1. Introduction

The pancreas is an organ located in the abdomen having both exocrine and endocrine functions. It plays an essential role in the digestion of food by releasing enzymes from its exocrine part, maintains blood glucose level by producing two major hormones: glucagon and insulin secreted from the endocrinal region of the pancreas. Normal healthy cells become cancerous when a series of changes take place in the DNA sequence, leads the cell to divide uncontrollably and migrate to adjacent cells. Cancer is the second leading cause of death worldwide and was accountable for an estimated 9.6 million deaths in 2018 (World Health Organization (WHO), 2018). It is the major public health issue and the main cause of death in Korea [1], second leading in the United States [2], and one of the leading causes of death in India [3]. One of the leading causes of cancer mortality and the most deadly malignant neoplasm is pancreatic cancer [4]. In 2012, around 338,000 individuals had pancreatic cancer worldwide, making it the eleventh most prevalent cancer. Around 458,918 new pancreatic cancer cases were identified worldwide in 2018, representing 2.5% of all cancers [5]. The American Cancer Society estimated about 57,600 new cases (30,400 male and 27,200 female) of pancreatic cancer and predicted that 47,050 patients (24,640 male and 22,410 female) will die of pancreatic cancer in 2020 [2]. In 2019, pancreatic cancer was the fourth leading cause of cancer deaths. It has been projected to become the second leading cause by 2030 ^[6][7][6,7].

Pancreatic cancer arises when cells in the pancreas start to divide uncontrollably and form a mass. There are different types of cancer cells based on their origin, for example, carcinoma (cancer of epithelial cells), sarcoma (cancer of mesenchymal cells in blood vessels, muscles, and other tissues), myeloma/leukemia/lymphoma (blood cell-related cancer), and adenocarcinoma (cancer of mucus-producing glandular cells). Two main subtypes of pancreatic cancer have been narrowly classified into exocrine and endocrine. Pancreatic ductal adenocarcinoma (PDAC) is an exocrine cell tumor mainly of the ductal cells, more common (>85%) than endocrine cell tumors (<5%) [8]. About 50% of PDACs are detected when the tumor is locally invasive or metastatic. PDAC has a 5-year survival rate of 6% (ranges from 2% to 10%) ^[6][9][6,9]. Exocrine cancer is the most common form of pancreatic cancer, which comprises 95% of all pancreatic cancers ^[10][11][10,11]. Out of all exocrine cancers, the most common and aggressive form is ductal cancer, i.e., PDAC. It is one of the most malignant tumors, characterized by uncontrollable growth [9]. Approximately 85% to 90% of pancreatic cancers are PDAC [11]. Recently, researchers have reviewed the current therapeutic options, dysregulated pathways, tumor microenvironment, and many other factors associated with PDAC ^[6][12][6,12]. Approximately 60% to 70% of cases emerge from the head of the pancreas, which comprises the bile duct; these cases are typically diagnosed earlier than body and tail tumors [13]. Tail and body tumors are linked with a poorer prognosis [14]. In patients with PDAC, the most common symptoms are abdominal pain, weight loss, and jaundice [15], whereas the new onset of type 2 diabetes is a less common symptom [16].

Additionally, studies have shown that PDAC and diabetes are co-related; at the time of cancer diagnosis, one- to two-thirds of patients with PDAC are diabetic [17]. The key concern is whether the growth of cancer is susceptible to diabetes or the consequence of the tumor is diabetes. The five leading behavioral and dietary risks, such as high body mass index, low consumption of fruit and vegetables, physical inactivity, alcohol, and tobacco, are responsible for about one-third of cancer deaths [4]. About 8% of pancreatic cancers occur in families who carry mutations in tumor suppressor genes, including P16Ink4a/CDKN2A, BRCA2, MLH1, MSH2, STK1, or VHL [18]. In 95% of PDAC cases, activating mutations in the KRAS oncogene are detected, but agents that can successfully target this high prevalence change in PDAC are not yet available. Available traditional strategies: surgery, radiation, and chemotherapy have been widely used, but no significant improvements have been shown. Overall survival remains poor for metastatic cancer, with less than 20% of patients surviving after the end of the first year [19]. For the better treatment of PDAC, alternative treatment approaches are desperately needed. Furthermore, stem cell therapy, which has shown therapeutic efficacy for solid tumors (breast, prostate, and lung carcinomas), can be one of the best options to treat PDAC [20].

2. Immunotherapy for Pancreatic Cancer

Several targeted strategies, including new stromal modulation, immunotherapeutic approaches, and targeting main signaling pathway effectors, are in progress, along with the development of novel cytotoxic therapeutic strategies. The stroma encompasses approximately 90% of the tumor mass, which promotes the progression of fibrosis and immunosuppression ^[21][169]. In addition to facilitating tumor development, the PDAC stroma has been shown to attenuate the delivery of antitumor treatments, inactivation of cytotoxic CD8⁺ T cells, and increasing the number of immunosuppressive cells ^[22][23][170,171]. During the progression of the disease, the number of pancreatic stellate cells and PDAC specific cancer associated fibroblasts increase abundantly ^[24][172]. These activated stellate cells promote tumor growth by reducing the migration of CD8⁺ T cells to juxtatumoral stromal compartments ^[25][173]. Stellate cells also stimulate T cell anergy and apoptosis induced by galectin-1, resulting in evasion of immune surveillance by the cancer cells ^[25][26][173,174].

