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Review Article
THE USE OF IMMUNE SYSTEM CELLS FOR THE TREATMENT OF METASTATIC CANCER: A PERSONALISED MEDICINE CONCEPT
Ebenezer Olaleye Olajuyin1,*Olorunfemi Ayeotan2, Kehinde Sulaimon Ayinde3, Tioluwani Victor Olubiyi4, Ilerioluwa Gabriel Oke5, Olajumoke Saidat Aluko6
1) Department of Medical Laboratory Science, Federal Medical Centre, Makurdi, Nigeria.2) Department of Medical Laboratory Science, University College Hospital, Ibadan, Nigeria.3) Institute of Biology, State University of Campinas, Campinas, SP, Brazil.4) Department of Medical Laboratory Science, State Specialist Hospital, Asubiaro, Osogbo,
Nigeria.5) Department of Medical Laboratory Science, National Hospital, Abuja, Nigeria.6) Department of Medical Laboratory Science, University of Osun Teaching Hospital, Osogbo,
Nigeria.
Correspondence :
OlorunfemiAyeotan , Department of Medical Laboratory Science, University College Hospital, Ibadan, Nigeria, [email protected]
Abstract
Cancer is initiated by an alteration or mutation of genes which may occur naturally i.e. inherited or
acquired over the years as a result of environmental factors or by exposure to certain chemicals
(carcinogens), exposure to various forms of radiations and lifestyle habit such as smoking ,alcohol,
poor diet and obesity. During cancer progression, various components of the innate and adaptive
immunity are activated in effort to reduce or remove the cancer mediated inflammation but tumour
cells avoid the immune attack posed by these cells. Various cancer cells have unique mechanisms
through which they escape from the immune response making them resistance to destruction by the
immune system. In effort to treat various forms of cnacers, scientists have been able to device means
by which the immune system can be modified in other to fight cancer cells, this form of treatment that
focuses on the modification of the innate and adaptive immune system in treatment of cancer is
termed immunotherapy.
Keywords: Cancer, Immunotherapy, Immune system, tumour, personalised medicine
INTRODUCTION
Cancer is a multigenic disease that can arise from all existing cell types (stem cells, red blood cells,
white blood cells, platelets etc) and organs with a multi-factorial etiology. It is the second leading
cause of death globally according to the World Health Organization (2018). About 12.7 million cases
of cancer are reported per year worldwide with the United Kingdom accounting for about 363,000
cases of cancer yearly (International Agency for Research on Cancer, 2008, Cancer Research UK,
2016).
Cancer is initiated by alteration or mutation of genes which may occur naturally i.e. inherited or
acquired over the years as a result of environmental factors, exposure to certain chemicals
(carcinogens), exposure to various forms of radiations, lifestyles not limited to smoking , drinking etc.
Hanahan and Weinber described six hallmarks of cancer which include; cells with unlimited
proliferative potential, environmental independence for growth, evasion of apoptosis, angiogenesis,
invasion and metastasis to different parts of body. An updated version of the Hallmark of cancer
described by Hanahan and Weinber in 2000 further classify the hallmark of cancer into Seven due to
clear understanding of tumorigenesis in recent times (Fouad and Aanei, 2017).
In a normal cell, DNA replication and cell division is well coordinated and regulated by the process of
the Cell division cycle. In the cell cycle, control mechanisms include cascade of protein
phosphorylation involving highly coordinated kinase family whose function is to direct cells from one
stage of the cycle to the next. Kinases becomes activated when they bind with cyclin which are
proteins produced at specific stages of the cycle thereby activating the Cyclin dependent Kinases
(CDK)responsible for Transcription regulation, mRNA processing and differentiation(Morgan,1995).
During cancer progression, various components of the innate and adaptive immunity are activated in
effort to reduce or remove the caner mediated inflammation (Dunn et al., 2006; Chen and Mellman
2013). Tumor cells cunningly avoid the immune attack posed by this cells using two main strategies
which are avoiding the immune recognition and instigating an immunosuppressive tumor
microenvironment (TME). Cancer cells have the ability to lose the expression of tumor antigens on
their cell surface which makes it difficult for the cytotoxic T-cell to recognize them. For instance
about 40% of non-small cell lung cancers (NSCLC) hold a loss of heterozygosity in human leucocytes
antigen (HLAs), which eventually leads to immune escape by presenting only a small number of
antigens (McGranahan et al., 2017). The resistance to T-cell transfer in metastatic colorectal cancer
and poor outcome of the response to checkpoint blockade immunotherapy in both lung and melanoma
cancer patient has also been associated to loss of HLA (Tran et al.,2016; Chowell et al., 2018). In this
respect, alteration and omission in gene- arrangement may result in down regulation of the antigen
presenting machinery of which this may confer resistance to T-cell effectors molecule such as the
IFN-γ and TNF-α (Patel et al., 2017).
