Immunotherapy in Various Cancers

Nirav Parmar

1st Year MSc Student

Department of Biosciences and Bioengineering, IIT- Roorkee India

Abstract:

Immunotherapy in the metastatic situation has changed the therapeutic landscape for a variety of cancers, including colorectal cancer. Immunotherapy has firmly established itself as a new pillar of cancer treatment in a variety of cancer types, from the metastatic stage to adjuvant and neoadjuvant settings. Immune checkpoint inhibitors have risen to prominence as a treatment option based on a better knowledge of the development of the tumour microenvironment immune cell-cancer cell regulation over time. Immunotherapy has lately appeared as the most potential field of cancer research by increasing effectiveness and reducing side effects, with FDA-approved therapies for more than 10 various tumours and thousands of new clinical studies.

Key Words:

Immunotherapy, metastasis, immune checkpoint.

Introduction:

In the late 1800s, William B. Coley, now generally regarded as the founder of immunotherapy, tried to harness the ability of immune system to cure cancer for the first time. Coley began injecting live and attenuated bacteria like Streptococcus pyogenes and Serratia marcescens into over a thousand patients in 1891 in the hopes of causing sepsis and significant immunological and antitumor responses. His bacterium mixture became known as "Coley's toxin" and is the first recorded active cancer immunotherapy treatment [1]. To better understand the processes of new and traditional immunological targets, the relationship between the immune system and tumour cells should be examined. Tumours have developed ways to evade immunological responses. To make the tumour undetectable to the immune system, cancer cells may de-regulate antigen presentation. Tumors also produce immunosuppressive substances that hinder immune cells and may recruit immunosuppressive cells [2][3][4]. Honjo and Allison were awarded the 2018 Nobel Prize in Physiology or Medicine for the their discovery of T cell immunological checkpoints like PD- 1 and ctla-4, which pushed the science of immuno-oncology into its present age [5]. Cancer immunotherapy inhibits immune response-regulating mechanisms, providing a new approach to cancer treatment. CD80/CD86 and programmed death-ligand 1 (PD- L1) connect to their corresponding receptors, programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated-4 (CTLA-4), on the surface of cytotoxic T lymphocytes, to control the immune response [6][7][8][9]. The use of the immune system of body to target tumour cells has gained popularity as a potential cancer therapy approach in recent decades [5]. Immune checkpoint inhibitors are currently extensively used to treat a variety of cancers. In addition, a number of current clinical studies are reviewing the impact of various agonistic or inhibitory checkpoints on tumour outcomes [10]. Immunotherapy medicines including nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1), as well as ipilimumab (anti-CTLA-4) have raised concerns about their potent anti-tumor action. The objective success rate to these treatments, on the other hand, varies considerably across individuals [11]. Cancer immunotherapies, which include antibodies, vaccinations, and T cell infusions, seek to adhering and block the function proteins produced by cancer cells in engaging immune system element may today and in the future react to cancer trials, according to new research [12][13][14][15]. The increasing knowledge of the critical function of the tumour microenvironment in the regulation of anticancer immune responses has resulted in a significant advancement in the area of immuno-oncology [16][17].

Mechanism:

Traditional therapeutic techniques such as surgery, radiation, and chemotherapy have been utilized to treat patients; nevertheless, morbidity and mortality have proven difficult to manage. Tumorigenesis has two characteristics: growing tumours need resources for fast development and evading the immune system's assault of the host. The immune system perform a critical function in tumour growth control. Certain inflammatory reactions may promote the growth of the cancer and can be inhibited by a tumor-specific adaptive immune response. Thus, immunotherapy, which seeks to improve immune function via artificial means, progressively limit tumour cell development, and ultimately eliminate tumour cells, has emerged as a strong therapeutic approach for cancer treatment [18]. Since the first cancer immunotherapy (cytokine interferon-) was authorized, this approach has emerged as a potential and appealing way to treat cancer, with a slew of medicines on the market and hundreds of studies conducted across the world [19]. The activation of antitumor responses by producing adequate numerous cytotoxic T lymphocytes and tumour antigen-specific helper T (Th1) cells is the primary aim of tumour immune prophylaxis and tumour treatment (CTLs) [20]. Through the time of approval, cancer immunotherapy has been divided into many major classes, including cytokines for lymphocyte promotion, checkpoint inhibitors, vaccines, oncolytic viruses, bispecific antibodies and modified T cell therapies [19]. Cytokines are proteins generated through immune cells that function as molecular messengers, enabling the immune system to communicate, to enhance cell identification, and to activate an immunological response to a certain antigen [21]. Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukins (IL) and Interferons (IFN) are three kinds of cytokines that have been created for cancer immunotherapy (GM-CSF). The second generation of cytokine medicines is now in clinical trials, and it consists of well-known JETIR2106809 Journal of Emerging Technologies and Innovative Research (JETIR) www.jetir.org f771

