Targeted therapy

Targeted therapy is a type of precise cancer treatment that targets mutated proteins which control the growth, division and metastasis of tumour in tumour cells but not in normal cells. It has rare side effects and is widely utilised and effective in many types of solid tumours (Ref. Reference Stella24). The Know Your Tumour programme revealed that about 25% of the pancreatic ductal adenocarcinoma (PDAC) profiles harboured actionable molecular alterations, and matched targeted therapy for these patients substantially improved their overall survival (OS) (Ref. Reference Pishvaian25). In this part, we reviewed the selected molecular targets of pancreatic cancer in clinical trials and summarised them in Table 1. The targets discussed here include epidermal growth factor receptors (EGFR), poly ADP-ribose polymerase (PARP), Kristen rat sarcoma viral oncogene (KRAS) G12C mutation, RAS-RAF-MEK-ERK (MAPK) pathway, human epidermal growth factor receptor-2 (HER2) signalling pathway and histone deacetylase (HDAC) (Refs Reference Zhu26, Reference Verma27).

Table 1.

Clinical trials of molecular targets of pancreatic cancer

EGFR inhibitors

EGFR is a large transmembrane glycoprotein with ligand-induced tyrosine kinase activity. Once epidermal growth factor (EGF) is bound to EGFR, EGFR can activate a number of downstream signalling cascades, resulting in cell division and proliferation. Overexpression and constitutive activation of EGFR family members are recognised in various cancers, including PDAC. Clinical effective drugs against EGFR can be divided into two categories: one is EGFR extracellular domain monoclonal antibody, which can block the binding of ligand to receptor; the other is small molecules of tyrosine kinase inhibitor (TKI) that block the interaction of EGFR with ATP by competitive binding to the phosphorylation site of tyrosine kinase in EGFR, thereby inhibiting tyrosine phosphorylation and downstream signal transduction of EGFR (Ref. Reference Wang28). In recent years, the development of small molecules of TKI has become a research hotspot for pancreatic cancer treatment (Ref. Reference Yoshida29). Special emphasis is placed here on preclinical/clinical studies of the latest discoveries of monoclonal antibodies and TKIs.

Monoclonal antibody inhibitors include cetuximab, panitumumab and nimotuzumab (Ref. Reference Patel30). Cetuximab combined with irinotecan has been widely used in the treatment of metastatic rectal cancer with irinotecan failure (Ref. Reference Gollins31). Gemcitabine and cetuximab combined with radiotherapy have a certain efficacy in the treatment of locally advanced pancreatic head cancer, significantly improving the clinical symptoms of the patients, and both toxic and side effects can be tolerated. Cetuximab combined with other traditional chemotherapy drugs is in clinical trials (Ref. Reference Fung32).

There are several generations of small molecular TKIs. The first generation of EGFR-TKIs that are used in clinical includes erlotinib, gefitinib and alectinib. They are reversible EGFR-TKIs and firstly utilised in advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitive mutations. In November 2005, the FDA approved that erlotinib combined with gemcitabine can be used to treat patients with locally advanced, unresectable, or metastatic pancreatic cancer (Ref. Reference Takeda33). However, after 10–12 months of treatment with these first-generation TKIs, a secondary T790 M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. So the second generation of irreversible EGFR inhibitors (afatinib and dacomitinib) was developed to overcome T790 M mutation (Ref. Reference Forster34). Afatinib combined with selumetinib had launched phase I clinical trial in patients with KRAS-mutated colorectal, NSCLC and pancreatic cancer, but the clinical efficacy was limited (Ref. Reference van Brummelen35). Afatinib plus gemcitabine launched phase II clinical trial in metastatic pancreatic cancer, but this combination did not improve treatment efficacy and was more toxic than gemcitabine alone (Ref. Reference Haas36). The serious adverse events were caused by lack of selectivity towards wild-type EGFR. The third generation of irreversible EGFR TKIs (osimertinib and lazertinib) are selective towards driving mutations and the T790 M mutation, while sparing wild type EGFR activity (Ref. Reference Jia37). The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, such as C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors (Ref. Reference Wang38). Based on this urgent medical need, the fourth generation EGFR TKIs, such as EAI045 that can overcome T790 M and C797S mutations was developed (Ref. Reference Wang, Song and Liu39). But its utilisation in treating pancreatic cancer still needs further investigation.