Furthermore, B lymphocytes contribute actively to PDAC fibrogenesis by activation and differentiation of cancer associated fibroblasts ^[27][175]. Minici et al. reviewed the immunological mechanisms that promote and inhibit the anti-tumor immunity of B cells. B cells can restrict tumor growth through phagocytosis by macrophages, facilitating tumor killing by NK cells, generating tumor-reactive antibodies, and the priming of CD4⁺ and CD8⁺ T cells ^[28][176]. B cells can facilitate tumor growth through the production of autoantibodies and tumor growth factors ^[28][176]. Further, targeting particular B cell subtypes can be beneficial for the treatment of cancer as the activities of Th1, and CD8⁺ cytolytic T cells can be directly and indirectly inhibited by regulatory B cells.

Presently, many clinical trials are trying to evaluate the efficiency of immunotherapeutic approaches in PDAC, including cancer vaccination ^[29][177], immune checkpoint inhibitors ^[30][178], monoclonal antibodies, adoptive cell transfer ^[31][179], chemo-radiotherapy or other molecularly focused agents, and combinations with other immunotherapeutic agents or immune modulators, though none of these studies have demonstrated improvements in practice. Activating a patient′s T cells is the key basis of cancer immunotherapy in order to destroy tumor cells. Furthermore, important steps of immunotherapy are defined as follows: reduction in tumor-specific cells presenting antigen, T cell activation, T cells infiltration into tumors, cancer cell recognition by T cells, and cancer cell elimination ^[32][180]. Anti-CTLA-4 (Ipilimumab) and anti-PD-1/anti-PDL-1 (Nivolumab/Pembrolizumab) agents have shown promising results in the activation of T cells and offer an efficient tumor immunotherapy strategy ^[33][181]. Despite showing Powerful outcomes of some malignancies, most of them in phase I and II clinical studies have not shown any clinical effectiveness in PDAC ^[34][182]. The immunosuppressive activity of CTL-4 results in the reduction of T effector cell activation and elevation in the activity of T regulatory cells ^[35][183]. The programmed cell death protein 1 (PD-1) is present largely on T cells, tumor cells, and tumor infiltrating lymphocytes ^[28][6]. The binding of PD-1 (Programmed death-ligand, PDL-1/PDL-2) leads to a reduction in T cell proliferation and secretion of antitumor cytokines ^[28][6].

A varied range of clinical trials (Table 1Table 3) on pancreatic cancer based on cytotoxic chemotherapy, vaccine-associated checkpoint inhibitors, immune checkpoint monotherapy, dual checkpoint combination therapy, and using other inhibitory agents have been completed or are presently ongoing. These clinical trials followed several therapeutic techniques:

Table 13. Clinical trials of novel agents for PDAC and other pancreatic cancers.

• Monotherapy includes the administration of several PD-1(MEDI4736, MPDL3280A, and pembrolizumab,) and CTL-4 (tremelimumab and ipilimumab) inhibitors and inhibition of double checkpoints: either by a combination of the above mentioned inhibitors or with other agents, such as anti-CCR-5 (mogamulizumab) ^[36][184].
• Combination of chemotherapeutic agents and immune checkpoint inhibitors: PD-1/CTL4 inhibitors leads to the activation of T cell that is efficient for immunotherapy. When PD-1/CTL4 inhibitors combined with commonly used chemotherapeutic agents such as Nab-paclitaxel, gemcitabine, carboplatin, and FOLFOX improved overall survival ^[37][47]. Remarkably, therapeutic procedures using a combination of immune checkpoint inhibitors with radiotherapy or chemotherapy have shown significant outcomes ^[38][39][185,186].
• Vaccination therapy is founded on the basis of the distribution of tumor antigens to antigen presenting cells (APCs), followed by induction of an organized immune response. Cancer specific DNA mutations produce new antigens, which, in turn, results in a unique sequence of the peptide. Variety of vaccines for pancreatic cancer treatment includes whole-cell vaccines, dendritic-cell based vaccines, peptide and DNA vaccines, telomerase peptide vaccines, Ras peptide vaccines, and survivin-targeted vaccines ^[40][187]; however, regardless of the enhanced immune system, showed poor clinical results. GVAX is an allogeneic irradiated whole-cell tumor vaccine genetically modified for the secretion of granulocyte macrophage colony stimulating factor and promotes cytolytic action against tumors, the most widely studied vaccine for pancreatic cancer ^[41][188]. Furthermore, the clinical studies when GVAX is applied in combination with 5-Fluorouracil/cyclophosphamide based chemotherapy have shown the same results regarding disease-free and median survival as that of GVAX applied alone ^[42][189]. On the other hand, when the above mentioned ipilimumab (immune checkpoint inhibitor) is applied in combination with GVAX, it leads to better survival ^[43][190].
• Adoptive T cell immunotherapy is based on the modification of autologous T cells, which stimulates the immune response against the tumor. The patients receiving mesothelin-targeting chimeric antigen receptor-T (CAR) cells have shown overexpression of a membrane antigen in pancreatic cancer, exhibited adequate patience but unsuccessful in showing good results ^[44][191]. Along with mesothelin, other cancer-associated antigens are being studied alone or in combination with chemotherapy as potential targets of CAR-T cells based therapy ^[44][191].
• Immune modulating agents that target the microenvironment of the pancreas can also exert extensive antitumor activity. Anti-CD40 agonistic antibodies used in combination with gemcitabine in PDAC patients showed significant results ^[45][192]. PDAC patients treated with a CCR2 inhibitor (PF-04136309) exhibited fractional response and constant tumor when used in combination with FOLFIRINOX ^[46][193]. Several chemokine receptor molecules are under examination in clinical trials against PDAC.