Review Open Access
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Oct 15, 2023; 15(10): 1691-1705
Published online Oct 15, 2023. doi: 10.4251/wjgo.v15.i10.1691
Systemic treatment for advanced pancreatic cancer
Wattana Leowattana, Pathomthep Leowattana, Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
Tawithep Leowattana, Department of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
ORCID number: Wattana Leowattana (0000-0003-4257-2480); Tawithep Leowattana (0000-0003-2316-3585).
Author contributions: Leowattana W wrote the paper; Leowattana T and Leowattana P collected the data.
Conflict-of-interest statement: The authors declare no conflicts of interest related to this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wattana Leowattana, BMed, MD, MSc, PhD, Full Professor, Department of Clinical Tropical Medicine, Mahidol University, 420/6 Rajavithi Road, Rachatawee 10400, Bangkok, Thailand. wattana.leo@mahidol.ac.th
Received: July 11, 2023
Peer-review started: July 11, 2023
First decision: August 15, 2023
Revised: August 24, 2023
Accepted: September 22, 2023
Article in press: September 22, 2023
Published online: October 15, 2023

Abstract

Pancreatic cancer is a deadly disease with an extremely poor 5-year survival rate due to treatment resistance and late-stage detection. Despite numerous years of research and pharmaceutical development, these figures have not changed. Treatment options for advanced pancreatic cancer are still limited. This illness is typically detected at a late stage, making curative surgical resection impossible. Chemotherapy is the most commonly utilized technique for treating advanced pancreatic cancer but has poor efficacy. Targeted therapy and immunotherapy have made significant progress in many other cancer types and have been proven to have extremely promising possibilities; these therapies also hold promise for pancreatic cancer. There is an urgent need for research into targeted treatment, immunotherapy, and cancer vaccines. In this review, we emphasize the foundational findings that have fueled the therapeutic strategy for advanced pancreatic cancer. We also address current advancements in targeted therapy, immunotherapy, and cancer vaccines, all of which continue to improve the clinical outcome of advanced pancreatic cancer. We believe that clinical translation of these novel treatments will improve the low survival rate of this deadly disease.

Key Words: Systemic treatment, Advanced pancreatic cancer, Personalized medicine, Biomarkers, Chemotherapy, Targeted therapy, Immunotherapy

Core Tip: Understanding the pathophysiology of pancreatic cancer and using personalized treatments might improve patients' overall survival. We think that targeted treatment, immunotherapy, and cancer vaccines can improve the prognosis of patients with advanced pancreatic cancer. As a result, additional study is required to identify the best combination of current drugs to help in early treatment and result in a better clinical outcome.



INTRODUCTION

It is expected that pancreatic cancer will continue to be the leading cause of cancer-related mortality despite a sharp rise in occurrence over the previous several decades. Many of the observed trends are explained by changes in the identified modifiable risk variables as well as changes in the age structure of the global population, particularly in emerging nations. The chance of developing pancreatic cancer is significantly influenced by genetic factors and modifiable exposures, either acting alone or in concert. In order to limit exposures and identify people most at risk of developing this commonly deadly cancer, preventive initiatives, especially primary prevention techniques, will benefit from an understanding of the underlying risk factors and how they interact. Pancreatic cancer detection rates and the precursor lesions that precede it are increasing. This strategy will assist in lowering the rising prevalence of this deadly disease[1-3]. An overview of the knowledge of known risk factors for pancreatic cancer is given in this review, including inherited genetic risk, lifestyle risk, and risk unique to the disease. In addition, we intend to summarize the most recent guidelines for the systemic treatment of pancreatic cancer. We present the data supporting the recommendations that are currently available, with an emphasis on first-line and second-line situations, based on a thorough evaluation of biomedical and clinical trial databases. Finally, we seek the present state of the art and research paths that can enhance targeted treatment and immunotherapy choices for this high-risk patient population.

EPIDEMIOLOGY AND RISK FACTORS

The frequency of pancreatic cancer diagnoses annually has doubled during the previous two decades. Compared to 196000 cases in 1990, there were 441000 cases of pancreatic cancer in the world in 2017. Given that the risk of developing pancreatic cancer rises with age and that it is uncommon to develop the disease before the age of 40, improved diagnosis techniques and the changing age structure of the global population account for the majority of the rise in pancreatic cancer incidence, especially in high-income countries. Incidence rates in low-income nations have remained low due to limited access to contemporary imaging and a lack of pathology expertise, and there is a dearth of high-quality data on mortality in these regions[4,5]. Obesity, type 2 diabetes, and smoking cigarettes are all modifiable risk factors for the development of pancreatic cancer. A significant National Institutes of Health cohort study found that individuals with a body mass index (BMI) outside the normal range had a higher risk of acquiring this malignancy than those with a BMI within the range, with hazard ratios ranging from 1.15 to 1.53. Pancreatic intraepithelial neoplasia, which is a precursor to pancreatic cancer, has been linked to fatty infiltration of the pancreas. There is a long-standing association between diabetes and the development of pancreatic cancer, with a relative risk (RR) of 2.1, even though cancer of the pancreas is also a risk factor for diabetes development[6-9]. One percent of those with newly diagnosed diabetes over the age of 50 experience diabetes as a result of concurrent pancreatic cancer. Similar to this, those who have had their diabetes diagnosis for less than one year have a greater RR of developing pancreatic cancer of 5.4-fold than those who have had it for a long time, who only have a 1.5-fold higher risk. These findings imply that newly diagnosed diabetes may be a significant risk factor and a sign of pancreatic cancer. Pancreatic cancer is thought to be around twice as common among smokers as in non-smokers, according to estimates; however, unlike other smoking-related malignancies, pancreatic cancer does not yet have a well-defined genetic signature[10,11].