© 2021 JETIR June 2021, Volume 8, Issue 6 www.jetir.org (ISSN-2349-5162) compounds including novel mechanisms of action, as well as new targets and fusion proteins that improve cytokine activity and shelf-life [22]. Immune checkpoint molecules such as programmed cell death protein (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have strong effects of immunomodulation in negative T cell activation regulators [23]. Tumor cells produce PD-L1, which binds to programmed cell death protein and causes T-cells to be inactivated, allowing them to avoid being eliminated. Interactions between CTLA4 and its ligands, on the other hand, decrease T cell function and therefore encourage tumour growth. Antibodies that target inhibitory receptors maintain T-cell function, such as the ability to recognize and destroy tumour cells. Other co-inhibitory receptors have been tested in clinical trials as possible immunotherapies [24]. Tumour cell lysate, nucleic acids, Dendritic cells, neo-antigens, have all been studied as potential cancer vaccines that activate the immune system [25]. Immunogenicity is the primary hurdle that these types of drugs must overcome in order to provide enough effectiveness [26][15]. Bispecific antibodies are antibodies that bind two or more tumour antigens on the identical or different cells at the same time to stop cancer from spreading. Blinatumomab, which consists of two odd segments, one of which binds to CD3 and the other to CD19. This construct has the ability to enhance safety and effectiveness and may be considered the next generation of immunotherapies [27]. Oncolytic viruses, which are attenuated and used to invade tumour cells and induce a previously existing native immune response to identify tumour apoptosis, are another kind of cancer immunotherapy [28]. Engineered T cell treatments using T cell receptor T cells (TCR T cells) and chimeric antigen receptor T cells (CAR T cells) are gaining popularity. Interestingly, CAR T proteins are generated and produced through patient T cells and their actions have deep consequences [29][30]. Immune checkpoint inhibitors have sparked interest because they seem to work by bypassing the pathways that cancers employ to dampen the antitumor immune response [31]. Therapy involves activating or enhancing the immune system's natural defences and repairing or increasing the immune system's capability to identify and destroy tumour cells. Due to its benefits, including local or systemic effects, degradation through ingestion prevention, and the quantity of immune cells in the epidermis and dermis, which may enhance a robust immune response, transcutaneous administration has been created and attracted clinical and scientific interest [32].

Immunotherapy in cancers:

Pancreatic cancer:

