Effect of Immunotherapy on Ovarian Cancer

This review article critically analyzes the various methods of immunotherapy for treating ovarian cancer, including monoclonal antibodies, immune checkpoint blocking, and more. It also discusses the research gap and concludes with the effectiveness of immunotherapy in treating ovarian cancer.

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
Effect of Immunotherapy on Ovarian Cancer
Name of the student
Name of the University
Author Note

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
Abstract
Cancer immunotherapy is one of the effective treatment of cancer nowadays. The cancer
immunotherapy is done by stimulating the immune system of the cancer patient itself and using
of artificially produced immune system proteins can also be used to do immunotherapy of the
patient. Ovarian cancer ( OC) is one of the major cause of gynecological mortality in the women.
Immunotherapy is used as alternative strategy along with the surgery and chemotherapy. In this
review article , various methods of immunotherapy is critically analyzed.
Key Words : Immune checkpoints, Check point blocking, monoclonal antibody, checkpoint
inhibitors, Intravenous, cytokines.

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
Table of Contents
1. Introduction..............................................................................................................................4
2.Discussion.....................................................................................................................................4
2.1 Monoclonal antibodies in immunotherapy............................................................................4
2.2 Folate receptor inhibition.......................................................................................................5
2.3 Blocking of Checkpoints.......................................................................................................6
2.4 Other Treatment.....................................................................................................................9
3. Research Gap...............................................................................................................................9
4. Conclusion...................................................................................................................................9

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
1. Introduction
Ovarian cancer ( OC) is one of the critical issue in women nowadays and
immunotherapy has become an important treatment technique for the ovarian cancer patients.
According to Siegel, Miller and Jemal (2015), OC is the principle cause of death in US.
Although, the chemotherapy and surgery is used to treat the disease, the immunotherapy has a
serious role in treating the OC in recent times. The immunotherapy is associated with the
adaptive and innate immunity system of the human system. In innate immune system, there
includes dendritic cells, natural killer cells (NK cells), macrophages, cytotoxic T cells ( CD8+ T
or CTL), helper cells ( CD4+ T) and NK T cells. The adaptive immunity on the other hand is
responsible for the antitumor immune response. In adapative immunity, T cells are activated by
the representation on antigen presenting cells ( APCs) by a major histocompatibility complex
( MHC) molecule. The presented T cells are completely activated by the interaction of CD28
with the B7 costimulatory molecules that are on APCs. In OC, the monoclonal antibodies,
inhibition of the receptors that is overexpressed in OC, immune checkpoint blocking mechanism,
marker antigen like CA-125, blocking of malignant cells by interferon, Interleukin ( IL)-2
therapy, inhibition of p53 by vaccination can be used (Drerup et al. 2015).
2.Discussion
2.1 Monoclonal antibodies in immunotherapy
The radio labelled anti-milk fat globulin-1 is the first therapeutic antibodies to treat
human OC and it was injected in the peritoneum of human body. In a study by Hird et al. ( 1993)
had shown effective clinical responses to a patient group of 52 and among them 21 showed

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
effective response against the OC and it showed higher rate of survival than previous other
studies. Mucin 1 ( MUC1) is overexpressed in cancers and its molecular nature make it a good
target for the immunotherapy. In malignancy, the expression of MUC1 is quite different from
that those are expressed in normal healthy tissue . MUC1 also play a critical role in tumor
production via extracellular and intracellular pathways. It also promote abnormal cell growth by
inhibiting the cell death process that is apoptosis (Mabuchi, Morishige and Kimura 2010).
MUC1 binds to the tyrosine kinases and increases the signaling process by lowering the
degradation and thereby increases cell proliferation. The monoclonal antibody of human milk fat
globule 1 ( HMFG 1) is a murine monoclonal antibody that can identify the extracellular domain
of the MUC1. Due to this property, radiolabelled HMFG1 is used in recognizing the patients
with metastatic and primary ovarian cancer (Rivalland, Loveland and Mitchell 2015). In a study
on mice model it is seen that, the i.p administration of radio labelled HMFG1 in mice with
ovarian cancer. In a phase I/II trial of the study showed the efficacy of the treatment. In this
study, the patients with i.p 90Yttrium-labelled HMFG1 has shown prolonged survival rate in
compare to the control groups (Mabuchi, Morishige and Kimura 2010).
2.2 Folate receptor inhibition
In most OCs folate receptor- alpha is overexpressed. To suppress this overexpression of
folate receptor, a humanized anti folate receptor- alpha named, Farletuzumab is produced and it
is assumed that, it works via cellular toxicity that is completely antibody dependent. According
to Hou et al. ( 2017), in epithelial ovarian cancer the folate receptor alpha is overexpressed and
and involves in enhancing of tumor stage and the proton-coupled folate transporter( PCFT) was
overexpressed in independent of tumor stage and it was recorded by RT- PCR and IHC