On average, genetic risk factors are thought to be responsible for 5%-10% of all pancreatic malignancies. There are several family cancer syndromes that have been linked to a higher chance of getting pancreatic cancer. A mutation in the tumor suppressor STK11 causes Peutz-Jeghers syndrome, which raises the risk of pancreatic cancer by 35%. The chance of acquiring this kind of cancer is further enhanced by the hereditary breast-ovarian cancer syndrome, which is typically linked to mutations in BRCA1 or BRCA2. Despite the fact that people with a BRCA1 mutation have a relatively low chance of developing the disease—a RR of 2.8 compared with 1.3 in the general population—mutations of BRCA2 are a more common genetic risk factor (RR = 3.5) for pancreatic cancer development[12,13]. An elevated risk of pancreatic cancer of 17% has been attributed to inherited mutations in the CDKN2A gene. An elevated risk of acquiring this kind of cancer is also linked to germline abnormalities in genes necessary for DNA damage response and DNA repair. Patients with Lynch syndrome are more likely than the general population to acquire pancreatic cancer by the time that they are 70 years old, and their tumors show microsatellite instability, making them particularly susceptible to immune checkpoint inhibitor treatment. Patients with hereditary pancreatitis syndromes, which are linked to mutations in SPINK1and PRSS1, have a 40% lifetime chance of getting pancreatic cancer as a result of chronic pancreatitis[14,15].

CLINICAL PRESENTATION

Only a small percentage of patients with pancreatic cancer initially have the illness that can be surgically removed, which is consistent with the fact that pancreatic cancer often causes minimal symptoms prior to progression to the advanced stage. Tragically, individuals who do experience symptoms frequently have vague complaints, such as nausea, bloating, stomach fullness, or changes in stool consistency, which are frequently appropriately ascribed to other benign causes and delay diagnosis and treatment. At the time of diagnosis, stomach discomfort, abnormal liver function tests, jaundice, newly diagnosed diabetes, nausea, vomiting, dyspepsia, weight loss, and back pain are the clinical symptoms that occur most often[16,17]. Approximately 60%-70% of pancreatic tumors are discovered near the head or neck of the organ, and they are more likely to result in biliary blockage and a patient with an identifiable jaundice-free appearance. The range of jaundice's positive predictive value for detecting pancreatic cancer is 4%-13%. Pancreatic body tumors frequently infiltrate nearby vascular systems, such as the portal vein, hepatic, and superior mesenteric veins, and are therefore more likely to manifest with back discomfort. Because they have fewer anatomical neighbors, pancreatic tail tumors frequently have room to develop unchecked and are typically advanced when discovered (Figure 1)[18,19].

Figure 1
Figure 1 The location of a tumor within the pancreas affects a patient's presentation.
ADVANCED PANCREATIC CANCER

TNM staging and clinical categorization, the two separate staging methods, both have prognostic consequences that are helpful for therapeutic suggestions. Patients with borderline resectable and locally advanced pancreatic cancer are grouped together in stage III of the TNM staging system. Most patients with stage I and stage II cancer will fall into the resectable category, although there are a few people with pancreatic cancer that is borderline resectable who may be categorized as stage II, especially when the superior mesenteric or portal vein is involved. As a result, clinical categorization is more beneficial when choosing a course of treatment. Pancreatic cancer is considered advanced when it is unresectable or cannot be removed surgically. The cancer has spread to neighboring lymph nodes or blood vessels, as well as to organs outside the pancreas. Typically, this is stage III or IV. The majority of pancreatic cancer patients are diagnosed with advanced disease. Patients who are detected at an earlier stage of the disease may acquire advanced cancer if it spreads[20].

ADVANCED PANCREATIC CANCER TREATMENTS
Chemotherapy

More than 33% of pancreatic cancer patients have locally progressive disease at the time of diagnosis, frequently as a result of severe vascular involvement that makes surgical resection impossible. The majority of these individuals have incurable illnesses, while a small percentage who have had a great response to treatment could qualify for surgical excision. This patient group is usually given systemic chemotherapy utilizing protocols that have been authorized for use in the context of metastatic disease. Due to a phase 3 trial that demonstrated gemcitabine's therapeutic advantage over fluorouracil, it has been the standard of care for metastatic pancreatic cancer for many years. However, the median survival time was only 5.6 mo, and the response rate (RR) was only 5%[21]. Since then, several trials have been conducted with gemcitabine serving as the main component of doublet or triplet regimens to enhance patients' overall outcomes. The majority of the trials' results were unsatisfactory, with the exception of one that used erlotinib and gemcitabine together. Gemcitabine with erlotinib resulted in a median survival of 6.2 mo in this randomized phase 3 study, as opposed to 5.9 mo in the gemcitabine-only group. Although the difference in 2-wk survival was statistically significant, the increased toxic effects may prevent it from being clinically important[22]. In 2011, Conroy et al[23] conducted a randomized control trial to compare the efficacy and safety of “Folinic acid, fluorouracil, irinotecan, and oxaliplatin” (FOLFIRINOX) with gemcitabine in the first-line treatment of 342 advanced pancreatic cancer patients. The trial lasted 6 mo. In the FOLFIRINOX group, the median overall survival (OS) was 11.1 mo, whereas in the gemcitabine group, it was 6.8 mo. The median progression-free survival (PFS) for the FOLFIRINOX group was 6.4 mo as opposed to 3.3 mo for the gemcitabine group. In comparison to the gemcitabine group, which had a 9.4% objective RR (ORR), the FOLFIRINOX group's ORR was 31.6%. More adverse events were recorded in the FOLFIRINOX group, and 5.4% of the patients in this group experienced febrile neutropenia. In contrast to gemcitabine-treated patients, 31% of FOLFIRINOX-treated patients had a significant deterioration in quality of life at 6 mo. They determined that, as compared to gemcitabine, FOLFIRINOX had a survival benefit but increased toxicity. FOLFIRINOX is a therapy option for people with metastatic pancreatic cancer who have a good performance status. Von Hoff et al[24] conducted a phase 3 study in 861 patients with metastatic pancreatic cancer to compare the effectiveness and safety of a combination regimen (nab-paclitaxel-gemcitabine) with gemcitabine alone in 2013. They found that the median OS was 8.5 mo in the nab-paclitaxel-gemcitabine combination group and 6.7 mo in the gemcitabine alone group. The nab-paclitaxel-gemcitabine group had a survival rate of 35% at one year compared to 22% in the gemcitabine alone group and 9% compared to 4% at two years. In comparison to the gemcitabine alone group, which had a median PFS of 3.7 mo, the nab-paclitaxel-gemcitabine group's PFS was 5.5 mo. They observed that gemcitabine combined with nab-paclitaxel importantly improved RR, OS, and PFS in patients with advanced pancreatic cancer but elevated rates of peripheral neuropathy and myelosuppression. Systemic chemotherapy such as FOLFIRINOX or gemcitabine plus nab-paclitaxel continues to be the principal treatment option for patients who have distant metastases at the time of their diagnosis, with the goals of relieving cancer-related symptoms and extending life. Even though first-line gemcitabine plus nab-paclitaxel and FOLFIRINOX have never been directly compared in a randomized controlled trial, real-world retrospective studies reveal that younger and physically fit participants are more likely to be treated with FOLFIRINOX, which results in a better OS in comparison with gemcitabine combined with nab-paclitaxel. Patients whose performance status or comorbidities prevent combination treatment still have the option of gemcitabine monotherapy[25,26]. If a patient's condition allows for chemotherapy and they have advanced on the first-line treatment with FOLFIRINOX, gemcitabine-based chemotherapy is a suitable second-line therapy[27-29].