Researchers have recently emphasized the significance of pancreatic cancer (PCa) in terms of its generalizability and severity. Notion of PCa has been subjected to many debates in various areas over the last few decades; nevertheless, the overall perspective of PCa has remained constant, and PCa remains one of the most lethal tumours on the planet. As a result, PCa is described as a disorder in which malignant cancer cells develop in pancreatic tissues [33]. Exocrine and neuroendocrine pancreatic cancers are distinguished by the cell from which they arise. This categorization is important because it distinguishes between these two kinds' functioning features and treatment methods [34]. Around 93 percent of PCa patients have exocrine tumours. According to the American Cancer Society, PCa patients make up about 3 percent of all adult cancer cases in the United States, with only around 22 percent of exocrine PCa patients still alive one year after the operation. In 2019, about 56 thousand Americans will be identified with PCa, with an average of more than 150 cases per day [35]. Significant progress has been achieved in understanding the staging, diagnosis, molecular biology and therapy of PCa in patients in recent years [36]. Monoclonal antibodies (mAbs) which block immune-effector cells and cells of the tumour cells or their ligands as inhibitory receptors (APCs) have become an important turning point in cancer immunotherapy (ICPs) [35]. Immune checkpoint inhibitors (ICIs), that have demonstrated significant anti-tumor effectiveness in several cancers [37][38][39]. Antibodies against negative immune regulators such as PD-1 ligand 1 (PD-L1), programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are used in these methods to prevent tumour cells from evading immune surveillance [40]. Despite substantial improvements in immunotherapy for almost all cancer types, success in pancreatic ductal adenocarcinoma (PDAC), especially for ICIs, has been challenging. Several clinical studies evaluating immune checkpoint inhibitors or other immunotherapies in pancreatic ductal adenocarcinoma have shown mixed outcomes, especially when compared to triumphs in other malignancies [36].Antibody against CTLA-4 The first ICI to be tested in pancreatic ductal adenocarcinoma was ipilimumab. In a Second Phase study conducted in 2010, 27 individuals with PDAC were recruited, 20 of whom had metastatic disease and seven of whom had localised illness. Ipilimumab was administered every three weeks in four dose cycles for a total of two cycles at a dose of 3 mg/kg. Although there were three people with serious, grade 3 immune-mediated side effects (hypophysitis, encephalitis and colitis ), control point inhibition was sufficiently powerful to cause autoimmune-mediated secondary symptoms [41]. In a pan-cancer trial in 2012, 14 patients with advanced pancreatic ductal adenocarcinoma were treated with increasing doses of the 0.3-10 mg/kg anti-PD-L1 antibody, BMS-936559, every 14 days in 6- week cycles, for up to 16 cycles. Furthermore no quantitative reactions, like with single-agent Ipilimumab, were seen in any patient [42]. Anti-PD-1 antiody Pembrolizumab (maximum dose 10 mg/kg every 2 weeks) and The anti-PD-L1 antibody MPDL3280A (maximum dosage 20 mg/kg every 3 weeks) were included in pan-carcina studies, but these anti-PDACs failed to provide any objective answers, despite their demonstrated effective in other cancer types [42][43]. The PDAC Phase 2 trial demonstrated an absolute response rate of 0 percent in 32 patients who had had either fluorurazil or gemcitabine treatment before (1500 mg every 4 weeks up to 12 months) [41].

Gastric cancer:

GC is the world's third most frequent cause of death and the fifth most prevalent cancer. Affected people are anticipated to survive for five years, but the rate in end-stage patients falls to less than a year [43]. TILs have long been utilised in the treatment of GC. Tumor-infiltrating lymphocytes are extracted from a patient's tumour and have already been exposed to trichostatin A, making them more useful in immunotherapy [44]. In a clinical trial of adaptive immunotherapy, employing a conjugation of chemotherapy and tumor-associated lymphocytes in stomach cancer patients ended in a 50% longer survival rate than chemotherapy alone [45]. JETIR2106809 Journal of Emerging Technologies and Innovative Research (JETIR) www.jetir.org f772

Cytokine-induced killer cells (CIK) are a kind of immune effector cell that has a high anti-tumor activity as well as the capacity to proliferate quickly. They're made by growing peripheral blood lymphocytes in the lab in the presence of anti-CD3 antibodies, , interferon (IFN) and IL-2 [46]. The heterogeneous T-cell population of CD3+ generated from the killer cell population of cytokine mostly belongs to the heterogeneous CD3+ population. CD3+CD56- and CD3+CD56+ are the two most common subsets [47][48]. As a result, CIK cells can identify tumour cells both in the presence and absence of MHC. Furthermore, through generating cytokines and chemokines, CIK cells may control and enhance host cellular immunity [49]. Clinical trials have shown that treating gastric cancer patients with a combination of cytokine-induced killer cells and chemotherapy is more effective than chemotherapy alone [50]. Furthermore, preclinical data indicates that merging Cytokine-induced killer cells with a monoclonal antibody opposing the epidermal growth factor receptor (EGFR) improves CIK cells' anticancer capacity in vivo and in vitro [51][52]. To induce particular lymphocyte responses in gastric cancer, both protein targeting and peptide have been utilised. Peptides based on the Melanoma-associated antigens (MAGE) and tumour related antigen HER2/neu-derived peptides that may activate cytotoxic T lymphocytes opposing tumours were utilised in these studies [53][54][55][55]. Furthermore, peptides generated from VEGF receptor 1 and 2 were shown to elicit a VEGF-specific cytotoxic reaction in advanced gastric cancer patients when administered on conjunction with chemotherapy, resulting in a longer overall survival [56]. Gastrin peptide targeting was explored in a phase II, multicenter gastric cancer test. The 9-amino-acid G17DT (aphthon) epitope produced from the amine terminus of 5-fluorouracil cisplatin and gastrine-17 were administered to individuals who had unresectable gastric carcinoma or untreated metastatic cancer and gastroesophageal adenocarcinoma. The results revealed that 65 of the 94 patients were responsive and developed two anti- gastrin antibody titers in a row [57].