PARP inhibitors

PARP, a post-translational modifying enzyme, is widely expressed in most eukaryotic cells. It can recognise DNA fragments with structural damage and is the receptor of DNA damage (Ref. Reference Gibbs-Seymour40). It also can perform polyadenosine, diphosphate and ribosylation on many nuclear proteins. Through ADP ribosylation of histones, histones can be detached from DNA, which is helpful to repair DNA damage. At the same time, PARP is the cleavage substrate of caspase. Therefore, it plays an important role in DNA damage repair and cell apoptosis (Ref. Reference McCann and Hurvitz41).

PARP inhibitors can enhance the efficacy of radiotherapy, alkylating agents and platinum-based chemotherapy by inhibiting DNA damage repair and promoting apoptosis of tumour cells (Ref. Reference Min42). Previous phase III clinical data from the American Society of Clinical Oncology (ASCO) reported the PARP inhibitor Olaparib significantly improved progression-free survival (PFS) in metastatic pancreatic cancer patients with BRCA1/2 embryonic mutant compared to placebo; the median PFS for Olaparib was 7.4 months compared with 3.8 months for placebo, nearly doubling (Ref. Reference Golan43). The mechanism of Olaparib effective for treating BRCA-mutated pancreatic cancer is that BRCA genes code for proteins that are involved in homologous recombination repair of DNA double-strand breaks. PARP inhibition prevents the repair of single-strand breaks and leads to a generation of double-strand breaks in replicating cells, which cannot be repaired accurately in tumours with defects in BRCA. Thus, PARP inhibitors cause an accumulation of DNA damage and tumour-cell death. The National Comprehensive Cancer Network (NCCN) pancreatic cancer 2019 guidelines were updated to include Olaparib, the PARP inhibitor, in the first-line treatment regimen for pancreatic cancer as maintenance therapy (Ref. Reference Le and Gelmon44). Olaparib maintenance therapy can significantly prolong the PFS of advanced pancreatic cancer patients with BRCA gene mutation after platinum-based first-line chemotherapy (Ref. Reference Golan45). More importantly, this maintenance treatment did not reduce the life quality of patients. These results open the era of targeted therapy for patients with advanced pancreatic cancer, and bring new hope for patients with BRCA gene mutation (Ref. Reference Golan43).

KRAS mutation inhibitor

KRAS is a mouse sarcoma virus oncogene in the RAS family. There are three kinds of human tumour-related genes in this family-HRAS, KRAS and NRAS, which are localised on chromosome 11, 12 and 1, respectively. KRAS is also known as p21 because it encodes the 21kD RAS protein that is involved in intracellular signal transmission (Ref. Reference Zinatizadeh46). Wild type KRAS controls pathways that regulate cell growth while mutated KRAS is permanently activated and causes intracellular signal transduction disorder and tumorigenesis (Ref. Reference Janssen47). KRAS mutations are one of the initial drivers in tumorigenesis. Mutations in KRAS produce a chain reaction of more than six signalling pathways. Patients who exhibit this mutation often have a poor prognosis and are resistant to standard care. According to statistics, KRAS gene mutation appears in about 90% of pancreatic cancers (Ref. Reference Li48).

Although researchers have identified KRAS as an important therapeutic target of cancer for decades, it has long been considered as an ‘indestructible’ protein (Ref. Reference Herbst and Schlessinger49). This is because of the difficulty to develop a drug that can bind and impair its function. There are many different types of KRAS mutation and G12C mutation is a very common mutation in NSCLC, colorectal adenocarcinoma and pancreatic cancer. After three decades of research, AMG 510 as the first KRAS^G12C inhibitor, was reached to the clinical stage in 2019 (Ref. Reference Canon50). It makes the ‘untreatable’ KRAS a thing of the past. The first clinical trial of AMG510 showed preliminary safety, tolerability and antitumour activity to KRAS mutant solid tumours (Ref. Reference Hong51). The FDA has approved AMG510 as an orphan drug for use in KRAS^G12C-positive NSCLC and colorectal cancer (Ref. Reference Blair52). MRTX849, another potent and specific inhibitor of KRAS^G12C, was reported to cause marked tumour regressions in 65% of pancreatic cancer cell lines (Ref. Reference Hallin53). Following antitumour activity in mouse models, the drug was used to treat two patients with metastatic PDAC that refractory to multiple lines of therapy. After three cycles of therapy, both patients experienced a partial response with >33% tumour regression (Ref. Reference Singh and O'Reilly54).