Targeted therapy

Conventional therapies are treatments that target multiple biological processes; they are unable to distinguish between oncogenic and normal cells, resulting in unfavorable side effects. As a result, tailored therapies using small molecule inhibitors (SMIs) and monoclonal antibodies (mAbs) are required. These drugs work by targeting tumor cell surface receptors, growth factors, or other proteins that are important in disease development and progression. Targeted treatment refers to medications that suppress tumor cell proliferation by interacting with essential molecules in the cells required for cancer development rather than just interfering with rapidly proliferating cells, as typical chemotherapy does. Many researchers are interested in targeted cancer therapy since it is likely to replace systemic chemotherapy in the future[30,31]. Targeted treatment blocks particular pathways useful in cancer initiation and proliferation, resulting in the inhibition of enzymes as well as growth factor receptors required for the evolution of oncogenic cells. Cancer treatment may be substantially better in the future with tailored therapy, and hair loss, the most common adverse effect of systemic chemotherapy, may be decreased.

SMIs: Small molecules are organic chemicals with a low molecular weight that are designed to penetrate the cell membrane, bind particular targets within the cell, and interfere with signaling cascades. The discovery of SMIs was a major breakthrough in cellular biology research. These compounds enable the investigation of numerous biological pathways in order to enhance patient outcomes. Protein kinases linked to cancer initiation and development are key targets in cancer treatment since many SMIs target these kinases. Different proteins and signaling or receptor pathways connected to cancer cells might cause changes in signal transduction cascades. So far, several SMIs with robust and efficient action have been reported, including proteasome inhibitors, VEGF-inhibiting compounds, immune system-regulating drugs, and histone deacetylase (HDAC) inhibitors[32]. Bortezomib, carfilzomib, and ixazomib are examples of proteasome inhibitors. These inhibitors kill pancreatic cancer cells by inducing apoptosis via endoplasmic reticulum stress; proapoptotic proteins and their anti-apoptotic target genes are upregulated, whereas numerous anti-apoptotic proteins, as well as signal transducers and transcription activators, are suppressed[33,34]. There was only one randomized study to assess the RR of tumor for bortezomib (PS-341) alone vs RR and the survival rate at 6 mo for the combination of bortezomib and gemcitabine in 85 patients with advanced pancreatic cancer. The findings demonstrated that neither bortezomib alone nor in combination with gemcitabine led to an improvement in OS or RR beyond what was anticipated for gemcitabine alone[35]. VEGF-blocking drugs, such as sorafenib and sunitinib, are tyrosine kinase inhibitors used to treat pancreatic cancer. They have two effects: Inhibiting rapidly accelerated fibrosarcoma kinase, which controls cell division and proliferation, as well as the platelet-derived growth factor receptor beta and VEGFR-2 signaling pathways, which block angiogenesis[36] (Figure 2). In a few randomized studies, sorafenib was used to treat advanced pancreatic cancer; however, neither sorafenib alone nor sorafenib in conjunction with gemcitabine showed signs of efficacy that would lead to hope for metastatic pancreatic cancer[37-39]. Sunitinib malate capsules were given Food Drug Administration approval on May 20, 2011, to treat patients with locally progressed or metastatic pancreatic neuroendocrine tumors that are unresectable. One hundred and seventy-one participants were randomly assigned to receive sunitinib (37.5 mg) or a placebo once daily in a phase 3 randomized study. The primary effective outcome was PFS time. OS time, ORR, patient-reported outcomes, and safety were considered secondary goals. For the sunitinib and placebo groups, the median PFS was 10.2 mo and 5.4 mo, respectively. In the sunitinib and placebo groups, the ORRs were 9.3% and 0%, respectively. The OS data lacked maturity[40]. Belinostat, vorinostat, and romidepsin are examples of HDAC inhibitors. They cause cell growth inhibition and apoptosis[41,42]. There has not yet been a randomized control study to assess HDAC inhibitors in advanced pancreatic cancer. SMIs have several advantages over chemotherapeutic drugs and RNA interference agents, including the ability to perform a wide range of in vivo assays using different temporal and titration designs, which result in higher penetration in isolation and are useful for testing the combined effects with existing antitumor drugs.