Ovarian Cancer:

Epithelial ovarian cancer (EOC) is the worst illness in the US, with a projected 22,530 new and 13,980 fatalities in 2019. in the United States [58]. Immune checkpoint inhibitors that inhibit immune-checkpoints such programmed death 1 (PD-1) receptor or cytotoxic T lymphocyte-associated protein 4 (CTLA-4), alone or in conjunction with other medicines, have been the focus of several research on immunotherapy in EOC in the past few years. After immunisation, autologous tumour cells have been changed to generate the colony-stimulation factor of granulocyte macrophage. Hodi et initially showed ipilimumab anticancer benefits (anti- CTLA-44) in 9 stage IV OC patients. In one patient every three to five months, multiple anti-CTLA-4 antibody infusions were maintained over 4 years; three patients also showed disease stability for 6, 4, and 2 months, as confirmed by Ca 125 levels and radiological assessment without any significant side effects [59][60]. The study concluded that ICIs may be used as monotherapy in recurrent platinum-resistant EOC or platinum-sensitive (PFI > 12 months) in the second, third, or fourth lines, with hopeful outcomes in the future [60]. Despite the fact that the biology of the tumour indicated that Epithelial ovarian cancer patients may get advantage from immunotherapy, mono-immunotherapy has not shown to be as effective in EOC patients as it has in other neoplasms. In EOC, for example, PD-1, or PD-L1 and single-agent antibodies targeting CTLA-4 had moderate effects, with median RRs of 10–15 percent. Furthermore, only around half of the women participating in the study demonstrated illness control [61][62][63][64]. Sabbatini et al. published 2013 Phase-III clinical trial findings to determine if maintenance abagovomab (Anti- Human CA-125) increases recurrence-free survival (RFS) and overall survival (OS) in initial-clinical remission ovarian cancer patients. Abagovomab in the first remission after debulking and platinum chemotherapy for advanced ovarian cancer patients did not prolong RFS and OS, the researchers reported [65]. A MIMOSA research was also sub-analysed to determine whether abagovomab in its first clinical remission generates protective immune responses in ovarian cancer patients. The scientists investigated anti-idiotypical (Ab3), human antimouse antibody, CA125-specific cytotoxic T (CTL), and discovered that CA125- specific CTL was not generated by abagovomab before starting treatment. Whatever the treatment with abagovomab, individuals with CTL-specific CA125 function more effectively than those without. Abagovomab-induced Ab3 is related to a prolonged RFS for people without CA125-specific CTL [66]. Based on these results, Battaglia et al. explored the possibility of predicting abagovomab sensitivity by evaluating immunological status before injection. A greater proportion of CD8+T-cells produced by the IFN and an absolute number above the threshold showed better RFS (P=0.042 and P=0.019 respectively) than that of individuals with a lower percentage of CD8+T-cells produced by the IFN, and an absolute level below the cutoff rate [67].

Conclusion:

The development of active immunotherapy with medication to help the innate immune system detect and fight malignancies via the recognition of antigen or cell surface markers has changed the treatment paradigm of solid tumours. Existing work is starting to have an effect, especially with ICIs, CTLA-4 inhibitors and other types of cellular therapy being explored and will help to better understand how these methods may enhance current strategy for intended treatment of these illnesses. Many studies are exploring and verifying alternative markers beyond dMMR-MSI-H that predict ICI and other immunotherapies. Understanding and differentiating between these and similar groups physiologically in the context of molecular causes and their general impact on carcinogenesis at different stages.

References:

[1] E. F. McCarthy, “The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas.,” Iowa Orthop. J., vol. 26, pp. 154–158, 2006.

[2] S. I. Labidi-Galy et al., “Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune JETIR2106809 Journal of Emerging Technologies and Innovative Research (JETIR) www.jetir.org f773

tolerance in ovarian cancer,” Cancer Res., vol. 71, no. 16, pp. 5423–5434, 2011, doi: 10.1158/0008-5472.CAN-11-0367.