RAS-RAF-MEK-ERK (MAPK)inhibitors

Genetic alterations of the MAPK signalling pathway yield constitutive activation of the ERK cascade that have been implicated as drivers of PDAC. As we introduced in the previous part, KRAS mutations were found in about 90% of PDAC. B-RAF, one of the three subtypes of the RAF-protein family of the serine-threonine kinase (A-RAF, C-RAF/ RAF-1), is the most common mutant type of RAF protein, which is commonly found in melanoma, thyroid cancer and colorectal adenocarcinoma. RAF further activates MEK, and although MEK1/2 does not have mutations as common as B-RAF and RAS, its downstream location of RAS and RAF makes it an ideal therapeutic target. Previous researches reported that MEK inhibitor (trametinib) in combination with gemcitabine can regress patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model (Ref. Reference Kawaguchi55). MEK inhibitor combined with HDAC inhibitor MPToE028 can benefit patients with pancreatic cancer beyond KRAS status (Ref. Reference Chao56). ERK inhibitors also showed effective treatment for pancreatic cancer. Researchers found that combinations of pharmacologic inhibitors that concurrently block both ERK and autophagic processes benefit pancreatic cancer patients (Ref. Reference Bryant57).

HER2 monoclonal antibody

HER2 protein is a transmembrane protein with tyrosine-protein kinase activity and belongs to the EGFR family. The tumourigenic mechanism of HER2 oncogene is to inhibit apoptosis, promote proliferation, increase the invasiveness of tumour cells, and promote tumour angiogenesis and lymph angiogenesis (Ref. Reference Foster58). Partial of pancreatic cancer patients overexpress HER2. Trastuzumab, a monoclonal antibody against HER2, blocks the growth of cancer cells by attaching to HER2 to prevent the binding of EGF. At present, it is mainly utilised in metastatic breast cancer with HER2 overexpression. For treating pancreatic cancer, a multicentre phase II clinical trial showed that the median OS of pancreatic cancer patients receiving trastuzumab combined with capecitabine was 6.9 months, which is similar to capecitabine monotherapy (6.0 months) (Ref. Reference Harder59). Trastuzumab cannot cause significant benefits in the survival of pancreatic cancer patients. The failure of the HER2 antibody in this trial may be because of considerable heterogeneous expression of HER2 and the dearth of gene amplification even in HER2 positive pancreatic tumour cells in recruited patients. But another recent multicentre phase II clinical trial showed that combining trastuzumab with gemcitabine and erlotinib is effective in terms of disease control rate, PFS and OS of metastatic pancreatic cancer patients (Ref. Reference Assenat60).

VEGFR2 inhibitors

Tumour angiogenesis is an important process for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1,2,3) regulate the proliferation and migration of endothelial cells. VEGFRs are highly expressed in different types of tumours (Ref. Reference Itatani61). VEGFR2 is persistently overexpressed in pancreatic cancer cells and its phosphorylation is considered to be a major driver of angiogenesis in pancreatic cancer (Ref. Reference Lian62).

Inhibiting this process is one of the main mechanisms to treat pancreatic cancer. Antibodies and small molecules that bind to VEGF or interfere with different VEGFR domains can block the VEGF signalling pathway. Several small-molecule inhibitors of VEGFR2 have been developed and most of them are multi-target inhibitors. SKLB261, a multi-kinase inhibitor potently inhibiting EGFR, Src and VEGFR2 kinases can inhibit cell proliferation, migration, invasion and induce apoptosis of human pancreatic cancer cells in vitro and in mouse models (Ref. Reference Pan63). There are also antibodies that target the VEGF/VEGFR2 pathway: Ramucizumab, an antibody of VEGFR2, specifically recognises and attaches to VEGFR2 and completely inhibits the VEGFR2 activation mediated by different ligands, including VEGF-A, VEGF-C and VEGF-D. Bevacizumab, an anti-VEGF-A antibody, can inhibit the VEGF/VEGFR2 pathway (Ref. Reference Gao and Yang64). Both of them have been approved by FDA for the treatment of several types of cancer, but not pancreatic cancer (Ref. Reference Gao and Yang64). However, there were clinical trials of bevacizumab on pancreatic cancer. A phase I /II clinical trial showed that bevacizumab combined with capecitabine-based radiation was safe for locally advanced pancreatic cancer patients and the PFS was 8.6 months, the response rate (RR) was 26% (Refs Reference Crane65, Reference Crane66). Two studies using bevacizumab plus gemcitabine or/and cisplatin to treat metastatic pancreatic cancer patients and found modest efficacy (Refs Reference Kindler67, Reference Ko68). A phase II clinical trial using bevacizumab with gemcitabine and oxaliplatin (GEMOX) to treat metastatic or locally advanced pancreatic cancer patients (Ref. Reference Fogelman69). The median OS in this regimen was 11.9 months, with 12.8 months for locally advanced patients and 10.2 months for metastatic patients. The efficacy result was excellent but the toxicity was significant, so researchers did not recommend further evaluation of this regimen. Although inhibiting the VEGF pathway showed benefits to pancreatic cancer patients, there is evidence suggest that, in the context of VEGF blockade, angiogenic signalling can be mediated by other tyrosine kinase signalling cascades, notably EGFR (Ref. Reference Tortora, Ciardiello and Gasparini70). Therefore, a phase I/II clinical study inhibited both VEGF and EGFR pathway through using the combination of gemcitabine, capecitabine, erlotinib and bevacizumab to treat advanced pancreatic adenocarcinoma patients, this regimen showed a manageable toxicity profile and encouraging efficacy data in a good performance status population (Refs Reference Watkins71, Reference Starling72). Another study assessed the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma and found no promising activity (Ref. Reference Ko73). Therefore, the regimen that targets both VEGF and EGFR should be evaluated further in treating pancreatic cancer.