Figure 2
Figure 2 Targeted therapies used in systemic treatment of advanced pancreatic cancers. AKT: Protein kinase B; VEGFR: Vascular epidermal growth factor receptor; ERK: Extracellular signal-related kinase; FGFR: Fibroblast growth factor receptor; GTP: Guanosine triphosphate; MEK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin; NTRK: Neurotrophic tyrosine receptor kinase; PI3K: Phosphoinositide-3-kinase; PKD1: Polycystic kidney disease 1; RAF: Raf proto-oncogene; RAS: RAS proto-oncogene.
Immunotherapy

The basis for immunotherapy is the distinct antigens that cancer cells release, which T lymphocytes recognize and eliminate. Cancer vaccines enhance the antigen presentation of cancer cells; immune checkpoint inhibitors disrupt the suppressive mechanisms of the immune system that impair effective immunosurveillance of T-cells; and tumor-specific T cells are modified to become more active after being adopted and transplanted. Immunotherapy has been shown in clinical studies to be a possible treatment for numerous solid tumors[43-45]. However, the pancreatic cancer microenvironment, also known as the stroma, contains a variety of noncancer cell components. It has been discovered that stroma, which may account for up to 50% of the overall mass of the tumor in cases with pancreatic cancer, suppresses both naturally occurring and artificially produced antitumor immunity. Immunotherapy for pancreatic cancer is, therefore, extremely challenging. However, there have been several attempts to employ immunotherapy either by itself or in conjunction with other cancer treatment modalities[46].

Immune checkpoint inhibitors: Immune cells include proteins called checkpoints that regulate the immune response. The immune response starts when the checkpoints are activated or deactivated. This process stops immune cells from attacking the body's normal cells, but cancer cells might exploit this defense and evade the immune system. Checkpoint inhibitors interfere with this pathway, causing the immune system to attack tumor cells. These techniques are now being researched for use in pancreatic cancer. The T-cell immunity inhibitors programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) are the two immunological checkpoints that have attracted the greatest interest. Exocytosis moves CTLA-4 from the naive T cells' intracellular space to their cell surface when they get activated, where it competes with the B7 protein to prevent T cells from becoming activated[47,48]. Numerous immune cells, including T cells, B cells, NK cells, and dendritic cells (DC), express the cell surface receptor PD-1. One of PD-1's ligands, PD-L1, was discovered to be expressed in a variety of cells, including several types of tumor cells. Inhibiting T-cell survival and proliferation, the binding of PD-1 to PD-L1 also allows tumor cells to evade immune surveillance. Upregulation of PD-L1 in pancreatic cancer is associated with tumor growth and a worse prognosis[49].

Anti-CTLA-4 antibodies: Ipilimumab is a anti-CTLA-4 mAb that has been humanized. In a phase 2 study with advanced pancreatic cancer, ipilimumab yielded no response by itself, as measured by the response evaluation criteria in solid tumors (RECIST). In a phase 1 study with previously treated pancreatic cancer patients, ipilimumab was combined with GVAX [granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine]. The efficacy of this combination treatment was demonstrated in this trial as ipilimumab plus GVAX raised median OS (5.7 vs 3.6 mo) and 1-year OS rate (27% vs 7%)[50] (Table 1). T cell receptor repertoires in peripheral blood from individuals taking ipilimumab with or without GVAX were evaluated using data from the same phase 1 trial. The results demonstrated that participants who had ipilimumab showed more repertoire alterations, particularly when paired with GVAX, which was linked to a much longer life span[51]. Gemcitabine and ipilimumab are a safe and practical treatment option for advanced pancreatic cancer, according to the findings of phase 1 clinical research that examined the long-lasting responses and OS benefit of this combination. Ipilimumab in combination with gemcitabine did not appear to be any more successful than gemcitabine alone in treating advanced pancreatic cancer, despite the fact that one patient in this research had a somewhat persistent response lasting over 20 mo[52] (Figure 3).

Figure 3
Figure 3 Treatment with immune check point inhibitors for advanced pancreatic cancer. CTLA4: Cytotoxic T-lymphocyte-associated protein 4; MHC: Major histocompatibility complex; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; TCR: T cell receptor.
Table 1 Summary of completed clinical trials investigating immunotherapy in advanced pancreatic cancer patients.
Ref.
Drug(s)
No. of patients
ORR (%)
Mean OS (mo)
Mean PFS (mo)
Results
Le et al[50], 2013Ipilimumab vs ipilimumab plus GVAX15/15-3.6/5.7 1-yr OS (%) 7/27-Ipilimumab combined with GVAX was efficacious in advanced pancreatic cancer treatment
Kamath et al[52], 2020Ipilimumab plus gemcitabine21146.92.78Gemcitabine plus Ipilimumab is a safe and tolerable regimen for advanced pancreatic cancer with a similar response rate to gemcitabine alone
Aglietta et al[53], 2014Tremelimumab plus gemcitabine34-7.4-Tremelimumab with gemcitabine had a favorable safety and tolerability profile, indicating that it should be studied further in patients with advanced pancreatic cancer
Renouf et al[54], 2022Gemcitabine, nab-paclitaxel, durvalumab, and tremelimumab vs gemcitabine and nab-paclitaxel119/6130.3/23.39.8/8.85.5/5.4The results did not demonstrate a benefit from adding durvalumab and tremelimumab to gemcitabine and nab-paclitaxel as a first line therapy in advanced pancreatic cancer patients
Reiss et al[57], 2022Niraparib and nivolumab vs niraparib and ipilimumab91 (46/45)7.1/15.413.2/17.31.9/8.1The advantage of niraparib with ipilimumab maintenance treatment extended to patients who did not have known DDR mutations, indicating that the impact is not dependent on DDR deficit
Bockorny et al[67], 2021Motixafortide, pembrolizumab and FOLFIRINOX4313.26.63.8In a group with poor prognoses and aggressive diseases, motixafortide and pembrolizumab in conjunction with FOLFIRINOX demonstrated effectiveness. The therapy was well tolerated
O’Reilly et al[69], 2019Durvalumab vs durvalumab and tremelimumab64 (32/32)0/3.13.6/3.11.5/1.5The medication was well tolerated, and both durvalumab monotherapy and durvalumab combined with tremelimumab were effective in treating advanced pancreatic cancer patients with a poor prognosis

A different mAb targeting CTLA-4 is tremelimumab. Tremelimumab plus gemcitabine was well tolerated in a phase 1 investigation with advanced pancreatic cancer, and two participants showed partial responses; nonetheless, this study did not show any RECIST improvement[53]. Tremelimumab did not appear to be beneficial in a separate phase 2 trial in pancreatic cancer patients who had tumor progression after receiving prior conventional first-line 5-FU or gemcitabine-containing treatment[54].

