Introduction is associated with abnormal cell growth

Introduction

Cancer
affects almost all multicellular organisms, plants and animals. It is a disease
that is associated with abnormal cell growth which grows uncontrollably and
spread throughout the body. In Singapore, breast cancer is the most common type
occurring in females that also accounts for top frequent deaths with lung and
colo-rectum cancer as the most important neoplasm in males (Singapore
Cancer Registry, 2015). Cancer appears as a tumour comprising
mass of cells which is visible in the end result (Baba &
Câtoi, 2007)
that may take many years to develop. Cancers that are fully developed are
classified as malignant tumours have a specific role that invade and destroy
the underlying mesenchyme (Coleman & Rubinas, 2009). In order to prosper
and survive, the tumour cells need nutrients via the bloodstream and produce
various proteins that assist in the stimulation of blood vessels.

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The
main purpose of cancer treatment is to eliminate or destroy all cancer cells
and ideally areas already predisposed to tumour development (Khan, et al.,
2005).
When these seems impossible, a good palliation that include relief of symptoms
and a longer lifeline is the least cancer treatment is able to offer. Cancers
emerge after a long dormant period and hence, multiple carcinogen treatments
are more likely used as they are more effective as compared to a single
application (Jie & David, 2008). Currently, wide
range of treatment strategies for cancer are available ranging from standard
treatments that have been used for the past several decades such as surgery,
radiation and chemotherapy to recent treatments that were just developed
recently involving biological agents such as immunotherapy and the newly small
molecule inhibitor therapy.

Figure 1. Mechanism of cancer
immunotherapy. TAAs can be expressed on the cell surface
or may be intracellular antigens that are presented by the major
histocompatibility complex(MHC) proteins. Tumor cells have the ability to
deactivate the detection and killing mechanism of T cell when they bind to the
T cell receptor. However, with the availability of immunotherapy drugs, it can
bind to the T cell and prevent the TAA from deactivating the T cell.

Source: (Columbia
University Medical Centre, 2017)

Cancer
immunotherapy is a treatment strategy recently introduced that has successfully
shown promising results (Thind, et al., 2017)since the first
development of chemotherapies in 1940s. Apart from having the potential to
destroy tumours, immunotherapy can also engender life-long immunity. The aim of
cancer immunotherapy is to enhance the body’s immune system to fight against
the cancer cells (Baxevanis, et al., 2009). Immunotherapy of
cancer can be classified as passive immunotherapy or active immunotherapy.
Recognition of the tumour-associated antigens (TAAs) by the immune system is imperative
for the generation of an immune response against the tumour (Figure 1). Several
different TAAs that can be identified by the human T cells were recognized.

 

 

 

Passive
Immunotherapy

Monoclonal antibodies

Table 1. TAAs that
can be targeted by mAbs.  The table shows a list of some TAAs that can be classified in
different categories such as CD antigens, glycoproteins,glycolipids, growth
factors and vascular targets usually expressed by different tumour cells. Source
of data: (Andrew, et al., 2012)

Selected
mAbs have been shown to have antitumour effects by inhibiting cell
proliferation and direct antibody mediated cell death (Drewe &
Powell, 2002).
Presently, many types of TAAs can be recognized by therapeutic mAbs (Table 1).
MAbs can elicit anti-tumour activity by binding to their specific targets and
ensure tumour cells lysis through complement mediated lysis or antibody
dependent cellular cytotoxity(ADCC). This can also be accomplished by
inhibiting the receptor for growth factor that is responsible for the proliferation
of the cell or by direct intracellular signaling that promotes cell apoptosis.

Figure 3. Generation of human
monoclonal antibodies. This diagram shows four types of mAbs
commonly used in recent years. (1) Murine antibodies are generated from the
mouse’s genome through the fusion of B lymphocytes and myeloma cells that are
retrieved from mice. As they differ from human genes, the final product of murine
antibodies will consist of different amino acid sequences from antibodies
generated naturally in humans. (2) Chimeric antibodies are generated using
recombinant genetic techniques that consists of mouse variable region with
human heavy- and light- chain constant region. (3) Similarly, humanized antibodies
are also generated using recombinant genetic techniques by replacing the human
heavy- and light chain complementary determining region (CDR) with murine CDR
regions specific for a particular mAb and to further reduce immunogenicity. (4)
Fully human antibodies are developed to eradicate all problems regarding
immunogenicity issues when used in human patients. It is made retrieving
hybridomas generated from mice that are genetically engineered having B lymphocytes
with fully human genes only with the end product of fully mAbs. Source: (Cell Biology
Wiki, 2010)

Most
MAbs are generally made using rodent cell lines. However, this presents a
problem when used as a treatment for human cancer as they are highly
immunogenic (Tjandra, et al., 1990)  to humans that results in the generation of
human anti-mouse antibody (HAMA) responses. Apart from affecting the clinical
efficacy and the half-life of antibody, HAMA responses also are associated with
the clinical symptoms of allergy and anaphylaxis (Mirick, et
al., 2004).
To overcome this problem, molecular genetic techniques have been introduced to
produce human mAbs (Figure 3).