Tumor cells has the capacity to instigate an immune tolerant tumor microenvironment, they achieve
this by expressing some inhibitory checkpoints blockade molecule such as CTLA-4, PD-L1 and V
domain immunoglobulin suppressive T- cell activation (VISTA) ( Topalian et al., 2012; Snyder et
al., 2014; Boger et al., 2017), secretion of some immunospressive molecules such as VEGF, TGF-β,
prostaglandin E2 and IL-10 (Gabrilovich et al., 1996; Massague, 2008; Dominguez- Soto et al., 2011;
Bottcher et al., 2018) and initiation of the recruitment of MDSCs, TAMs and Tregs by tumors-
derived chemokines such as CCL2, CCL5, CCL22, CXCL5, CXCL8, and CXCL12 (Weitzenfeld and
Ben-Baruch 2014; Kumar et al., 2016; Mantovani et al., 2017; Tanaka and Sakaguchi 2017).
Combination of all this strategies makes it easy for tumor cells to escape the action of the immune
system.
The concept that the immune system can be influenced and modified to counter and fight neoplastic
antigens have been in existence for a very long time, this concept is refer to as immunotherapy (Ichim,
2005). In year 1777, the great surgeon Duke of Kent first contributed to the development of cancer
vaccine, he did this by injecting himself with malignant tissue as a prophylaxis against cancer cell
growth and development. (Coley, 1891). Another great contributor to immune system modification
and manipulation in other to produce vaccine is that of Louis XVII who inoculated himself with
breast cancer tumour cells with the hope of reversing soft tissues sarcoma. With all this effort, there
was no major success recorded not until the year 1891 when a clinician at the memorial Sloan
Kettering Cancer Institute in New York used heat killed endotoxin- contain bacteria (streptococci and
serratia marseceus) to cure soft tissue sarcoma (Wiemann and Starnes, 1994).
This review describes the current and evolving finding that contributes to the field of
immunooncology, as well as the important of immunotherapies as a potential treatment method for
cancer.
CANCER IMMUNOTHERAPY AND PERSONALIZED MEDICINE.
According to the data released by National Cancer Institute (NCI) in 2016, about 1.6 million cases of
newly diagnosed cancer cases were recorded that year alone (Siegel et al., 2016). With this high
increase in the number of cancer cases, it is imperative to provide a more effective treatment to halt
the progression or completely cure cancer disease.
Over the past decades, various studies have shown clearly that no two patient’s cancer are the same
and hence may have variable response to genetic treatment (Burney et al., 2017). As understanding of
complexity and distinctiveness of each neoplastic cell have greatly improved, the propriety of a
singular therapeutic intervention for the cure of cancer should be questioned (Laura et al., 2017). An
effective model aimed to change this ‘one-size –fits –all’ approach is based on personalized and
precision medicine (PPM) (Williams et al., 2015). Personalized medicine has significantly improved
Overall Response (ORR) and Overall Survival (OS) rates of cancer patients (Laura et al., 2017). It
involves the development of a specialized treatment for each specific subtypes of neoplastic disease,
based on the quantification and manipulation of the patients genetics and patients ‘omic’ data
( metabolomics, proteomics, transcriptomics ) (Paulina et al., 2018).
Omics technology has contributed immensely to the characterization of various molecular changes
that underlie the development and continuance of a wide range of complex human disease, including
cancer. This technology has contributed greatly to the advancement of precision medicine (Oliver et
al., 2019). Beginning with the field of genomics, the investigation and rapid elucidation of the entire
human genome once and for all, not having to undergo gene by gene analysis has now become more
fascinating and cost effective due to development of this novel sequencing technology (Yadav, 2007).
Genome sequence information has helped to diagnosed patients; predict individual risk for developing
a disease and also to assess whether a particular treatment option is suitable and successful in an
individual patient (Oliver et al., 2019).It focus on DNA sequencing to recognize cancer-specific
mutations (inheritable and spontaneous cancers) and examine chromosomal re-arrangement to
characterize subtypes of cancer (Tomczak et al., 2015).