Anti-PD-1 and anti-PD-L1 antibodies: Nivolumab, a monoclonal IG4 anti-PD-1 antibody from human, inhibits the interaction of PD-1 with either PD-L1 or PD-L2. Fifteen pancreatic cancer patients were treated with nivolumab and mogamulizumab, an anti-CC chemokine receptor 4 antibody, in a phase 1 study for patients with advanced or metastatic solid tumors, and only two unconfirmed responses were found[55]. In a multicenter, prospective clinical study, Klein et al[56] treated seven advanced cancer patients with pancreatic neuroendocrine neoplasms (NEN) with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 wk for four doses, then nivolumab 3 mg/kg every 2 wk for up to 96 wk, or until severe toxicity or disease progression occurred. They discovered that 43% of pancreatic NEN patients had an objective response. They proposed that combining nivolumab and ipilimumab immunotherapy revealed considerable therapeutic activity in subgroups of patients with advanced, high-grade pancreatic NEN. For 91 advanced pancreatic cancer patients who had not improved after 16 wk platinum-based treatment in 2022, Reiss et al[57] conducted a randomized, open-label, phase 1b/2 trial of niraparib with nivolumab or ipilimumab treatment. Using permuted block randomization, the patients were assigned (1:1) to receive four doses of oral niraparib 200 mg daily along with either intravenous nivolumab 240 mg or 480 mg every 2 wk or ipilimumab 3 mg/kg intravenously every 4 wk. They reported that the 6-mo PFS for niraparib plus nivolumab was 20.6% and 59.6% for niraparib plus ipilimumab. They concluded that the main goal was achieved in the niraparib plus ipilimumab maintenance group, while the PFS was reduced in the niraparib plus nivolumab group.

Another monoclonal IG4 antibody from human against PD-1 is pembrolizumab. In a phase 1b study of 11 advanced pancreatic cancer patients, pembrolizumab combined with nab-paclitaxel and gemcitabine produced six cases of stable disease and two cases of partial response. This combination's efficacy was marginally higher than that of gemcitabine combined with nab-paclitaxel in previous studies[58,59]. In comprehensive clinical research involving a variety of cancer types, it was shown that biomarkers related to the clinical success of pembrolizumab included the PD-L1 expression level, T-cell-inflamed gene expression profile, and tumor mutation burden. Patients with pancreatic cancer who received pembrolizumab had an ORR of 0% and an average PFS of 1.7 mo[60]. Another phase 2 clinical trial of pembrolizumab in patients with advanced pancreatic cancer and other solid tumors that are sensitive to the mismatch repair pathway loss-of-function mutations found that the objective radiographic response was 53% and the complete response was 21%[61]. The clinical response was not seen in a phase 1 study that tested the p53-expressing modified vaccinia Ankara virus (p53MVA) alone, but a phase 1 study that combined pembrolizumab with p53MVA showed that three out of 11 patients demonstrated clinical response and the disease was stable for 30, 32, and 49 wk[62,63]. Pembrolizumab was coupled with nab-paclitaxel or gemcitabine in a phase 1/2 clinical study. The OS and PFS were 15.0 and 9.1 mo, respectively, and the disease control rate in the 11 evaluable chemotherapy-naive pancreatic cancer patients was 100%[59]. In a phase 1, multicenter trial, the monoclonal IG4 antibody from human, BMS-936559, against PD-L1 was investigated for the treatment of several advanced cancers. Patients with renal-cell carcinoma, non-small-cell lung cancer, and melanoma all experienced long-term tumor reduction and stable illness as a result of BMS-936559; however, none of the 14 patients with pancreatic cancer who participated in this trial experienced a response[64]. Furthermore, Mehnert et al[65] found that pembrolizumab had anticancer efficacy in a subgroup of pancreatic cancer patients with NETs and was well tolerated. Moreover, to examine the CXCR4 antagonist BL-8040 (motixafortide)'s safety, efficacy, and immunobiological effects when combined with pembrolizumab and chemotherapy, Bockorny et al[66] conducted a phase 2a, open-label, two-cohort study in 37 chemotherapy-resistant, metastatic pancreatic cancer patients. They stated that further randomized trials should validate their findings before combining CXCR4 and PD-1 inhibition to treat pancreatic cancer[67].

Another choice is durvalumab, a monoclonal IgG1 antibody from human that targets PD-L1 and infiltrating T cells in solid tumors. In patients with relapsed or refractory solid tumors, durvalumab was studied in a phase 1b/2 study alongside ibrutinib (a Bruton's tyrosine kinase inhibitor). This study's pancreatic cancer RR was 2% overall, with a median OS of 4.2 mo and median PFS of 1.7 mo. Despite having a good tolerability profile, this regimen had very limited antitumor activity against pancreatic cancer[68]. Another randomized phase 2 study using durvalumab was conducted in individuals with metastatic pancreatic cancer, either alone or in combination with tremelimumab. However, the ORR for individuals receiving tremelimumab plus durvalumab was just 3.1%, and patients treated with durvalumab alone had no response[69]. During a phase 1 study to establish the dose, atezolizumab, an engineered mAb against PD-L1, was found to be well tolerated in a Japanese group[70]. In a phase 1 study for advanced malignancies, atezolizumab was also evaluated in conjunction with navoximod, a small-molecule inhibitor of indoleamine 2,3-dioxygenase 1. There was no evidence to support the addition of navoximod to atezolizumab, but the safety and tolerability of this combination therapy were established, and anticancer efficacy was noted in a variety of tumor types, including pancreatic cancer[71].