[3] D. Wolf et al., “The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer,” Clin. Cancer Res., vol. 11, no. 23, pp. 8326–8331, 2005, doi: 10.1158/1078-0432.CCR- 05-1244.

[4] T. J. Curiel et al., “Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival,” Nat. Med., vol. 10, no. 9, pp. 942–949, 2004, doi: 10.1038/nm1093.

[5] T. T. Nguyen, T. T. D. Nguyen, Q. T. H. Ta, and V. G. Vo, “Advances in non and minimal-invasive transcutaneous delivery of immunotherapy for cancer treatment,” Biomed. Pharmacother., vol. 131, p. 110753, 2020, doi: 10.1016/j.biopha.2020.110753.

[6] P. Sharma and J. P. Allison, “Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential,” Cell, vol. 161, no. 2, pp. 205–214, 2015, doi: 10.1016/j.cell.2015.03.030.

[7] E. I. Buchbinder and A. Desai, “CTLA-4 and PD-1 pathways similarities, differences, and implications of their inhibition,” Am. J. Clin. Oncol. Cancer Clin. Trials, vol. 39, no. 1, pp. 98–106, 2016, doi: 10.1097/COC.0000000000000239.

[8] Y. Yang, “Cancer immunotherapy: Harnessing the immune system to battle cancer,” J. Clin. Invest., vol. 125, no. 9, pp. 3335–3337, 2015, doi: 10.1172/JCI83871.

[9] A. Sukari, M. Nagasaka, A. Al-Hadidi, and L. G. Lum, “Cancer immunology and immunotherapy,” Anticancer Res., vol. 36, no. 11, pp. 5593–5606, 2016, doi: 10.21873/anticanres.11144.

[10] N. Parmar, “PARP inhibitors in various cancers,” vol. 6, no. 6, pp. 273–279, 2021.

[11] Z. Xu, X. Wang, S. Zeng, X. Ren, Y. Yan, and Z. Gong, “Applying artificial intelligence for cancer immunotherapy,” Acta Pharm. Sin. B, no. xxx, 2021, doi: 10.1016/j.apsb.2021.02.007.

[12] Y. Lee et al., “Therapeutic effects of ablative radiation on local tumor require CD8 + T cells: Changing strategies for cancer treatment,” Blood, vol. 114, no. 3, pp. 589–595, 2009, doi: 10.1182/blood-2009-02-206870.

[13] T. Jiang, G. Xu, G. Chen, Y. Zheng, B. He, and Z. Gu, “Progress in transdermal drug delivery systems for cancer therapy,” Nano Res., vol. 13, no. 7, pp. 1810–1824, 2020, doi: 10.1007/s12274-020-2664-5.

[14] L. M. Weiner, R. Surana, and S. Wang, “Monoclonal antibodies: Versatile platforms for cancer immunotherapy,” Nat. Rev. Immunol., vol. 10, no. 5, pp. 317–327, 2010, doi: 10.1038/nri2744.

[15] S. A. Rosenberg, J. C. Yang, and N. P. Restifo, “Cancer immunotherapy: Moving beyond current vaccines,” Nat. Med., vol. 10, no. 9, pp. 909–915, 2004, doi: 10.1038/nm1100.

[16] F. Pagès et al., “International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study,” Lancet, vol. 391, no. 10135, pp. 2128–2139, 2018, doi: 10.1016/S0140-6736(18)30789-X.

[17] M. Camus et al., “Coordination of intratumoral immune reaction and human colorectal cancer recurrence,” Cancer Res., vol. 69, no. 6, pp. 2685–2693, 2009, doi: 10.1158/0008-5472.CAN-08-2654.

[18] A. Singh and N. A. Peppas, “Hydrogels and scaffolds for immunomodulation,” Adv. Mater., vol. 26, no. 38, pp. 6530–6541, 2014, doi: 10.1002/adma.201402105.

[19] R. S. Riley, C. H. June, R. Langer, and M. J. Mitchell, “Delivery technologies for cancer immunotherapy,” Nat. Rev. Drug Discov., vol. 18, no. 3, pp. 175–196, 2019, doi: 10.1038/s41573-018-0006-z.

