cells (e.g. CTLs) efficiently inhibits TCR-induced activation (killing) signals
(Figure 7.). PD1 is also expressed on the surface of regulatory T-cells (Tregs). PD1/PD-L1
interaction promotes the generation and activation of Tregs that as discussed in the next sections
greatly contribute to the induction and maintenance of the immunosuppressive environment
induced by tumors.
4.6.3. Induction of a tolerogenic microenvironment
In addition to expression of inhibitory co-receptors some tumors secrete TGF-β and other
immunosuppressive cytokines that create a tolerogenic microenvironment in and around the
tumor. As shown in Figure 11., TGF-β inhibits the tumor-specific CTLs and the TH1-type
CD4+ cells. In addition, TGF-β promotes the differentiation of Treg-cells and increases their
functional activity which in turn further decrease tumorspecific responses by secretion of immunosuppressive
citokines. Moreover Treg cells render dendritic cells
tolerogenic by multiple mechanisms, e.g inhibiting
stimulatory co-receptor signaling or induction of IDO
secretion (see the tolerance section for more details).
Interaction of tumor-specific T-cells with these
tolerogenic dendritic cells induces anergy of the tumorspecific lymphocytes.
As tumors grow, they become heavily infiltrated with
leukocytes. The more numerous the regulatory T-cells are,
the poorer is the clinical prognosis. Conversely, increasing
numbers of cytotoxic T-cells are associated with a better
prognosis.
Other cell types such as tumor-associated macrophages
and neutrophils called TAMs and TANs are often found in
Figure 11. Manipulation of the tumors in large numbers. In the majority of tumors these
immune response by a tumor.
cells are also immunosuppressive and indicate bad
prognosis for the patients.
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5. Cancer immunotherapy
Although arising from a single cell tumors are not simply the collection of identical cells with
the same phenotype, metabolic pathways and function. They are more similar to tissues with
cells of different functions. This heterogeneity and the above discussed genomic instability
makes treatment very difficult. However, the immune system which has evolved to control a
plethora of pathogens with sophisticated immune-escape mechanisms may be manipulated to
break the strong tumor-specific tolerance characteristic of most tumors. Thus enhancing the
intensity of the adaptive immune response against tumors is a promising, yet poorly explored
approach that may be more efficient than standard chemotherapies. The use of the immune
system to eliminate tumors is referred to as cancer immunotherapy. Cancer immunotherapy
includes vaccination against tumors and various passive immunization approaches.
5.1. Vaccination against tumors
5.1.1. Vaccines against human papilloma viruses (HPV) can prevent genital cancers
When tumors are induced by tumorigenic viruses the development of an effective vaccine is
easier than in cases when point mutations led to tumor formation. One of the few recent success
stories in immunotherapy is the development of effective HPV-vaccines. Cervical cancer is one
of the most frequent cancer among women taking approximately 250 000 lifes each year. Most
people contact HPV shortly after they have become sexually active. About 95% of women
overcome the virus within 1-2 years. In about 5% of women the virus manages to establish a
long-term chronic infection. The presence of oncogenic E6 and E7 proteins inactivates p53 and
Rb and promotes transformation leading to cervical
and other types of cancer. To reduce the spread of the
virus and the frequency of long-term chronic
infection recombinant virus vaccines were
developed. The characteristics of two available HPV
vaccines are depicted in Figure 11. Both vaccines
contain a capsid protein (L1) of HPV16 and HPV18
responsible for 70% of cervical cancers. In addition
one of the vaccines contains the capsid protein of the
HPV6 and HPV11 genoptypes that are responsible
for 90% of genital warts. Both vaccines protect
against infection with the included HPV genotypes
and show some cross protection against other
tumorigenic HPV types. The vaccine, however,
cannot clear an established HPV infection or cure an
Figure 11. Characteristics of the
bivalent and tetravalent HPV vaccines.
existing cervical cancer.
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5.1.2. Vaccination with tumor antigens can sometimes cause tumor regression
Many recent cancer vaccine trials have used tumor antigen-derived peptides (e.g. peptides from
cancer-testis antigens) to immunize animals or humans against melanoma. The first CT antigens
were discovered as targets for cytotoxic T-cells obtained from melanoma patients, and were
called MAGEA1 and MAGEA3 (melanoma antigen encoding). Figure 12 shows the effects of
vaccination with an epitope of the CT1 antigen MAGEA3, which is presented to CD8 T-cells
by HLA-A1. Before vaccination the patient went through surgery and developed metastases
within 2 months. The patient was first immunized four times with a recombinant virus
expressing the MAGE peptides followed by 7 immunizations with a synthetic peptide of the
same sequence. The patient developed a robust CD8+ T-cell response that lead to regression of
the tumor. The complete remission lasted for more than two years. Several trials have been
made but for unknown reasons only 20% of the patients showed regression and 10% of them
showed remission of the tumors. The lack of beneficial effect was correlated with vaccinespecific regulatory T-cells that infiltrated the tumors. (In addition, not every HLA-type presents
the same peptide with the same efficiency.) These trials and others suggested that tumorregression is not warranted by the presence of CD8+ tumor-specific T-cells. The abovedescribed tumor escape/suppressor mechanisms many times overcome the anti-tumor response.