Adoptive
cellular therapy

A
rapidly emerging strategy that have recently been introduced is adoptive
cellular transfer (ACT) that involves isolation and reinfusion of the T cells
into patients to treat cancer. Chimeric antigen receptor (CAR) T-cell is a type
of ACT which have shown promising results in cancer treatment and is the
closest in getting an approval from the food and drug administration (FDA) (National
Cancer Institute , 2017). 
The development of CAR T cells can be classified as first, second, third
and fourth generation (Figure 4). They are classified based on different
characteristics that are present in the intracellular domains. Clinical studies
have shown that CAR T cells have significantly benefit patients with
hematologic malignancies by targeting the CD19 antigen. CAR T cells consist of
an artificial receptor that allows binding to tumour antigen that results in a
signaling cascade and activation of the T cells that kill the tumour cells directly
or indirectly through other immune cells (Figure 5). A significant feature of
using CAR T cell is the immunological memory that it processed which serves as
a great benefit in destruction of tumour cells and prevention of tumour relapse
in the future.

Figure
4. Development of CAR T cells. CARs generally have a
single-chain variable fragment(scFv) originating
from an antibody that targets surface antigens. The heavy and light chains
which constitute the scFv is separated by a linker. The hinge ensures
flexibility and is connected to the transmembrane region. The difference
between the four generations of CAR developed is the intracellular signaling
domains. The first generation is made up of only CD3?
as the intracellular signaling domain while the second generation included an
additional costimulatory to overcome problems of the first generation such as
weak proliferation ability, poor anti-tumour effects and short survival of T
cells. Third generation consist of 2 costimulatory domains to further enhance
the cytotoxity and durability. The most recent development is the fourth
generation CAR T cells also known as T cell redirected for universal cytokine
killing (TRUCK) T cells are the modification of second generation of CAR T
cells with the addition of inducible expression of gene cassettes for cytokines
for a transgenic protein.

Source
of image: (Bsargent, 2017)

Figure 5. Mechanism of tumour cell
death by CAR T cell therapy. Activation of T cells starts
when selected CD3/CD28 antibodies bind to the T cells that were retrieved from
patient’s blood. Viral vectors or non-viral approach were used to allow the CAR
gene to be transferred. Upon the binding of antigen on tumour cells to the CAR,
it triggers a series of signaling cascade that activates the cytotoxic CD8 and
CD4 CAR T cells. CD8 CAR T cells will directly promote tumour cell death by
releasing perforin and granzymes while CD4 CAR T cells promote proliferation of
CAR T cells, release cytokines and thus recruit other immune cells for tumour
cell death.

Source: (Mingxue, et al., 2017)

 

 

 

Cytokines

Many
cytokines have been utilized in cancer immunotherapy. These molecules are
selected as they are known to regulate various aspects of the immune response. Cytokines
are molecular messengers that allow communication between cells of the immune
system. Although cytokines such as interferons (IFN) and interleukin 2 (IL-2)
are frequently targeted in cytokine therapy, other cytokines such as
interleukin 4 (IL-4) and tumour necrosis factor (TNF?) have also being evaluated
in for their antitumour activity representing a novel approach in cancer
immunotherapy.

IFN-? have often been evaluated for human cancer treatment
as it has been proven to be a valuable of combinatorial strategies for
immunotherapy in solid tumours. It inhibits cell proliferation and increase
gene expression. IFN-? promotes responses
in majority of patients with hairy cell leukemia despite most patients going
into relapse within 2 years. It may also extend remissions acquired with
chemotherapy in patients with chronic myelogenous leukemia. Although it is
approved in Europe for renal cancer, it is dose limiting and serious side
effects are often present.

IL-2 stimulates the proliferation of immune cells such as T
cells, natural killer(NK) cells and lymphokine-activated killer(LAK) cells. It
plays a significant role in the treatment of renal cell carcinoma and malignant
melanoma. Factors secreted by tumours may prevent T cells from becoming fully
activated by downregulating the zeta chain of the T cells but with histamine
present, it may protect the T cells from the harmful effects of reactive oxygen
species(ROS) that may mediate the down modulation of CD3 zeta chain signaling.
Studies have also shown that there is a statistically significant prolongation
survival with IL-2/histamine combination. However, the major drawback of IL-2
treatment is severe toxicity and thus, hospitalization is often required for
high dose of IL-2. Toxicity associated with the administration of IL-2 is
mainly the capillary-leak syndrome that results in hypotension and pulmonary
edema.