For better characterization of tumor cells abnormalities, other advanced omics technologies have been
applied to tumor and cancer samples in the past several years and this are beginning to contribute
greatly a better understanding to the molecular mechanism of various diseases. One of this advance
technology is transcriptomics, the study of the expression of all genes contains in a cell or in an
organism. Genetic research has extensively used this approach to outline and quantitatively analyze
all the transcriptomes of cells and tissues and determine how changes that occur in gene transcription
can be used to distinguished disorders and recognized the molecular mechanism underlying the
disease development and progression (Oliver et al., 2019). At present, almost 800,000 gene
expression database related to malignant tumors has been deposited in the Gene Expression Omnibus
(GEO) of NCBI of NIH. In addition, TCGA has also make use of transcriptomics technology to
provide a detailed gene expression examination of individual tumors and tissues from more than 1,000
patients (Weinstein et al., 2013).
Proteomics helps in the analysis and quantification of cellular proteins ( Aebersold and Mann, 2015)
which are the translational product of RNA transcript and the principal mediator of all cellular
functions. TCGA consortium was the first large-scale effort to outline the tumor proteome in cancer
proteomics, this analysis was performed using reverse protein arrays and was limited to only the
target protein, about few hundreds of them. However, several studies have used avant-grade
spectrometry approach to detect tumor specific biomarkers in gynecological cancer (Swiatly et al.,
2018) and also use proteomics data in classification of breast cancer.
The analysis of small molecules present in cells, tissues or fluid has been the main focus of biomarker
discovery studies for decades and this has been achieved by metabolomics. The products of cellular
processes mediated by protein are metabolites. Changes in this metabolite are presumed to be changes
in function of the mediated enzymes and proteins. Majority of metabolomics have focused in the
analysis of patient’s serum and plasma for possible detection of biomarkers that can be used in cancer
diagnosis without invasive tumor biopsy sample. Metabolomics has been used in detecting serum
diacetylspermine (DAS), a diagnostic maker for non-small cell lung cancer (NSCLC) (Wikoff et
al., 2015).
Immunotherapy is the field of immunology that aims to identify treatments for diseases through
induction, enhancement or suppression of an immune response. Various cancer cells have unique
mechanisms through which they escape from the immune responses making them resistance to actions
of the immune system (Schreiber et al., 2011). In effort to treat various forms of malignancies,
scientists have been able to device means by which the immune system can be modified in other to
fight cancer cells, this form of treatment that focus on the modification of the innate and adaptive
immune system in treatment of cancer is called immunotherapy (Mellman et al., 2011).
The significance of immunotherapy was acknowledged in year 2008 when James Allison and Tasuku
Honjo won the Nobel prize in medicine as a result of their work, where they discovered cytotoxic T-
lymphocyte associated protein (CTL-A) and programmed cell death ligand 1 (PD-1/PD-L1)
respectively (Altmann et al., 2018).
Cancer immunotherapy can be categorized into various types such as: cytokines, cancer vaccines,
monoclonal antibodies (mAb), small molecules and autologous T- cell (Adams et al., 2015). The type
of therapy to be used depends on cancer types and their location (Pankita et al., 2016).
Major categories of immunotherapy and their mechanisms
Oncolytic Virus Therapies
The form of immunotherapy that uses viruses to infect and destroy cancer cells is known as oncolytic
virus therapy. Cervical cancer and Head and neck cancer is associated with human papiloma virus,
while hepatocellular carcinoma (HCC) is caused by the inflammatory action of hepatits B virus
(HBV) on the liver hepatocyetes. Various vaccines have been discovered for preventing the action of
these cancer causing viruses (Schiller et al., 2010). Oncolytic virus therapies rely on genetically
modified viruses in other to infect neoplastic cells, and thus they encourage a pro- inflammatory
environment to increase systemic antitumor immunity (Orange et al., 2016, Russell et al., 2012). The
current advancement in DNA cloning and virus modification technologies, oncolytic virus therapies
have recorded major progress in recent years. For example Talimogene harparevec (T-Vec) which is
also known as lmlygic, a genetically modified herpes simplex virus has been approved by the FDA for
the treatment of metastatic melanoma (Andtbacka et al., 2016)
Talimogene harparevec is a double stranded herpes simplex virus with deletion in the ϒ34.5 and α47
genes. The deletion in the ϒ34.5 gene is responsible for cancer selective replication and attenuate
pathogen (Chou and Roizman, 1992). The deleted loci are replaced by GM-CSF gene (Hu et al.,
2006). The original function of the deleted ϒ34.5 gene is to negate the host cell’s shut-off protein
synthesis upon viral infection (Markert et al., 2006) but once deleted it renders the virus unable to
replicate in a normal cell. The deletion of α47 genes relive the virus of it function to antagonize the
host cell’s transporter associated with antigen presentation. It deletion precludes the down regulation
of Major histocompatibility complex class I expression which should amplify immune response
(Goldsmith et al., 1998).