Chimeric antigen receptor T-cell therapy

Using modified T-cell receptors or chimeric antigen receptors (CARs), in an effort to target tumor-associated antigens (TAAs), adoptive T-cell immunotherapy, a possible strategy for cancer immunotherapy, alters autologous cells that infiltrate tumors. The optimal target antigen is overexpressed on tumor cells but is seldom or never expressed on normal cells when employed in CAR-T cell therapy. Mesothelin, a cell-surface antigen that is raised in pancreatic cancer but is relatively weakly expressed in the peritoneum, pericardium, and pleura, is the perfect antigen for CAR-T cell treatment[72,73]. A mesothelin-targeted CAR-T-cell therapy has also been demonstrated to be efficient against tumor cells in preclinical conditions, according to several studies. Treatment with modified CAR-T cells targeting mesothelin resulted in strong anticancer action for tumor xenografts and the cell lines of pancreatic cancer[74-76]. In phase 1 research with metastatic pancreatic cancer that had become resistant to chemotherapy, autologous mesothelin-specific CAR-T cells (CARTmeso cells) were found to have potential anticancer benefits and be safe[77]. The cancer stem cell markers CD24 and HER2 are thought to contribute to the emergence of pancreatic cancer[78]. In addition, a phase 1 trial evaluated the safety, viability, and effectiveness of CAR-T cells combined with nab-paclitaxel and cyclophosphamide against HER2 in advanced pancreatic and biliary tract cancers. Five of 11 subjects had stable illness, with a median PFS of 4.8 mo, while one patient had a partial response lasting 4.5 mo. The study established the viability, safety, and the possibility of therapeutic efficacy of HER2-targeting CAR-T treatment[79]. In 60%-80% of pancreatic cancers, prostate stem cell antigen is expressed, but not in healthy tissues. CAR-T cells that target the prostate stem cell antigen have been shown to be beneficial for pancreatic malignancy in two different investigations[80,81]. When used as an antigen in CAR-T therapy, the Tn glycoform of MUC1 demonstrated target-specific cytotoxicity and reduced the development of xenografts made of pancreatic cancer cells[82]. Ex vivo-expanded cytokine-induced killer (CIK) cells were used in a phase 2 trial to assess the efficacy and safety of adoptive immunotherapy for advanced pancreatic cancer that is gemcitabine-refractory. The results showed promising improvements in patient quality of life (QoL)[83]. To evaluate the security and efficiency of autologous anti-EGFR CAR T-EGFR cells, Liu et al[84] carried out a phase 1 clinical study in patients with advanced pancreatic cancer. Immunohistochemically-detected EGFR expression levels on tumor cells must be over 50%. Six months after being chosen, 16 patients had one to three rounds of CAR T-EGFR cell injection after conditioning with 15 to 35 mg/kg cyclophosphamide and 100 to 200 mg/m2 nab-paclitaxel. Grade > 3 adverse effects that might be reversed were fever, tiredness, mucosal or cutaneous toxicities, nausea, vomiting, pulmonary interstitial exudation, and pleural effusion. Eight of the 14 patients who were evaluable had stable disease for 2-4 mo, and four of them saw a partial response. The median OS was 4.9 mo for 14 evaluable patients who were treated with CAR T-EGFR cells for the first cycle, and the median PFS was 3 mo. Lower EGFR expression was seen on tumor cells in patients who experienced stable disease and a reduction in liver metastatic lesions. Additionally, the clinical response was enhanced by central memory T cell enrichment in the injected cells. They claimed that patients with advanced pancreatic cancer can get a safe and effective therapy using CAR T-EGFR cells.

Cancer vaccines

Compared to preventive cancer vaccines, therapeutic cancer vaccines have drawn more attention. Vaccines made from a patient's tumor antigens or cells are known as autologous vaccines, whereas allogeneic vaccines are made from biological material from a different individual. Pancreatic cancer has been the subject of research into many therapeutic cancer vaccines, including whole-cell tumor, DNA, idiotype, DC viral vector, and antigen vaccines[85,86].