[20] N. T. Trac and E. J. Chung, “Peptide-based targeting of immunosuppressive cells in cancer,” Bioact. Mater., vol. 5, no. 1, pp. 92–101, 2020, doi: 10.1016/j.bioactmat.2020.01.006.

[21] S. Lee and K. Margolin, “Cytokines in cancer immunotherapy,” Cancers (Basel)., vol. 3, no. 4, pp. 3856–3893, 2011, doi: 10.3390/cancers3043856.

[22] P. Berraondo et al., “Cytokines in clinical cancer immunotherapy,” Br. J. Cancer, vol. 120, no. 1, pp. 6–15, 2019, doi: 10.1038/s41416-018-0328-y.

[23] E. S. Webb, P. Liu, R. Baleeiro, N. R. Lemoine, M. Yuan, and Y. Wang, “Immune Checkpoint Inhibitors in Cancer,” Immune Checkp. Inhib. Cancer, vol. 32, no. 5, pp. 317–326, 2019, doi: 10.1016/c2016-0-05251-8.

[24] C. Granier et al., “Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer,” ESMO Open, vol. 2, JETIR2106809 Journal of Emerging Technologies and Innovative Research (JETIR) www.jetir.org f774

no. 2, pp. 1–8, 2017, doi: 10.1136/esmoopen-2017-000213.

[25] C. Guo, M. H. Manjili, J. R. Subjeck, D. Sarkar, P. B. Fisher, and X. Y. Wang, Therapeutic cancer vaccines. Past, present, and future, 1st ed., vol. 119. Elsevier Inc., 2013.

[26] B. Yang, J. Jeang, A. Yang, T. C. Wu, and C. F. Hung, “DNA vaccine for cancer immunotherapy,” Hum. Vaccines Immunother., vol. 10, no. 11, pp. 3153–3164, 2014, doi: 10.4161/21645515.2014.980686.

[27] E. Dahlén, N. Veitonmäki, and P. Norlén, “Bispecific antibodies in cancer immunotherapy,” Ther. Adv. Vaccines Immunother., vol. 6, no. 1, pp. 3–17, 2018, doi: 10.1177/2515135518763280.

[28] J. Raja, J. M. Ludwig, S. N. Gettinger, K. A. Schalper, and H. S. Kim, “Oncolytic virus immunotherapy: future prospects for oncology,” J. Immunother. Cancer, vol. 6, no. 1, pp. 1–13, 2018, doi: 10.1186/s40425-018-0458-z.

[29] A. D. Fesnak, C. H. June, and B. L. Levine, “Engineered T cells: The promise and challenges of cancer immunotherapy,” Nat. Rev. Cancer, vol. 16, no. 9, pp. 566–581, 2016, doi: 10.1038/nrc.2016.97.

[30] D. L. Porter et al., “Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia,” Sci. Transl. Med., vol. 7, no. 303, pp. 1–13, 2015, doi: 10.1126/scitranslmed.aac5415.

[31] S. Mehdizadeh, H. Bayatipoor, S. Pashangzadeh, R. Jafarpour, Z. Shojaei, and M. Motallebnezhad, “Immune checkpoints and cancer development: Therapeutic implications and future directions,” Pathol. Res. Pract., vol. 223, no. March, p. 153485, 2021, doi: 10.1016/j.prp.2021.153485.

[32] Z. Yang, Y. Ma, H. Zhao, Y. Yuan, and B. Y. S. Kim, “Nanotechnology platforms for cancer immunotherapy,” Wiley Interdiscip. Rev. Nanomedicine Nanobiotechnology, vol. 12, no. 2, pp. 1–28, 2020, doi: 10.1002/wnan.1590.

[33] A. A. Khorana et al., “Potentially curable pancreatic cancer: American society of clinical oncology clinical practice guideline update,” J. Clin. Oncol., vol. 35, no. 20, pp. 2324–2328, 2017, doi: 10.1200/JCO.2017.72.4948.

[34] J. Kleeff et al., “Pancreatic cancer,” Nat. Rev. Dis. Prim., vol. 2, no. April, pp. 1–23, 2016, doi: 10.1038/nrdp.2016.22.

[35] A. Collins and M. Bloomston, “Diagnosis and management of pancreatic cancer,” Minerva Gastroenterol. Dietol., vol. 55, no. 4, pp. 445–454, 2009.