Pexastimogene-devacirepvec, Pexa-Vec (JX, 954) is a genetically modified vaccinia virus which was
originally discovered by edmuid lattime’s laboratory at Thomas Jefferson University. It was
engineered by the deletion of TK gene and replaced it with the GM-CSF which limits the viral
replicative ability. It also consists of a LacZ gene insertion as a marker (Parato et al., 2012). The
benefit of using vaccinia virus includes strong cytotoxicity of the virus, Intravenous stability for
delivery and extensive safety experience as a live vaccine (Kirn and Thorne ,2009).
Cancer vaccines
Cancer vaccines use tumour specific antigens (TSA) to activate T-Cell mediated anti-tumour
feedback. The first validation of active immunotherapy for treatment of neoplastic diseases was the
approval of provenge (sipuleucel-T) by the US food and drug agency (FDA) in year 2010 for the
treatment of prostate cancer (Mellman et al., 2011). It is a form of autologous cellular immunotherapy
which consist of granulocyte macrophage colony stimulating factor (GM-CSF), peripheral
mononuclear cells, and immuno surveillance of cancer antigen- prostatic and acid phosphatise (PAP)
(Cipponi et al., 2011). The mechanism of action includes activation, differentiation and initiation of
effector function of the T-cell, This occurs when the PAP taken up by the antigen presented cell
(APCs) is presented to the T-cell (Cipponi et al., 2011). The GM-CSF helps in stimulating the growth
of APC such as macrophages (Shi et al., 2006). Another cancer vaccine is GVAX, an irradiated and
autologous pancreatic cancer vaccine which consist of genetically modified patient pancreatic cells, it
aim at triggering the secretion of GM-CSF (Dranoff et al., 1993). It has been shown to augment the
tumor- specific immune response in cancers (Salgia et al., 2003).
Adoptive T-cell therapy
Adoptive T-cell therapy utilizes autologous immune cells, most especially T-cells which are
extracted, genetically modified, in vivo amplified and re-injected back to the patient in other to
eliminate cancer cells (Lee et al., 2016).
Recently, chimeric antigen receptor T-cell (CAR-T cell) has gained attention from their clinical
success. In this CART- cell approach, T-cell are collected from patient blood, they are genetically
engineered to express CARs that are specific for the antigen present on the cancer cell and are
administered back to the same patient (Rachel et al., 2019). Once the CART gene is injected into the
patient, it recognizes the tumour cells and induced tumour cell death (Lim and June, 2017). A new
CAR-T cell therapy called brexucabtagene autoleucel (Tecartus) was approved by US FDA on 24th of
July 2020 for the treatment of mantle cell lymphoma, a fast growing cancer of the blood that has been
difficult to treat over the years. A Large percentage of people living with this disease are diagnosed
with aggressive form of the disease. A clinical trial accessing ZUMA-2, a CAR-T therapy was
approved by the FDA. In this trial, brexucabtagene was tested on 60 patients suffering from mantle
cell lymphoma, who had received some prior treatment in time past. 87% of patients that undergone
this trial responded to a single infusion of brexucabtagene, while 62% of the patient had a complete
response. All patients that participated in this trial were initially treated with a drug that blocks the
activity of bruton `s tryosine kinase (BTK), a protein that facilitates the growth and
development of neoplastic cells.
Immune checkpoint inhibitors
Despite the major succeses recorded in adoptive T-cell therapies, a recently developed class of
monoclonal antibodies (mAbs) (Scott et al., 2012), immune checkpoint inhibitors (ICIs) are gaining
more recognition in medical practice and have become one of the most successful immunotherapies.
Ipilimumab was approved by the FDA in 2011 for the treatment of melanoma, it is a monoclonal
antibody that targets CTLA-4 on the T-cell.it inhibit the suppressive activities of CTLA4 on the T-cell
thereby allow full activation of the T-cell for immune response against neoplastic cells (Chambers et
al., 2001). Ipilimumab is also known to inhibit the immunosuppressive activity of Tregs (Mellman et
al., 2011). Similarly, pembrolizumab (Keytruda) is an IgG4 monoclonal antibody that inhibits the
suppression activity of PD-1 (Callahan et al., 2016). PD-1 is expressed on the T-cell and play the role
of suppressing the immune action of T-cell, treatment with the use of keytruda prevent the inhibitory
activity of PD-1 hence activation of T cells (Aris and Barrio, 2015). It was approved by the FDA in
September 2014 for the treatment of melanoma and also approved for the treatment of non-small-cell
lung cancer (NSCLC) in October 2015 (Lee1 et al., 2016). Nivolumab (Opdivo) is also an IgG4
monoclonal antibody, it targets anti- PD-1 in melanoma, renal cell carcinoma and squamous non-
small-cell lung cancer patients (Callahan et al., 2016). Nivolumab function in the same manner as
Keytruda (Aris and Barrio, 2015) because they are both anti PD-1 immunotherapies, they facilitate
ADCC and this result to death of cancer cells (Chen and Mellman, 2015). In the past years, some
biotech company has put in efforts to develop potent monoclonal antibodies against the ligand for PD-
1, PD-L1, as another means to inhibit the suppressive activity of PD-1 in certain cancers (Chen and
Mellman, 2015).