HDAC inhibitors

HDAC, a histone deacetylase, can deacetylate histones and lead to chromatin condensation and transcriptional silencing (Ref. Reference Seto and Yoshida74). Besides histones, HDAC can also epigenetically regulate other proteins and substrates to impact their biological function (Ref. Reference Delcuve, Khan and Davie75). HDAC inhibitors sustain the relaxation of chromatin and other proteins or substrates to promote the transcription of related RNAs. Through these ways, HDAC inhibitors induce cell cycle arrest, autophagy, apoptosis and differentiation and can be used as anticancer agents (Ref. Reference Mottamal76). Based on chemical properties, HDAC inhibitors are divided into different classes: hydroxamic acids, such as suberoylanilide hydroxamic acid (SAHA or vorinostat), trichostatin A (TSA), LBH589 (panobinostat) and PXD101 (belinostat); short-chain fatty acids, such as sodium butyrate (NaBu), 4-phenylbutyrate (4-PB) and valproic acid; cyclic tetrapeptides, such as trapoxin, apicidin and depsipeptide, also known as FK228 or romidepsin; benzamides, such as MS-275, CI-994 and MGCD0103, and a variety of other chemical compounds and synthetic inhibitors (Ref. Reference Moertl77).

There are more than 700 clinical trials registered on the web of ClinicalTrials.gov for HDAC inhibitors and almost all of these clinical trials are focused on various types of cancer. SAHA or vorinostat is the first HDAC inhibitor approved by FDA for the treatment of refractory cutaneous T-cell lymphoma (Ref. Reference Marks and Breslow78). For pancreatic cancer, HDAC inhibitor alone didn't show any efficacy. Through combined with other treatments, HDAC inhibitor showed promising results in animal experiments(Ref. Reference Edderkaoui79) and in some of the clinical trials (Refs Reference Ikeda80, Reference Booth, Poklepovic and Dent81). A single-institution phase I trial using the combination of vorinostat and capecitabine with radiation (30Gy in 10 fractions) to treat non-metastatic pancreatic cancer. Researchers found this regimen was well tolerated with encouraging median OS (Ref. Reference Chan82). Although the clinical trials of HDAC inhibitor on pancreatic cancer patients showed efficacy, there are still many uncertainties: the number of patients recruited in clinical trials is rare and there is no phase III clinical trial yet. So the regimen of HDAC inhibitors to treat pancreatic cancer is still need to be investigated and improved.

Immunotherapy

Immunotherapy is the treatment of disease by inducing, enhancing or suppressing an immune response. The goal of cancer immunotherapy is to enhance or restore the immune system's ability to detect and destroy cancer cells by overcoming the mechanisms by which tumours evade and suppress immune responses. Although in recent years, immunotherapy has marked a therapeutic renaissance in many solid tumours, it alone didn't reveal any significant efficacy in pancreatic cancer, one of the most immune-resistant tumour types. But it is still the promise for viable treatment options of pancreatic cancer especially metastatic pancreatic cancer that resists all other therapies. At present, immunotherapy for pancreatic cancer mainly focuses on vaccination, adoptive immunisation and immunological checkpoint blockade. Data from preclinical mouse models and early phase clinical studies offer important insights that combined with other therapy can induce immunoreactions and enhance the efficacy of immunotherapy in pancreatic cancer (Ref. Reference Bear, Vonderheide and O'Hara22). In the following, we introduced these therapies in detail and summarised them in Table 2.