Fortunately, suppressor mechanisms induced by the tumor or by tumor-associated stroma
(TAS) can be overcome by checkpoint control antibodies that block the inhibitory receptors
present on regulatory T-cells or on other immune cell types.
Figure 12. A patient with metastatic
melanoma was vaccinated with an antigenic
peptide from the MAGEA3 protein. The first
four immunizations used a recombinant viral
vaccine (open arrowheads); the last seven
immunizations (black arrowheads) were with
synthetic peptides. The red line shows the
percentage of total CD8 T-cells in the
peripheral blood that were specific for the
peptide. The status of the cancer’s growth is
indicated in the blue box above the graph
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5.2. Monoclonal antibodies in tumor therapy
5.2.1. Blockade of inhibitory receptors increases the strength of tumor-specific immune
responses. A promising new approach to cure cancer.
The concept of breaking tumor induced immune tolerance using checkpoint inhibitor antibodies
to treat patients with advanced cancer was validated in melanoma patients. As described in the
Tolerance section CTLA-4 is constitutively expressed by regulatory T-cells. CTLA-4 by
inhibiting the interaction of CD28 with B7 and by inducing a tolerogenic DC phenotype is one
of the most powerful inhibitory receptor of T-cell activation. Blocking CTLA-4 by a specific
antibody releases CD28 which in turn can activate tumor-specific CD8+ T-cells and strengthen
the immune response in the tolerogenic milieu created by the tumor (Figure 13.). About 75%
of patients diagnosed with advanced melanoma will live less than a year. 46% of metastatic
melanoma patients (stage III and stage IV) treated with CTLA4-specific monoclonal antibodies
were still alive at 1 year and 24% at 4.5 years after the start of treatment.
Activation of T-cells by antigen is
dependent on signals coming from the costimulatory receptor CD28 on engaging the
B7 co-stimulatory molecule on an antigen
presenting cell (APC) (first panel). CTLA4
inhibits T-cell activation by competing
with CD28 for binding to B7 (second
panel). A therapeutic anti-CTLA4
monoclonal antibody, such as ipilimumab,
prevents CTLA4 from competing with B7
and thus promotes T-cell activation (third
panel).
Figure 13. Blocking the inhibitory effects of CTLA4 with a
human monoclonal antibody.
While switching off CTLA-4 often unleashes autoreactive T-cell clones blocking the interaction
of PD1 and its ligands by PD1-specific antibodies have less side effects with comparable or
superior rates of survival. Recent reports describe that one third of advanced melanoma patients
treated with anti-PD1 antibody are still alive at 5 years from the start of the treatment (life
expectancy in the absence of treatment is around 11 months). These antibodies are used in
clinical trials of other cancers including prostate, lung and colon cancer.
In case of less immunogenic tumors (melanoma is one of the most immunogenic tumor) the
induction of co-stimulatory signals may be required for successful treatment.
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5.2.2. Cancer therapy by monoclonal antibodies targeting other cell-surface antigens
Besides checkpoint-specific antibodies cell surface receptor- specific monoclonal antibodies
are increasingly used to treat patients with various cancers (Table 4.). Naked antibodies can be
used to block cell surface receptors or cytokines generating proliferative and survival signals
(e.g. Bevacizumab – VEGF, Trastuzumab – ErbB2 or Rituximab – CD20-specific).
Besides blocking, these antibodies also label tumor cells for destruction by NK-cells using
antibody-dependent cellular cytotoxicity (ADCC) (Figure 14.).
Antibodies can also be coupled with toxins or radioactive isotopes that are delivered by the
antibodies to the tumors. Unlike in regular chemotherapy this approach provides selective
accumulation of the toxic agents in vicinity of the tumor.
Unfortunately, tumors often develop resistance if a single antibody is used for therapy. As
discussed, tumors may downregulate the targeted receptors or inhibit the activation of effector
cells/mechanisms. Combination of antibodies or combination of multiple antibodies with
conventional chemotherapies may further improve efficacy of the treatment in the future.
Table 4. Therapeutic antibodies approved for
treatment of cancer. Naked antibodies are not
modified and exert their therapeutic effect by
binding to the tumor cells and delivering them to
Fc receptor-mediated killing by NK cells or
phagocytes, or to complement mediated
elimination. Conjugated antibodies have been
chemically modified so that they are linked to an
inactive form of a toxin, such as vedotin, or to a
radioactive isotope, such yttrium-90. Conjugated
antibodies deliver the toxin or radioactive isotope
specifically to the surface of cancer cells, where
they poison or irradiate the cells and bring about
their death.
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Figure 14. Many anti-cancer monoclonal
antibodies eliminate tumor cells by NK cellmediated ADCC. Antibodies bind to a cell-surface
antigen of the tumor cells, for example CD20. The
Fc regions of the antibodies binds FcγRIII on an
NK cell, which then becomes activated to kill the
tumor cell.
In summary, immunotherapy is a promising new field of cancer therapy. Passive
immunotherapy by the administration of tumor-specific antibodies or active immunization
using various cancer vaccines all have shown potential to cure various types of cancer. Using
combination of targeted immunotherapies or combinations of conventional cancer therapies
with immunotherapies will inevitably improve survival and the quality of life of cancer patients.
The incredible effect of checkpoint inhibitor antibodies on melanoma tumors initiated a plethora
of clinical trials to test CTLA-4 and PD1-specific antibodies in cancers other than melanoma.
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