Cytokines
Another immunotherapeutic approach embrace for cancer treatment is the use of cytokines or small
molecules (Pankita et al., 2016). They are the first class of immunotherapy introduced to medicine
with the approval of IFNα therapies in 1986 (Thomas et al., 1986) The mechanism of action of
cytokines is different from that of check point inhibitors because injected cytokines stimulate the
direct growth of immune system cells. They increase the activity of the immune system. Interferons,
interleukins and granulocyte-macrophage colony stimulating factor (GM-CSF) are the 3 types of
cytokines sought after in immunotherapy (Lee et al., 2011). Interferons are group of signalling
proteins which are normally produced by the immune cells in response to microbial pathogens. It
elicits immune by inciting the maturation of numerous immune cells such as NK cells, macrophages,
dendritic cells and lymphocytes (Müller et al., 2017). The activation of interferon can also inhibit
angiogenesis in tumour cells causing its death (Enomoto et al., 2017). Interleukin promotes the
development and maturation of T-cells (CD4+ and CD8+ cells) , B- cells and haemopoietic cells (Cox
et al., 2012). Finally the GM-CSF improves the immune response by promoting T-cells homeostasis
and supporting the differentiation of dendritic cells (Yan et al., 2017). Various cytokines have been
approved for the treatment of cancer, for example proleukin is an FDA approved IL-2 cytokine for the
treatment of melanoma and renal cancer (Mellman et al., 2011). The mechanism of action is based on
its ability to promote T- cell activation and activation of other immune cells that express IL-2
receptors (Nelson 2004). Through proleukin activation, the immune system is activated and this helps
in destroying cancer cells. (Mellman et al., 2011). Recombinant G-CSF which is known as Filgratism
has also been approved from the treatment of neutropenia in patients with certain form of leukaemia
(Buchsel et al., 2002). It binds to its corresponding receptors on neutrophil progenitor cells thereby
causing stimulation and activation of neutrophil (Buchsel et al., 2002). Increase neutrophil production
can help in cancer treatment as it mediate cytotoxic effect on cancer cells and therefore phagocytosed
the cancer cell (Murphy et al., 2008).despite this functions of neutrophil in cancer treatment,
neutrophil also has an important role in cancer pathogenesis as it enhance cancer metastasis(Gregory
and Houghton, 2011). Filgratism should be used in combination with other immunotherapeutic
agents (Buchsel et al., 2002).
The use of small molecules for cancer treatment has increase greatly over the years, small molecules
have great advantage over other biologics, this include oral bioavailability, greater penetration of
tumour cells and ability to cross the cell membrane (Weinmann, 2016).
Immiquiod, a TLR 7/8 agonist induce the secretion of pro inflammatory cytokines, induce Th1 cell
mediated activation of natural killer cells to eradicate cancer cells and also suppress Tregs action
(Adams et al., 2015). It has been approved for the treatment of basal cell carcinoma (Weinmann,
2016), metastatic melanoma and localized cell carcinoma (Read et al., 2017). Immiquiod in
combination with resmiquiod has yielded positive result in treatment of cutaneous T-cell lymphoma
(Rook et al., 2015). Despite the positive result obtained from this combination, administration of
TLR7/8 agonist has a potential severe toxicity as they can trigger a serious cytokine storm which has
the potential to be harmful and this has limited its clinical use (Weinmann, 2016).
Table 1: Selected US Food and Drug Administration (FDA) approved cancer Immunotherapies (Riley et al., 2019).
THERAPY TYPE APPROVED CANCER YEAR OF FIRST APPROVAL
Cytokines for lymphocyte promotion
Imiqumiod
Aldesleukin
Intron A
Stimulates the production of IFN-γ, tissue necrotic factor (TNF) and IL-12
Recombinant IL-12
Recombinant IFNα2b
Basal cell carcinoma
Renal cancer and skin cancer
Melanoma, Kaposi sarcoma, chronic myeloid leukaemia, hairy cell leukaemia.
2004
1992
1986
Roferon A Recombinant IFN α2a Melanoma, Kaposi sarcoma, chronic myeloid leukaemia, hairy cell leukaemia.