Whole-cell vaccines: In a preclinical investigation, increased GM-CSF expression was shown to enhance long-term anticancer efficacy in vaccine-based therapy. As a result, GVAX, the first allogenic pancreatic cancer whole-cell-based vaccine, was created using two cell lines from pancreatic cancer patients and had been engineered for the expression of GM-CSF followed by radiation to block cell division in the future. In a phase I clinical investigation, GVAX was initially evaluated in people who had their pancreatic cancer surgically removed. The results of this trial showed that GVAX was risk-free, had few side effects, and looked to prolong at least 25 mo for the disease-free time in 4 of the 14 patients who took part in the study[87]. Furthermore, in these three participants, delayed-type hypersensitivity reactions were exacerbated by GVAX. GVAX was investigated in conjunction with cyclophosphamide in patients with advanced pancreatic cancer in a phase 2 study because of the encouraging outcomes. Pancreatic cancer has an elevated level of mesothelin, a tumor differentiation antigen. In this study, mesothelin-specific T-cell responses were seen in the patients who received GVAX treatment and were shown to be improving. GVAX alone or in combination with cyclophosphamide demonstrated no harm. However, as compared to cyclophosphamide alone, the inclusion of GVAX did not appear to improve median survival[88]. In a phase 2 trial including surgically resected pancreatic cancer patients, GVAX was used as a neo-adjuvant therapy combined with chemoradiation (5-FU-based). Immunotherapy resulted in the discovery that mesothelin-specific CD8+ T cells were associated with the disease-free survival rate, and when chemoradiation and GVAX were used together, the OS looked to be better than that in previously reported studies for pancreatic cancer that had been surgically removed. In previously treated pancreatic cancer patients, GVAX was also tried in conjunction with ipilimumab. Ipilimumab with the inclusion of GVAX produced a significant longer median OS and 1-year OS of 5.7 vs 3.6 mo and 27% vs 7%, respectively[89]. Additionally, in patients with an OS of more than 4.3 mo, the peak number of T-cell repertoire and mesothelin-specific T cells was increased. Further research into how immunotherapy affects pancreatic cancer TME revealed that GVAX treatment upregulated immunosuppressive regulatory mechanisms. This indicates that individuals with pancreatic cancer who have received a vaccination may be better candidates for immune checkpoint and other immunomodulatory therapies, such as PD-1/PD-L1 inhibitors, than vaccine-naive patients[90]. The efficiency of the Listeria monocytogenes expressing mesothelin (CRS-207) and GVAX booster vaccines combined with cyclophosphamide minimum dose was evaluated in advanced pancreatic cancer patients who had previously received treatment. According to this study, CRS-207 and Cy/GVAX heterologous booster had a superior OS than using only Cy/GVAX (6.1 vs 3.9 mo)[91]. However, a recent phase 2b, multicenter trial of CRS-207 and GVAX found no survival advantages for the combination of Cy/GVAX and CRS-207 over single-agent chemotherapy in patients with metastatic pancreatic cancer who had previously received treatment[92]. In a phase 1 clinical trial, CRS-207 produced immunological activation, mesothelin-specific T-cell responses, and listeriolysin O, and and the participant survival rate was 37% within 15 mo. It was also demonstrated to be safe[93]. Two pancreatic cancer cell lines were altered to generate murine 1,3-galactosyltransferase to create algenpantucel-L, a second allogenic, irradiated, whole-cell-based tumor vaccine. Adoptive transfer of lymphocytes from mice that received melanoma tumor cell lines as a vaccine in a preclinical animal model expressing β-1,3-galactosyltransferase reduced mouse lung metastases[94]. These findings sparked a phase 2, multicenter study of algenpantucel-L in patients with resected pancreatic cancer receiving gemcitabine- or 5-fluorouracil-based chemoradiotherapy. In contrast to recent trials, which found 45% and 65%, respectively, for the median 1-year PFS and OS, the addition of algenpantucel-L to traditional adjuvant therapy may have improved survival in this trial[95]. In a recent multicenter, phase 3, open-label, randomized trial, algenpantucel-L immunotherapy in combination with standard of care (SOC) chemoradiation and chemotherapy therapy was compared to SOC chemoradiation and chemotherapy therapy alone in 303 Locally advanced or borderline resectable pancreatic cancer patients[96]. They found that the experimental group's median OS was 14.3 mo, whereas the SOC group’s median OS was 14.9 mo. The median PFS for the SOC group was 13.4 mo as opposed to 12.4 mo for the experimental group. The researchers found that patients who received SOC chemoradiation and neoadjuvant chemotherapy and had locally advanced unresectable or borderline resectable pancreatic cancer had not a longer OS benefit after algenpantucel-L immunotherapy.

Peptide vaccines: About 90% of pancreatic cancers have KRAS mutations, and the mutant KRAS peptide is presented to CD4+ and CD8+ T lymphocytes as a foreign antigen. In a recent study, two out of five pancreatic cancer patients who received treatment with a synthetic KRAS mutant peptide showed a brief KRAS-specific T-cell response[97-99]. In a subsequent phase 1/2 pancreatic cancer research trial, 58% (25/43) of patients developed peptide-specific immunity after receiving a KRAS peptide vaccine and GM-CSF adjuvant therapy, which also helped advanced pancreatic patients live longer (146 vs 61 d)[100]. Patients with an immunological response to a KRAS peptide vaccination had a 20% 10-year survival rate compared to 0% in a group of pancreatic cancer patients who had not received the vaccine, and this difference persisted more than ten years after the start of long-term follow-up for these patients[101]. In a recent therapeutic study, individuals with resected pancreatic cancer and detected KRAS mutations received GM-CSF treatment plus a KRAS peptide vaccination. Nine patients (or 25%) had an evaluable immune response, of which three had a delayed-type hypersensitivity reaction and one had a specific immune response to their KRAS mutation[102]. Pancreatic cancers have overexpression of mucin 1 (MUC1), a type I transmembrane protein that is highly immunogenic. Various MUC1 vaccine formulations have been tested in phase 1 trials; however, it appears that MUC1-specific T-cell responses are exclusively induced by the vaccination of DC with the MUC1 peptide[103-105]. Gastrin has been linked to both endocrine and autocrine growth pathways and is overexpressed in pancreatic cancer. An antibody response was found in 67% (20/31) of patients in a phase 2 study employing the anti-gastrin immunogen G17DT in advanced pancreatic cancer, and antibody responders lived much longer than non-responders[106]. Patients who had an anti-G17DT response (73.8%) had a significantly higher median survival than non-responders (151 vs 82 d) in a different randomized multicenter trial using G17DT[107]. A vaccine that targets telomerase, called GV1001, was made using the human TERT peptide. Patients with nonresectable pancreatic cancer received treatment with GV1001 and GM-CSF in a phase 1/2 study, and the treatment's safety, tolerability, and immunogenicity were assessed. Immune responses that were seen in 24 of 38 individuals and were connected to longer lifespans served as proof of the safety of GV1001[108]. In a phase 3 study, GV1001 was also evaluated in individuals taking gemcitabine or capecitabine for locally advanced or metastatic pancreatic cancer. However, compared to pancreatic cancer patients receiving chemotherapy alone, the incorporation of GV1001 had no positive impact on OS[109]. The identical outcomes were seen in a different clinical experiment as well[110].