[36] D. R. Principe, M. Korc, S. D. Kamath, H. G. Munshi, and A. Rana, “Trials and tribulations of pancreatic cancer immunotherapy,” Cancer Lett., vol. 504, no. December 2020, pp. 1–14, 2021, doi: 10.1016/j.canlet.2021.01.031.

[37] G. T. Gibney, L. M. Weiner, and M. B. Atkins, “Predictive biomarkers for checkpoint inhibitor-based immunotherapy,” Lancet Oncol., vol. 17, no. 12, pp. e542–e551, 2016, doi: 10.1016/S1470-2045(16)30406-5.

[38] E. B. Garon et al., “Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer,” N. Engl. J. Med., vol. 372, no. 21, pp. 2018–2028, 2015, doi: 10.1056/nejmoa1501824.

[39] C. Robert et al., “Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma,” N. Engl. J. Med., vol. 364, no. 26, pp. 2517–2526, 2011, doi: 10.1056/nejmoa1104621.

[40] S. C. Wei, C. R. Duffy, and J. P. Allison, “Fundamental mechanisms of immune checkpoint blockade therapy,” Cancer Discov., vol. 8, no. 9, pp. 1069–1086, 2018, doi: 10.1158/2159-8290.CD-18-0367.

[41] E. M. O’Reilly et al., “Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial,” JAMA Oncol., vol. 5, no. 10, pp. 1431–1438, 2019, doi: 10.1001/jamaoncol.2019.1588.

[42] J. R. Brahmer et al., “Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer,” N. Engl. J. Med., vol. 366, no. 26, pp. 2455–2465, 2012, doi: 10.1056/nejmoa1200694.

[43] R. Dolcetti, V. De Re, and V. Canzonieri, “Immunotherapy for gastric cancer: Time for a personalized approach?,” Int. J. Mol. Sci., vol. 19, no. 6, pp. 1–24, 2018, doi: 10.3390/ijms19061602.

[44] Zweier, “基因的改变NIH Public Access,” Bone, vol. 23, no. 1, pp. 1–7, 2014, [Online]. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624763/pdf/nihms412728.pdf.

[45] K. Kono et al., “Prognostic significance of adoptive immunotherapy in patients with advanced gastric cancer: A randomized trial,” Biotherapy, vol. 17, no. 1, pp. 15–19, 2003.

[46] X. Gao et al., “Cytokine-Induced killer cells as pharmacological tools for cancer immunotherapy,” Front. Immunol., vol. 8, JETIR2106809 Journal of Emerging Technologies and Innovative Research (JETIR) www.jetir.org f775

no. JUL, 2017, doi: 10.3389/fimmu.2017.00774.

[47] A. R. Elia et al., “Cytokine-induced killer cells engineered with exogenous t-cell receptors directed against melanoma antigens: Enhanced efficacy of effector cells endowed with a double mechanism of tumor recognition,” Hum. Gene Ther., vol. 26, no. 4, pp. 220–231, 2015, doi: 10.1089/hum.2014.112.

[48] C. Zanon et al., “Multivariate statistical data analysis as a tool to analyze ex vivo expansion dynamics of cytokine-induced killer cells,” Cytom. Part B - Clin. Cytom., vol. 86, no. 4, pp. 257–262, 2014, doi: 10.1002/cyto.b.21124.

[49] S. Kuçi et al., “Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: Implications for adoptive immunotherapy after allogeneic stem cell transplantation,” Haematologica, vol. 95, no. 9, pp. 1579–1586, 2010, doi: 10.3324/haematol.2009.019885.

[50] J. Jiang et al., “Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells,” Anticancer Res., vol. 26, no. 3 B, pp. 2237–2242, 2006.

[51] L. Zhang, G. Zhao, Y. Hou, J. Zhang, J. Hu, and K. Zhang, “The experimental study on the treatment of cytokine-induced killer cells combined with EGFR monoclonal antibody against gastric cancer,” Cancer Biother. Radiopharm., vol. 29, no. 3, pp. 99–107, 2014, doi: 10.1089/cbr.2012.1381.

[52] J. Xie, L. Fu, and L. Jin, “Immunotherapy of gastric cancer: Past, future perspective and challenges,” Pathol. Res. Pract., vol. 218, no. August 2020, p. 153322, 2021, doi: 10.1016/j.prp.2020.153322.