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
technique. The EOC cell line model that includes cispaltin sensitive (IGROV1 and A2780) and
cisplatin resistant ( SKOV3 and TOV112D) cells are overexpressed 17 times of Folate Receptor
alpha in the OC. The AGF94 and AGF154 has shown antiproliferative action towards the over
expressive folate receptor alpha cell line of the OC. In this study it was seen that, the previous
treatment of the IGROV1 by the AFG94 at pH 6.8, cell killing was observed by inhibition of
clonogenicity. In this experiment, the folate receptor alpha of the IGROV1 was eliminated to
reduce the upatake and binding of the folic acid and on the same time, concentration of [ 3H ]
was maintained by the AGF154 uptake by PCFT in compare to the control group. In another
study, 54 patient was treated with the farletuzumab, and it shows effective results in the patients.
Although, various side effect like fatigue, hypersentivity, cough was reported by the patients. In
this study, either the drugs used alone or it is used as a combination of docetaxel or carboplatin
plus placitaxel.
2.3 Blocking of Checkpoints
In recent time, one of the important immunotherapy technique is blocking of checkpoints
that are associated with the activation process of T cells. The blockage on any point of the
activation of process can be effective procedure for the immunotherapy . The checkpoints like
CLAT-4 (Robert et al. 2011) or the Programmed cell death 1 (PD-1) receptor is found to be very
much effective for the treatment of the OC. CLAT-4 belongs to the immunoglobin family of
CD28: 27 and it is generally less expressive in the surface of the T cells. During the stimulation
of the T cells through the T cell receptor ( TCR), the expression of CTLA-4 is increased and
suppress the T cell activity (Brahmer et al 2012). It is seen that, the CLAT-4 blockade may also
be gained by the deletion of regulatory T cells (Treg) and it was concluded from the melanoma
of mouse model (Takahashi et al. 2000). The inhibition of Treg activity by the blockade of

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
CLAT-4 cause a severe antitumor response. PD-1 is mostly expressed in the stimulated T cells
and also in Tregs, NK cells, activated B cells. Unlike the CLAT-4, PD-1 downregulates the T-
lymphocytes and at the primary level of activation. PD-1 mainly inhibits the activation of T
lymphocytes at various phases of activation (Nishimura et al. 2001). In a study , it seen that , PD-
1 silenced mice showed more immune response with phenotypes characterized by the lupus like
syndrome and autoimmune cardiomyopathy (Pedoeem et al. 2014). The activity of the PD-1 is
associated with the interaction between the PD-1 and its ligands PD-1L and PD-1L2. The PD-1L
is mainly expressive in many human tumor tissues. In OC, the PD-1 mainly binds with the
ligands and T cell activity is attenuated. This inhibits the rejection of tumor by the T cells and
activate the PD-1 inhibitory mechanism and ultimately silenced the immune response against the
malignancy (Hamanishi et al. 2015). The investigation of the CLAT-4 showed that ipilimumab
and tremlimumab can be used as antagonistically to CLAT-4 immune checkpoint. The use of
ipilimumab had shown such effective response in treatment of the cancer that, FDA had given
approval to this drug for treating the metastatic melanoma in 2011. In case of OC the experiment
was done on a very small group, however the result was quite satisfying (De Felice et al. 2015).
In a study by Hodi et al. ( 2008) showed that patients with OC had severe anti tumor effect by
the immune checkpoint therapy. According to them, the single administration of ipilimumab in
stage IV of OC patients, previously vaccinated with granulocyte macrophage showed a decrease
in CA-125 levels of the patients. After that, in order to rectify the toxicity and the study was
conducted on 9 stage- IV OC patients with the same dose of antibody. Among them, in only
patient , noticeable radiographic change was noted and transfusion of anti CLAT-4 antibody in
an interval of every 3-5 months showed effective disease control in the patients. The correlation
of CD+8/ Treg ratio with the tumor regression, also indicated that Treg depletion is an effective