Table 2.

Summary of reported immunotherapy for pancreatic cancer

Vaccine

Vaccines stimulate a patient's immune system with tumour specific antigens and recruit the patient's immune cells to fight cancer. Antigen vaccines and cell vaccines are major parts of tumour vaccines.

Antigen vaccines include neoantigen vaccine and tumour-associated antigen (TAA) vaccine. There are various kinds of neoantigen vaccines, such as peptide vaccine, DNA vaccine, etc. Peptide neoantigen vaccine has been used in clinical trials against pancreatic cancer and shows promise in partial patients (Ref. Reference Chen83). As neoantigens only appear in tumour cells, neoantigen vaccines have the advantage of specificity and minimal toxicity. However, neoantigens vary significantly between patients, so this vaccine should be personalised (Ref. 84). This makes the neoantigen vaccine too laborious and costly to be used by most patients. According to TAA, current vaccine research of pancreatic cancer mainly focuses on mutated RAS peptides (Ref. Reference Moskaluk, Hruban and Kern85), telomerase peptides(Ref. Reference Suehara86) and Mucin 1(MUC1) peptides (Ref. Reference Rong87). KRAS mutations are prevalent in patients with pancreatic cancer. Some patients had detectable immune responses to KRAS mutation through the combined injection of synthetic mutant KRAS peptide and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Refs Reference Weden88–Reference Abou-Alfa90). At the same time, some investigators have loaded mutated KRAS peptides to antigen-presenting cells (APC) to produce individualised vaccines, which also induce specific T cell responses (Refs Reference Gjertsen91–Reference Gjertsen93). Telomerase activity is high in most cancers including pancreatic cancer. Telomerase peptide GV1001 combined with GM-CSF was used to vaccinate patients with pancreatic cancer, and results showed that this vaccine could induce an immune response and prolong patients' OS (Ref. Reference Bernhardt94). MUC1 is widely distributed and abnormally expressed on the surface of cancer cells. In view of this, researchers vaccinated pancreatic cancer patients with MUC1 peptide combined with adjuvant or APC loaded with MUC1 peptide and found that a stable MUC1 antibody response was produced after immunisation (Refs Reference Lepisto95, Reference Yamamoto96).

Cell vaccines for pancreatic cancer include allogenic cell vaccines, autologous cell vaccines and dendritic cell (DC) vaccines. Allogenic pancreatic tumour cell vaccine is the hotspot of cell vaccine. They are produced by one patient's tumour cells and delivered to another patient. Allogeneic whole-cell vaccines for pancreatic cancer can present a large number of TAAs in the appropriate HLA environment and are recognised by the immune system of the host, resulting in an immune response against the host's own tumour cells. However, due to extensive degrees of inter-and intra-tumoural heterogeneity found among patients, clinical trials of allogeneic whole-cell vaccine alone have shown limited success (Ref. Reference Srivatsan97). Combination of this vaccine with other therapies may enhance its efficacy such as the GVAX vaccine, which is an allogenic tumour cell vaccine that secretes GM-CSF. Researchers found that GVAX therapy in combination with chemotherapy drugs or with ipilimumab increased survival and induced an enhanced T-cell specific response in patients with advanced pancreatic cancer (Refs Reference Laheru98–Reference Le101). Nevertheless, the clinical efficacy of GVAX still needs to be validated. In 2015, patients with advanced pancreatic cancer received tumour vaccine Cyclophosphamide (Cy)/GVAX combined with a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) and results showed that the addition of CRS-207 prolonged the median survival of pancreatic cancer patients with limited toxicity (Ref. Reference Le102); In 2019, researchers compared patients treated with tumour vaccine Cy/GVAX followed by CRS-207 with patients treated by single-agent traditional chemotherapy and found no significant difference in survival time between these two groups. This result suggested that the combination of Cy/GVAX and CRS-207 did not improve survival over chemotherapy (Ref. Reference Le103). In order to improve the treatment efficacy of Cy/GVAX and CRS-207 regimens, patients were treated by Cy/GVAX followed by CRS-207 with or without PD1 inhibitor Nivolumab. However, researchers didn't find any difference in OS between these two groups and the OS was comparable with standard chemotherapy (Ref. Reference Tsujikawa104).