1986
Vaccines
Sipuleucel-T Autologous PBMLs activated with recombinant human PAP-GM-CSF
Prostate cancer 2010
Bacillus calmette-Guerin
Strain of mycobacterium tuberculosis variant bovis
Bladder cancer 1990
Engineered T-cells therapies.
Axicabtagene ciloleucel
CD19- specific CART cells Large B cell lymphoma 2017
Tisagenlecleucel CD19- specific CART cells B cell acute lymphocytic leukaemia and non- Hodgkin lymphoma.
2017
Oncolytic viruses
Talimogene laherparepvec
Checkpoint inhibitors
Durvalumab
Ipilimumab
Pembrolizumab
Nivolumab
Avelumab
Genetically modified HSV type 1 designed to replicate within tumor and produce GM-CSF.
PD-L1 mAb
CTLA-4mAb
PD-1 mAb
PD-1 mAb
PD-L1 mAb
Melanoma
Urothelia and non-small-cell lung cancer
Melanoma
Hodgkin lymphoma, advanced gastro cancer, head and neck cancer, non-small-cell lung cancer, bladder cancer.
Kidney cancer, bladder cancer, colorectal cancer, hepatocellular cancer.
Meike cell carcinoma and urothelia cancer.
2015
2017
2011
2014
2014
2017
CURRENT IMMUNOTHERAPHY UPDATE
From the first description of immune infiltrates in tumours by Virchow in 1863 up until now, there
has been a notable progression in the number of cancer immunotherapy discoveries and techniques
available. The most recent updates on cancer immunotherapy include chimeric antigen receptor
(CAR) T-cell therapy, cancer vaccinations and immune checkpoint blockade therapy (Mellman et al.,
2011, Voena et al., 2016). Strategies such as engineered T-cell therapy or the application of next-
generation sequencing to identify new tumour antigens are current approaches with great potentials in
cancer immunotherapy (von Rundstedt & Necchi, 2017).
In 2017, the first cellular cancer immunotherapy drug, tisagenlecleucel, was approved by the FDA,
followed in 2018 by the EMA approval of a second drug called axicabtagen-ciloleucel. Approval of
these medications was based on impressive response rates seen in the ELIANA trial (relapsed or
refractory)[r/r] in Acute lymphoblastic leukemia in paediatric patients or young adults treated with
tisagenlecleucel), JULIETH trial ([r/r] DLBCL, Tisagenlecleucel) and ZUMA-1 trial ([r/r] DLBCL,
axicabtagen-ciloleucel). Although sold under different brand names, both medications have been
approved to treat patients with acute lymphoblastic leukaemia (ALL, tisagenlecleucel) and diffuse-
large B cell lymphoma (DLBCL, tisagenlecleucel and axicabtagen-ciloleucel) (Neelapu et al., 2017,
Schuster et al., 2019).
Tisagenelecleucel is a second generation CAR which is directed by CD19. CD19 is majorly expressed
within B cells, making tisagenelecleucel a suitable target of DLBCL. It uses 4-1BB co stimulatory
domain with a single chain variable fragment (scvf) capable of recognising CD19 in its native form.
The scvf is obtained from FMC63 which is a monoclonal antibody from mouse ( Zavras et al.,
2019).
Structure of Tisagenelecleucel ( Zavras et al., 2019)
The use of cancer vaccines to modify the body’s immune responses by stimulating it to fight cancer is
also a current trend in cancer immunotherapy. It consists of preventive vaccines and therapeutic
vaccines. The preventive vaccines are based on antigens carried by infectious agents which the host’s
immune system recognises as foreign invaders followed by the stimulation of an immune response
which confers long term immunity (Speiser and Flats, 2014). The hepatitis B virus (HBV) vaccines
and human papilloma virus (HPV) vaccines are FDA-approved (Knutson and Mittendorf, 2015).
Within the immune system are a number of checkpoint pathways focusing on T-cell activation that
play a crucial part in modulating anti-tumour immunity (Sasidharan and Elkord, 2018). Immune
checkpoint inhibitors, a class of drugs aimed to increase immune response against cancer cells, binds
with the T-cell surface molecules such as CTLA-4, PD-1, T-cell immunoglobulin and mucin domain
containing protein 3 (Tim-3), to remove inhibition and enable cytotoxic T cells to attack cancer cells
for destruction (Kakimi et al., 2016). From 2011 to 2016, a number of checkpoint inhibitors became
FDA approved. Anti-CTLA-4 antibodies ipilimumab to treat metastatic melanoma was the first to be
approved in 2011, which marked the start of a new dimension of cancer immunotherapy. The anti-PD-
1 antibodies pembrolizumab and nivolumab were approved for metastatic melanoma in 2014,
Nivolumab in 2015 for previously treated advanced or metastatic squamous lung cancer and small cell
lung cancer, and in 2016, anti-PD-L1 atezolizumab was approved for bladder cancer and nivolumab
were approved for Hodgkin lymphoma (Barbee et al., 2015; Hatae and Chamoto, 2016; Swart et al.,
2016; Kates et al., 2016; Marrone and Brahmer, 2016).
