Discussion

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).

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 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).

Monoclonal antibodies in immunotherapy

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 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.

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 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 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 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.

Folate receptor inhibition

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).

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).

Conclusion

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.

References

Brahmer, J.R., Tykodi, S.S., Chow, L.Q., Hwu, W.J., Topalian, S.L., Hwu, P., Drake, C.G., Camacho, L.H., Kauh, J., Odunsi, K. and Pitot, H.C., 2012. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. New England Journal of Medicine, 366(26), pp.2455-2465.

Brahmer, J.R., Tykodi, S.S., Chow, L.Q., Hwu, W.J., Topalian, S.L., Hwu, P., Drake, C.G., Camacho, L.H., Kauh, J., Odunsi, K. and Pitot, H.C., 2012. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. New England Journal of Medicine, 366(26), pp.2455-2465.

Chen, J.T., Hasumi, K. and Masubuchi, K., 1992. Interferon-α, interferon-γ and sizofiran in the adjuvant therapy in ovarian cancer—a preliminary trial. Biotherapy, 5(4), pp.275-280.

De Felice, F., Marchetti, C., Palaia, I., Musio, D., Muzii, L., Tombolini, V. and Panici, P.B., 2015. Immunotherapy of ovarian cancer: the role of checkpoint inhibitors. Journal of immunology research, 2015.

Disis, M.L., Patel, M.R., Pant, S., Infante, J.R., Lockhart, A.C., Kelly, K., Beck, J.T., Gordon, M.S., Weiss, G.J., Ejadi, S. and Taylor, M.H., 2015. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: a phase Ib, open-label expansion trial.

Drerup, J.M., Liu, Y., Padron, A.S., Murthy, K., Hurez, V., Zhang, B. and Curiel, T.J., 2015. Immunotherapy for ovarian cancer. Current treatment options in oncology, 16(1), p.1.

Blocking of Checkpoints

Freedman, R.S., Kudelka, A.P., Kavanagh, J.J., Verschraegen, C., Edwards, C.L., Nash, M., Levy, L., Atkinson, E.N., Zhang, H.Z., Melichar, B. and Patenia, R., 2000. Clinical and biological effects of intraperitoneal injections of recombinant interferon-γ and recombinant interleukin 2 with or without tumor-infiltrating lymphocytes in patients with ovarian or peritoneal carcinoma. Clinical cancer research, 6(6), pp.2268-2278.

Hamanishi, J., Mandai, M., Ikeda, T., Minami, M., Kawaguchi, A., Murayama, T., Kanai, M., Mori, Y., Matsumoto, S., Chikuma, S. and Matsumura, N., 2015. Safety and antitumor activity of anti–PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. Journal of Clinical Oncology, 33(34), pp.4015-4022.

Hamanishi, J., Mandai, M., Ikeda, T., Minami, M., Kawaguchi, A., Matsumura, N., Abiko, K., Baba, T., Yamaguchi, K., Ueda, A. and Kanai, M., 2014. Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer.

Heery, C.R., O’Sullivan Coyne, G.H., Madan, R.A., Schlom, J., von Heydebreck, A., Cuillerot, J.M., Sabzevari, H. and Gulley, J.L., 2014. Phase I open-label, multiple ascending dose trial of MSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies.

Hird, V., Maraveyas, A., Snook, D., Dhokia, B., Soutter, W.P., Meares, C., Stewart, J.S.W., Mason, P., Lambert, H.E. and Epenetos, A.A., 1993. Adjuvant therapy of ovarian cancer with radioactive monoclonal antibody. British journal of cancer, 68(2), p.403.

Hodi, F.S., Butler, M., Oble, D.A., Seiden, M.V., Haluska, F.G., Kruse, A., MacRae, S., Nelson, M., Canning, C., Lowy, I. and Korman, A., 2008. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proceedings of the National Academy of Sciences, 105(8), pp.3005-3010.

Hou, Z., Gattoc, L., O’Connor, C., Yang, S., Wallace-Povirk, A., George, C., Orr, S., Polin, L., White, K., Kushner, J. and Morris, R.T., 2017. Dual targeting of epithelial ovarian cancer via folate receptor α and the proton-coupled folate transporter with 6-substituted pyrrolo [2, 3-d] pyrimidine antifolates. Molecular cancer therapeutics, pp.molcanther-0444.

Mabuchi, S., Morishige, K. and Kimura, T., 2010. Use of monoclonal antibodies in the treatment of ovarian cancer. Current Opinion in Obstetrics and Gynecology, 22(1), pp.3-8.

Miller, K.D., Siegel, R.L., Lin, C.C., Mariotto, A.B., Kramer, J.L., Rowland, J.H., Stein, K.D., Alteri, R. and Jemal, A., 2016. Cancer treatment and survivorship statistics, 2016. CA: a cancer journal for clinicians, 66(4), pp.271-289.

Nishimura, H., Okazaki, T., Tanaka, Y., Nakatani, K., Hara, M., Matsumori, A., Sasayama, S., Mizoguchi, A., Hiai, H., Minato, N. and Honjo, T., 2001. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science, 291(5502), pp.319-322.

Pedoeem, A., Azoulay-Alfaguter, I., Strazza, M., Silverman, G.J. and Mor, A., 2014. Programmed death-1 pathway in cancer and autoimmunity. Clinical Immunology, 153(1), pp.145-152.

Rivalland, G., Loveland, B. and Mitchell, P., 2015. Update on Mucin-1 immunotherapy in cancer: a clinical perspective. Expert opinion on biological therapy, 15(12), pp.1773-1787.

Robert, C., Thomas, L., Bondarenko, I., O’day, S., Weber, J., Garbe, C., Lebbe, C., Baurain, J.F., Testori, A., Grob, J.J. and Davidson, N., 2011. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New England Journal of Medicine, 364(26), pp.2517-2526.

Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T.W. and Sakaguchi, S., 2000. Immunologic self-tolerance maintained by CD25+ CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte–associated antigen 4. Journal of Experimental Medicine, 192(2), pp.303-310.

Topalian, S.L., Sznol, M., McDermott, D.F., Kluger, H.M., Carvajal, R.D., Sharfman, W.H., Brahmer, J.R., Lawrence, D.P., Atkins, M.B., Powderly, J.D. and Leming, P.D., 2014. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. Journal of clinical oncology, 32(10), p.1020.

Varga, A., Piha-Paul, S.A., Ott, P.A., Mehnert, J.M., Berton-Rigaud, D., Johnson, E.A., Cheng, J.D., Yuan, S., Rubin, E.H. and Matei, D.E., 2015. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study.