[53] K. Kono et al., “Identification of HER2/neu-derived peptide epitopes recognized by gastric cancer-specific cytotoxic T lymphocytes,” Int. J. Cancer, vol. 78, no. 2, pp. 202–208, 1998, doi: 10.1002/(SICI)1097-0215(19981005)78:2<202::AID- IJC14>3.0.CO;2-C.

[54] F. Tanaka et al., “Induction of antitumor cytotoxic T lymphocytes with a MAGE-3-encoded synthetic peptide presented by human leukocytes antigen-A24,” Cancer Res., vol. 57, no. 20, pp. 4465–4468, 1997.

[55] J. Herman et al., “A peptide encoded by the human MAGE3 gene and presented by HLA-B44 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE3,” Immunogenetics, vol. 43, no. 6, pp. 377–383, 1996, doi: 10.1007/BF02199806.

[56] T. Masuzawa et al., “Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer,” Int. J. Oncol., vol. 41, no. 4, pp. 1297–1304, 2012, doi: 10.3892/ijo.2012.1573.

[57] J. A. Ajani et al., “An open-label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5- fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer: The GC4 study,” Cancer, vol. 106, no. 9, pp. 1908–1916, 2006, doi: 10.1002/cncr.21814.

[58] A. S. Shirali et al., “It’s not a mystery, it’s in the history: Multidisciplinary management of multiple endocrine neoplasia type 1,” CA. Cancer J. Clin., vol. 0, no. 0, pp. 1–12, 2021, doi: 10.3322/caac.21673.

[59] C, “Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients,” Proc. Natl. Acad. Sci. U. S. A., vol. 100, no. 8, pp. 4712–4717, 2003, doi: 10.1073/pnas.0830997100.

[60] F. S. Hodi et al., “Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients,” Proc. Natl. Acad. Sci. U. S. A., vol. 105, no. 8, pp. 3005–3010, 2008, doi: 10.1073/pnas.0712237105.

[61] M. L. Disis et al., “Efficacy and Safety of Avelumab for Patients with Recurrent or Refractory Ovarian Cancer: Phase 1b Results from the JAVELIN Solid Tumor Trial,” JAMA Oncol., vol. 5, no. 3, pp. 393–401, 2019, doi: 10.1001/jamaoncol.2018.6258.

[62] E. Ghisoni, M. Imbimbo, S. Zimmermann, and G. Valabrega, “Ovarian cancer immunotherapy: Turning up the heat,” Int. J. Mol. Sci., vol. 20, no. 12, pp. 1–16, 2019, doi: 10.3390/ijms20122927.

[63] J. Hamanishi et al., “Safety and antitumor activity of Anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer,” J. Clin. Oncol., vol. 33, no. 34, pp. 4015–4022, 2015, doi: 10.1200/JCO.2015.62.3397.

[64] J. F. Liu et al., “Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers,” Gynecol. Oncol., vol. 154, no. 2, pp. 314–322, 2019, doi: 10.1016/j.ygyno.2019.05.021.

JETIR2106809 Journal of Emerging Technologies and Innovative Research (JETIR) www.jetir.org f776

[65] P. Sabbatini et al., “Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: A phase III trial of the AGO OVAR, COGI, GINECO, and GEICO-the MIMOSA study,” J. Clin. Oncol., vol. 31, no. 12, pp. 1554–1561, 2013, doi: 10.1200/JCO.2012.46.4057.

[66] A. Buzzonetti, M. Fossati, V. Catzola, G. Scambia, A. Fattorossi, and A. Battaglia, “Immunological response induced by abagovomab as a maintenance therapy in patients with epithelial ovarian cancer: relationship with survival—a substudy of the MIMOSA trial,” Cancer Immunol. Immunother., vol. 63, no. 10, pp. 1037–1045, 2014, doi: 10.1007/s00262-014-1569- 0.

[67] A. Battaglia, M. Fossati, A. Buzzonetti, G. Scambia, and A. Fattorossi, “A robust immune system conditions the response to abagovomab (anti-idiotypic monoclonal antibody mimicking the CA125 protein) vaccination in ovarian cancer patients,” Immunol. Lett., vol. 191, no. September, pp. 35–39, 2017, doi: 10.1016/j.imlet.2017.09.006.

JETIR2106809 Journal of Emerging Technologies and Innovative Research (JETIR) www.jetir.org f777