Active
Immunotherapy

Oncolytic Virus

Apart from DNA, oncolytic
viruses are also used for vaccination purposes (Bartlett, et
al., 2013).
They can also be armed with immune modulatory transgenes or used in combination
with other immunotherapies (Chiocca & Rabkin, 2014). This therapy makes
use of the ability of the viruses to replicate in cancer cells and subsequently
spreading within a tumour without the destruction of normal tissues (Russell, et
al., 2012).
OVs that are used include a variety DNA and RNA viruses that can be genetically
engineered or naturally cancer-selective. An example includes onyx-15 which is
the world first oncolytic virus that had been approved by China for cancer
treatment (Ken, 2006). The main objective
of OV-mediated immunotherapy is to make use of the body’s innate and adaptive
immunity directed towards the tumour
(Figure 7).

Figure 7. OV-mediated effects
resulting in destruction of tumour cells. 1st phase: Administration of OV can be delivered
through intratumorally or systemically. The process starts by the virus
infecting the tumour cell. The virus then replicates, spreads itself within the
tumour cells and induce tumour cell death through the recruitment of other
immune cells. This process spreads throughout the tumour leading to an
inflammatory response. Immunomodulatory transgene is expressed when an armed OV
is used. Transgene products can further enhance the anti-tumour responses. The
process of OV-infection, replication and spreading can also inhibited by
different immune mechanisms. 2nd
Phase: The spread of the OV within the tumour cells will lead to a series of
signaling cascade due to the inflammation occurring. Dendritic cells will be
recruited and will present the TAAs on its surface resulting in an adaptive
immune response which targeting the tumour cells. This can be inhibited by Treg
cells. Source: (Chiocca & Rabkin, 2014)

The
use of OVs as a cancer treatment strategy have several features that makes it
advantageous as compared to other current cancer treatment strategies. Firstly,
the use of OVs will not generate resistance against the tumour cells as it uses
various oncogenic pathways in order to induce cytotoxity to the tumour cells.
In addition, they are non-pathogenic and able to replicate only within a
tumour-selective environment. However, drawbacks such as the presence of
anti-OV antibodies that can be induced by multiple administrations may cause
clearance of the virus by immune system before the therapeutic effects are
elicited (Gong, et al., 2016). Recent clinical
trials have demonstrated the use of OVs expressing GM-CSF to be efficient in
inducing an anti-tumour immune response with minimal toxicity (Heo, et al.,
2013).

Immunization with tumour
cells

Having
tumor cells as the source of biological material for a vaccine is another
therapeutic vaccination strategy for cancer. Immunization with tumor cells can
originate from autologous or allogenic tumour cells. Preparation and
administration of allogenic or autologous tumor vaccines can be done by using
irradiated whole cells or cell lysates. This ensure that the injected tumour
cells are incapable of replicating, hence allowing the vaccine to be safe and
reproducible for use.

Autologous
tumour cells are derived from patient’s tumour for personalized treatment and
this vaccination is usually done so that patients are vaccinated using similar
tumor antigens from the tumor that their tumor expresses. The advantage
autologous vaccine has over allogenic vaccines is that it contains all of the
TAAs found in patient’s tumours and hence, the vaccine will express patient’s
own MHC types to allow presentation of processed TAAs to the immune system. As
autologous tumor cells share similar major histocompatibility complexes (MHC)
as the cells of the patient’s immune system, they may also mimic as antigen
presenting cells (APCs).  This approach
is also expensive and time consuming as developing a vaccine line that expresses a standardized amount of
cytokine is not always attainable. In a trial which autologous vaccine
was administered with BCG as an adjuvant involving patients with stage I and II
colon cancer following surgery, there were no significant differences in
survival were found although better disease-free survival and overall survival
in response to the vaccine (Harris JE, et al., 2000).

On
the other hand, allogenic tumour vaccines contain tumour cells that originates
from another different individual but of the same species. The advantage of
using allogenic vaccine is that it can be produced in large amounts and made
easily available. Several different cell lines from different tumours can be
used to create a vaccine and therefore, the vaccine will most likely contain
cells that are also expressed by the patient’s tumour which may include certain
tumour antigens that are overexpressed or mutated in high amount in a certain
cancer. Polyvalent melanoma cell vaccine(PMCV) contains many melanoma antigens
that would be able to cover more that 95% of the population (Chan &
Morton, 1998)
However, the major concern in using allogenic tumour vaccine is the HLA
mismatch that occur can between the patient and the vaccinating line which will
result an immune response directed towards the foreign HLA molecules instead of
the tumour antigens.