SUCCESSES AND FAILURES OF IMMUNOTHERAPHY
So many successes have been attributed to immunotherapy in variety of cancers including Non- small
cell lung cancer (NCSLS), and metastatic melanoma.
SUCCESS RECORDED IN NCSLS
A case study report by Hamid in 2014, A 60-year-old man with a smoking history presented at the
clinic with a lung mass. Biopsy showed area of necrosis and malignant cells. Chemotherapy was
administered (Cosplastin and Pemetrexed in this case) which was accompanied by response such as
tumor shrinkage that allowed for surgical resection but after 6 months there was relapse as
computated tomography (CT) scan reveals new lesions in the left lung.
In 2013, He enrolled for immunotherapy trial with check point inhibitor. Nine weeks after the
commencement of the trial, it was reported to be stable and subsequent scans revealed tumour
shrinkage.
Subsequently in 2008, a 66-year-old man with a mass on the neck (Left side) presents at the clinic and
went through parotidectomy with evidence of malignancy found. He was treated with chemotherapy
(Carboplatin, docetaxel) and radiation which was completed 2009 and went into remission until 2011
when lung and lytic iliac lesions was observed. In 2013, patient enrolled for immunotherapy clinical
trial and six weeks after the initiation of the trial, he became stable and there was huge reduction in
the size of his tumour (Pulmonary nodules) (Hamid, 2014).
SUCCESS IN METASTATIC MELANOMA
Immunotherapy was found to improve survival of patients with metastatic melanoma in a phase III
study conducted by Hodi et al and published in the New England Journal of Medicine (NEJM). In the
study, 676 patients positive for HLA- A*0201 with stage III or IV melanoma that had not been
excised surgically were recruited. Out of the participants, some groups were treated with Ipilimumab,
another with Ipilimumab and glycoprotein (gp) 100 peptide vaccine, and another with gp100 alone.
They concluded that the immunotherapy agent Ipilimumab is effective and improves patients survival
with or without the gp100.
In August 2015, it was announced that Jimmy Carter had overcome metastatic melanoma three
months after the administration of pembrolizumab, his tumour is now in remission (Cancer Research
Institute, 2020).
FAILURES
Successes recorded in the past since the inception of immunotherapy has been huge but not without its
corresponding challenges and failures. A few of these include; Inability to pre-determine effectiveness
of immunotherapy and patient’s overall response - Inability to identify tumor specific biomarker -
variations and heterogeneity of the different cancer types, and the cost implications of immunotherapy
agents (Adams, 2015, Chiriva-Internati and Bot, 2015, Tartari et al, 2015 Zugazagoitia, 2016).
Immunotherapy (immune-oncology) has been a major approach that shifted cancer treatment
paradigm as many solid tumors are found to be immunogenic (Schreiber et al. 2011).
Immunotherapies rely on the activation of the immune system and they can therrefore have a delayed
antitumor activities (Hoos et al. 2010). Non-self, tumor-associated antigens generated during
malignant transformation can be recognized by the immune system, leading to tumour
antigen−specific T-cell responses and consequent cancer cell elimination (Galon et al. 2013;
Schreiber et al. 2011; Tartour and Zitvogel 2013). Immunotherapy involving the use of monoclonal
antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1,
and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is an effective approach which has yielded
clinical benefits in several tumor types (Pardoll 2012; Topalian et al. 2015). However, downside and
complications associated with this approach includes inability to accurately predict treatment
outcome, propensity for resistant, efficacy , individual patient response, and side effects (immune-
related adverse events) (Chiriva-Internati and Bot 2015; Pauken et al. 2019; Ventola 2017).
Identifying significant markers such as the availability of known targetable tumour-specific antigens
is a great limitation in immune-oncology. Similarly, targeting tumour-associated antigens, which are
also expressed by normal tissues, may cause off-target toxicities (Alatrash et al. 2013). Till date only
few predictive biomarkers for immunotherapy have been elucidated. PD-L1 and other check point
molecules have proved to be inconsistent and may vary in different tumours. The need to identify
predictive biomarkers that are more efficient has been a challenge because clinically predictive
genomic mutations in cancer differ with respect to their distributions across many cancer types
(Zugazagoitia et al. 2016). Therefore, the identification of these mutations requires highly sensitive,
and comprehensive genetic sequencing technology, even for routine clinical care (Yuan et al. 2016;
Zugazagoitia et al. 2016).