In addition, it is well known that pancreatic cancer has a long developmental period. The long tumorigenesis period means they can be prevented in the precancerous stage in populations at risk. Prophylactic vaccines may be a good choice to prevent tumorigenesis. In 2020, a research group reported a personalised prophylactic vaccine against pancreatic cancer. They developed a virus-infected, reprogrammed somatic cell-derived tumour cell (VIReST) vaccine which was produced by combining induced pluripotent stem cell (iPSC) technology with oncolytic virus and found that this vaccine could delay the occurrence and progression of pancreatic cancer in spontaneous pancreatic cancer mice model K-Ras ^G12D; P53 ^R172H; Pdx1-cre(KPC) (Ref. Reference Lu105). The results provide a preventive strategy for people at high risk of pancreatic cancer.

DC vaccine-based immunotherapy also provides clinical benefits for patients with pancreatic cancer. Recently, a clinical study treated pancreatic cancer patients with an injection of lymphokine-activated killer (LAK) alone or combined with DC vaccination. Results showed that DC vaccine therapy can prolong the survival time of pancreatic cancer patients compared with LAK alone therapy (Ref. Reference Nakamura106). Another trial showed that DC immunotherapy combined with chemotherapy is effective in patients with refractory advanced pancreatic cancer (Ref. Reference Kimura107).

Adoptive immunotherapy

Adoptive immunotherapy is the method of transferring immune cells with antitumour activity into patients to mediate tumour regression. The adoptive immune cells were stimulated and expanded by exposing to tumour cells or antigens or by artificial engineering in the laboratory and then were infused into patients. For stimulating T cells by tumour cells or antigens, previous research induced MUC1 peptide-pulsed DC (MUC1-DC) and activated T lymphocytes from the peripheral blood mononuclear cells of patients by MUC1-DC. After that, the stimulated T cells were reinfused into patients, and the symptoms of metastatic patients were relieved (Ref. Reference Kondo108). For artificial engineering, T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T are major parts. There is no report about TCR-T therapy for pancreatic cancer until now. CAR-T cell therapy is very popular and gets great success in lymphomas. Carcinoembryonic antigen (CEA) and MUC1 are overexpressed in membranes of pancreatic cancer cells and were chosen as targets of CAR-T cells (Refs Reference Allum109, Reference Qu110). Pancreatic tumour volume decreased or even disappeared in CAR-T treated group in pancreatic cancer mouse models (Refs Reference Chmielewski111, Reference Posey112). This result suggested that CEA and MUC1 CAR-T cells had strong anti-pancreatic cancer efficacy.

Immune checkpoint inhibitor therapy

Immune checkpoints are regulators of the immune system which prevent the immune system from attacking self-antigens indiscriminately. While it is critical to prevent auto-immune disease, it also causes the immune system to be ineffective in eradicating or suppressing cancer, such as immune checkpoints CTLA-4 and PD-1 play key roles in the ability of tumour cells to evade host immune system (Ref. Reference Disis113). Immune checkpoint inhibitor therapy is a method to target regulatory pathways in T cells to enhance antitumour immune responses. Ipilimumab, which recognises CTLA-4 and blocks its ligand-receptor interaction, has shown efficacy in melanoma (Ref. Reference Weber114). In contrast, the use of ipilimumab in pancreatic cancer is unsatisfactory (Ref. Reference Royal115). While combining tremelimumab which also blocks CTLA-4 binding to its ligands, with gemcitabine revealed a prolonged survival of pancreatic cancer patients (Ref. Reference Aglietta116). The inconsistent effects of immune checkpoint inhibitors in pancreatic cancer patients may be because of the different tumour microenvironments. Tumours sensitive to checkpoint inhibitors therapy have abundant infiltrated CD8⁺ T cells and could be classified as ‘immunoactive’ tumours. While ‘immunoquiescent’ tumours that lack infiltration of effector T cells, are not sensitive to checkpoint inhibitors and fail to eradicate the tumour. Therefore, the success of immune checkpoint inhibitors therapy should only be achieved in immunoactive pancreatic cancer patients, which are a small ratio of the whole patients (Ref. Reference Clark, Beatty and Vonderheide117).

Summary

In order to conquer the big challenge of pancreatic cancer, improving prevention strategies and early detection are very important to benefit the surgical outcomes. At the same time, combination therapy, such as traditional therapy (surgery, radiotherapy or chemotherapy) combined with target therapy and immunotherapy, should also be promising in pancreatic cancer treatment as we summarised from this review (Figure 1). Refining our molecular understanding of pancreatic cancer and identifying more effective personalised systemic therapies will contribute to the success of combination therapy.