 

Antigen pulsed dendritic cells

Dendritic
cells(DCs) are antigen presenting cells(APC) that regulates both innate and
acquired aspects of the immune system and balancing homeostatic tolerance by activating
lymphocyte responses. They are able to express high cell-surface levels of
critical costimulatory and adhesive molecules, as well as MHC class I and MHC
class II molecules. Dendritic cells can be retrieved and purified from mouse
bone marrow or from the peripheral blood of humans. Several cytokines such as
IL-4, CD40 ligand and TNF? are able to promote
the proliferation of DCs, hence, ensuring adequate amount for use in anti-tumor
therapies.

Figure 8. Typical antigen
pulsed dendritic cells scheme in active immunotherapy. DCs are obtained from the peripheral blood of a patient and
are incubated with a source of TAA that can be generated from recombinant
genetic techniques, retrieved from tumor cell lysates or from common pooled
TAAs that may be commercially available. The DCs will process and display the
TAA on MHC molecules with the costimulatory molecules expressed by the
dendritic cells and become sensitized. These sensitized DCs will then be
injected intradermally into patients as vaccines stimulating tumor-specific T
cells.

Antigen-pulsed
dendritic cells (DCs) have been widely used as cellular vaccine as they are
able to induce protective immune responses (Graffi, et al., 2002). In active
immunotherapy involving the use of antigen-pulsed DCs, small amount of DCs are
incubated or pulsed with an ovalbumin peptide against challenge with melanoma
tumour cells transfected with the peptide (Figure
8). In a clinical study whereby DCs are pulsed with tumor cell lysates or
melanoma TAAs and then injected into lymph nodes of 16 melanoma patients with
keyhole limpet hemocyanin(KLH) added as a nonspecific cell adjuvant, promising
results were shown (Nestle, et al., 1998). Presence of
delayed-type hypersensitivity responses to peptide developed in 11 of the 16
patients. Immunotherapy using tumour antigen-pulsed dendritic cells in 12
patients with hepatocellular carcinoma (HCC) have been shown to be safe and
tolerable with 9 patients confirmed had no tumour occurrence within 24 weeks (Lee, et al.,
2015).

 

 

Future
Directions

With many recent advances in immunotherapy
as a solution for cancer treatment, there have been more emphasis on targeted
therapy and personalized medicine. The first direction that should be focus on
is combination therapy. More novel combinations of drugs should be identified
and tested to expand the number of available combinations for cancer treatment.
Combination therapy has shown great clinical success in recent trials that
involved checkpoint blockade antibodies such as anti-CTLA-4
and anti-PD-1 that show a significant reduction of tumor in patients with
advanced metastatic melanoma (Jedd, et al., 2013) Combination therapy
should not only be restricted to immunotherapy drugs but also to targeted
therapies that act on particular signaling pathways as well as other forms of
cancer treatment such as chemotherapy and radiation (Tontonoz,
2014).

The
development of CAR T-cell in cancer immunotherapy have also recently been an
attractive immunotherapeutic modality. Remarkable results have been shown
especially in patients with acute and chronic lymphoblastic leukemia using
CD-19 CAR T cells (Singh, et al., 2016). Modification of T
cells with CARs can further be enhanced by sequencing the tumor’s whole exome
followed by recognizing unique and specific neoantigens (Marinos, et
al., 2016).
The T cells can then be engineered for the expression of CAR against the
neoantigen that was identified which hopes to bring a better clinical response (Tran, et al.,
2015).

Conclusion

Immunotherapy
have already shown to make significant contributions in terms of cancer
treatment and management. Presently, there are many immune-based therapies
available for cancer treatment that can be classified as passive immunotherapy
and active immunotherapy. Amongst all, the development of monoclonal antibodies
has provided the greatest impact on clinical practice showing positive results
in mAbs such as rituximab or trastuzumab, combined with other cytotoxic drugs.  Some active vaccinations have shown to provoke
immune responses in humans. However, there are still many challenges that lies
ahead such as inducing immune responses that are able to overcome both
intrinsic immune tolerance to self-TAAs. Also, immunotherapy has the potential
to provide life-long protection as compared to other cancer treatment
modalities such as surgery, radiotherapy and chemotherapy, While there are many
clinical trials that are currently going on regarding immunotherapy as a
treatment strategy for cancer in many aspects, further breakthroughs are
expected in the near future to develop new and better therapies with minimum
complications while preserving the therapeutic benefits.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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