One major factor contributing to failure of immunotherapy is the development of drug resistance,
which is believed to be caused by sub clonal cancer cell populations and branched clonal evolution
amongst others (Zugazagoitia et al. 2016). Mechanisms involved in drug resistance may be through
secondary genomic mutations in the drug, activation of alternative signalling pathways or reactivation
of a cancer pathway (Camidge et al. 2014; Zugazagoitia et al. 2016). Several patients with advanced
melanoma who had developed acquired treatment resistance to the pembrolizumab were assessed in a
study and factors that might have induced resistance were investigated using tumour biopsies obtained
from participants before treatment and after relapse, comparison was made in a bid to detect
mutations that evolved after imitating treatment (Zaretsky et al. 2016). Mutation in the JAK1/2 gene
interfering with the IFN-gamma signalling pathway leading to reduced gene expression in T cell
recognition and destruction of cancer was observed in two patients with observation of B2M gene
mutation in the third patients (Zaretsky et al. 2016).
Drugs targeting an immune checkpoint inhibitor for cancer therapy such as FDA approved
ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab are found to induce immune-
related adverse events (irAEs) have presented a major obstacle for the safe use of these therapies.
These irAEs have different types related to the target immune checkpoint inhibitor (Haanen et al.
2018). For example, hypophysitis is a common endocrine irAE observed following CTLA-4 blockade
in cancer patients, but rarely seen following PD-1 pathway blockade, in which thyroiditis is more
comon in the patients (Boutros et al. 2016; Eggermont et al. 2016; Robert et al. 2015). Combination
therapies involving these inhibitors are also found to cause irAEs, for instance, the use of nivolumab
and ipilimumab patients with melanoma caused high rate of severe irAEs (Shoushtari et al. 2018).
IrAEs may be caused by activation of immune responses unrelated to those targeting the tumor.
Alternatively, on target/off tumor responses may occur. However, the types of irAEs that occur
following checkpoint blockade do not appear to be specific to the type of cancer which suggests that
the cause of irAEs is a drug-induced loss of immune tolerance unrelated to the tumor (Boutros et al.
2016; Postow et al. 2018). The mechanism of irAEs may be explained by (i) initiating a new
autoimmune or inflammatory condition, (ii) exacerbation of a pre-existing autoimmune condition in
the patient (patients with pre-existing autoimmune diseases have largely been excluded from cancer
immunotherapy trials to date), (iii) tissue injury due to antitumor responses and (iv) aberrant reactions
to the checkpoint inhibitor itself (Haanen et al. 2018; Pauken et al. 2019).
Therefore, The need to manage irAEs has complicated the use of cancer immunotherapies and
subsequent, cancer treatment. Recently, high-dose corticosteroids effective in mitigating the
symptoms are used as first line for managing irAE, although this approach may be detrimental to the
development of host immune responses (Hu et al. 2003).
CANCER IMMUNOTHERAPY CLINICAL TRIALS
Clinical trial isa type of research that is based on studying and evaluationof outcomes of new
interventions and treatments on human subjects (WHO, 2018).
Current clinical trials in Immunotherapy listed on 'clinicaltrials.gov' include the use of tumour
infiltrating lymphocytes (TIL) in treating ovarian, urothelial, breast, and digestive tract cancer to see if
it could shrink tumour and as well safe to use. In this Phase II trial sponsored by the National Cancer
institute, patients white blood cell (WBC) were harvested from the tumour and grown into TIL
products which was later administered alongside Aldesleukin and followed up. This trial is estimated
to be completed by December 2024.
In another phase II trial sponsored by the Newlink Genetics corporation, patients with stage IV
melanoma were treated with ipilimumab, and Nivolumab (Check point inhibitors alone or in
combination with an experimental drug Dorgenmeltucel which is made up of irradiated allogeneic
melanoma cell lines HAM - 1, HAM 2 and HAM-3 to access safety of the drug and efficacy. This trial
is estimated to be completed by May 2033.
Conclusion
Cancer has been established to be a multigenic disease with high rate of mortality globally. It has
multiple aetiology ranging from genetics, environmental factors, smoking, and drug use. The immune
system has been bypassed by several mechanisms in various cancers and it has been worked on as a
potential source of treatment through immunotherapy. Further research is therefore necessary to
develop more treatment that would prevent and limit genetic predisposition, cure and overall contain
cancer globally.
Conflict of interest
All authors declared that there are no conflicts of interest.
© The Authors (s) 2021.
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