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
immune therapy for the OC. The therapeutic role of CLAT-4 inhibition also helped to identify
various other checkpoint inhibitor and those are very much effective and have less adverse
effect. PD1 and PD-1L inhibitor were assumed to be more effective than that of the other
checkpoint inhibitor. Instead of inhibiting the activation of T lymphocytes in initial stages, the
PD-1 and PD-1L inhibitors stops the activation process in various steps of T cell activation. To
block those PD-1 receptor, various monoclonal antibodies were developed and it worked by
either interacting with the PD-1 receptors or by interacting with the PD-1 ligands (Topalian et al.
2014). Nivolumab is a completely human IgG4 monoclonal antibody and its target component is
the PD-1. In 2014,at ASCO meeting, the effect of Nivolumab was experimented against
platinum-resistant OC. In this study, 18 patients were treated with the Nivolumab and among
them, 10 patients were given dose of 1mg/ kg body weight and the rest of the 8 patients were
given 3mg/kg body weight and this process was continued for 1year in an interval of two weeks.
In this study, there was mainly two type of adverse effect in the patients. In the group of
1mg/kg group one patiemt complained about fever, gait disorder and disorientation and in the
3mg/kg group one patient had complained about deep vein thrombosis and grade three fever. The
ultimate response arte was 17%. Moreover, the 3mg/kg group had shown more effectiveness
( 25%) and the other group showed 10% effectiveness. Another, PD-1 antibody is
pembrolizumab and it is also a IgG4 humanized monoclonal antibody. It was mainly discovered
to be active in treatment of melanoma. However, no such effective study had shown the
difference in between the mechanism of the two effective PD-1 antibody (Varga, et al. 2015). In
a study with 17 OC patients, the IV dose of 0.3-10 mg/kg body weight were given in each 14
days in a 6 week cycles and the process was continued until the patients showed complete
response to the disease. In this study, only 1 patient, showed desired response with 10 mg/ body

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
weight dose, 1 person showed partial response and 3 showed stable disease lasting for more than
24 weeks (Brahmer et al. 2012). In another study by Heery et al. ( 2014), phase I trial was
conducted with 27 patients with malignancies and they were treated with MSB0010718C at
1,3,10 and 20 mg/kg body weight for two times a week. The 3 and 10 mg/kg dose showed
inhibition of PD-L1 in 93.8% and 93.2% patients. In this study with 23 patients with OC showed
48% of the disease stability. Disis et al. (2015) showed in a study that, 23 patients were kept
under treatment for 2-8 months and among them, 47.8% patient gained unconfirmed partial
response, > 30 % shrinkage was reported by two patients, 47.8% had still the stable disease.
2.4 Other Treatment
In a mouse model of OC treatment, Interferon-alpha showed improved clinical efficacy
(Chen, Hasumi and Masubuchi 1992.). The interferon-gama is used to treat OC and Interferon-
gama in combination with IL-2 showed upregulation of tumor cell leucocyte antigen class I and
class II expression and that suggested immunogenicity of tumor (Freedman et al. 2000).
3. Research Gap
In various studies, it is seen that, patients complained about various adverse effects
related to the treatment. Moreover, most of the studies did not show complete desired result.
Although it is a crucial therapy for cancer treatment. Another gap is that, various studies were
done in mice model and it was not evident that those studies would show same result in the
human model . However there is a scope of more studies to establish the effect of
immunotherapy on ovarian cancer ( Derup et al. 2015).
4. Conclusion

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
It conclusion it can be said that, immunotherapy is one of the most effective way of
treating OC and other type of cancer too. This therapy is very much effective as it involves
various molecular immune mechanism and blocking of several steps of cell cycle and it causes
downregulation of tumor cell cycles. It causes ultimate downregulation of the uncontrolled cell
growth of malignant cells.

Running head: EFFECT OF IMMUNOTHERAPY ON OVARIAN CANCER
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