DC vaccines: Because the most important antigen-presenting cells are DCs which excite innocent T cells, a DC vaccine is made by loading TAAs ex vivo and then reinfusing them into patients. An autologous DC vaccination containing a MUC1 peptide was tested in resected pancreatic and biliary cancers in an innovative phase 1/2 trial. The DC vaccination was well tolerated and had no obvious side effects. Four of the twelve patients were still alive and had no recurrence throughout a follow-up period of more than four years[105]. In patients with resistant pancreatic cancer, a DC vaccination was also examined in conjunction with gemcitabine and/or S-1 treatment. Two of the 49 patients that were included experienced complete remission, while five others did so partially, and ten had stable disease[111]. Compared to those who received a DC vaccination and chemotherapy alone, patients who also received lymphokine-activated killer cells had a higher rate of survival. This study established the safety and possible efficacy of combining a DC vaccine with chemotherapy in patients with advanced pancreatic cancer who had not responded to standard treatment. In a phase 1 study, poly-ICLC, a Toll-like receptor-3 agonist, was combined with DC-based immunotherapy. The peripheral blood of HLA-A2+ patients was utilized to generate autologous DCs, which were then combined with three definite A2-restricted peptides and was returned to advanced pancreatic cancer patients. On the days of their vaccinations, subjects concurrently got poly(IC:LC) intramuscularly. The median OS for all 12 subjects was 7.7 mo, and of the eight subjects who received imaging on day 56, four had stable disease and four had progression of the disease[112]. An investigation of the clinical outcomes and safety of immunotherapy using DC-CIK in combination with chemotherapy S-1 in pancreatic cancer was the goal of a phase 1/2 trial. In comparison to DC-CIK alone (85 and 128 d), chemotherapy alone (92 and 141 d), or supportive care alone (43 and 52 d), the combination of DC-CIK infusions and S-1 caused importantly longer median PFS and OS (136 and 212 d), proving that it was safe, changed the peripheral blood immune repertoire, and produced a good PFS and OS[113]. In a phase 1 study of patients with pancreatic cancer that was surgically resected, the Wilms' tumor 1 (WT1) peptide was loaded in a DC (WT1-DC) vaccine and evaluated with chemotherapy. There was no discernible toxicity when WT1-DC was combined with S-1 or S-1 with gemcitabine, and seven out of the eight patients had WT1-specific cytotoxic T-lymphocytes[114].

CONCLUSION

Our understanding of the biology of pancreatic cancer has significantly advanced over the past few decades, but tragically, this has not led to a meaningful increase in the therapeutic management of the majority of patients. The aggressiveness of pancreatic cancer and the lateness of its discovery make it very challenging to cure. The majority of patients have advanced stages, which makes therapy difficult. Although advanced pancreatic cancer can be treated with chemotherapy, radiation therapy, and surgery to increase survival and manage symptoms, there is no definite treatment for the disease. The inability of chemotherapy to distinguish between cancer and healthy cells when it targets a range of biological pathways leads to severe side effects. In order to target growth factors, other proteins involved in the development of the illness, and cancer cell surface receptors, therapies based on SMIs and mAbs are necessary. If the condition is discovered quickly and a focused treatment is employed, patients with pancreatic cancer may have a better chance of living. The majority of the targeted treatments investigated for the treatment of pancreatic malignancies have been shown to be unsuccessful, despite the fact that many of them have been developed. There is a need for innovative treatment approaches for pancreatic cancer, such as cancer vaccines, in addition to the conventional targeted medicines and immunotherapies that have been investigated for years. As an alternative, strategies that combine already-existing technology or therapy modalities might also be very helpful, but this would need further investigation and testing.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: Thailand

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): 0

Grade C (Good): C, C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Wang GX, China; Zhang C, China S-Editor: Yan JP L-Editor: Wang TQ P-Editor: Yan JP

References
1.  GBD 2017 Pancreatic Cancer Collaborators. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2019;4:934-947.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 207]  [Cited by in F6Publishing: 326]  [Article Influence: 65.2]  [Reference Citation Analysis (0)]
2.  Cipora E, Partyka O, Pajewska M, Czerw A, Sygit K, Sygit M, Kaczmarski M, Mękal D, Krzych-Fałta E, Jurczak A, Karakiewicz-Krawczyk K, Wieder-Huszla S, Banaś T, Bandurska E, Ciećko W, Deptała A. Treatment Costs and Social Burden of Pancreatic Cancer. Cancers (Basel). 2023;15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 4]  [Reference Citation Analysis (0)]
3.  Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021;18:493-502.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 353]  [Article Influence: 117.7]  [Reference Citation Analysis (0)]
4.  Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol. 2019;10:10-27.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 893]  [Cited by in F6Publishing: 1262]  [Article Influence: 252.4]  [Reference Citation Analysis (0)]
5.  Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A, Bray F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144:1941-1953.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3585]  [Cited by in F6Publishing: 4358]  [Article Influence: 726.3]  [Reference Citation Analysis (1)]
6.  Stolzenberg-Solomon RZ, Schairer C, Moore S, Hollenbeck A, Silverman DT. Lifetime adiposity and risk of pancreatic cancer in the NIH-AARP Diet and Health Study cohort. Am J Clin Nutr. 2013;98:1057-1065.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 82]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
7.  Rebours V, Gaujoux S, d'Assignies G, Sauvanet A, Ruszniewski P, Lévy P, Paradis V, Bedossa P, Couvelard A. Obesity and Fatty Pancreatic Infiltration Are Risk Factors for Pancreatic Precancerous Lesions (PanIN). Clin Cancer Res. 2015;21:3522-3528.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 144]  [Article Influence: 16.0]  [Reference Citation Analysis (0)]
8.  Blackford A, Parmigiani G, Kensler TW, Wolfgang C, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Klein A, Cameron JL, Olino K, Schulick R, Winter J, Vogelstein B, Velculescu VE, Kinzler KW, Hruban RH. Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res. 2009;69:3681-3688.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 94]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
9.  Naudin S, Viallon V, Hashim D, Freisling H, Jenab M, Weiderpass E, Perrier F, McKenzie F, Bueno-de-Mesquita HB, Olsen A, Tjønneland A, Dahm CC, Overvad K, Mancini FR, Rebours V, Boutron-Ruault MC, Katzke V, Kaaks R, Bergmann M, Boeing H, Peppa E, Karakatsani A, Trichopoulou A, Pala V, Masala G, Panico S, Tumino R, Sacerdote C, May AM, van Gils CH, Rylander C, Borch KB, Chirlaque López MD, Sánchez MJ, Ardanaz E, Quirós JR, Amiano Exezarreta P, Sund M, Drake I, Regnér S, Travis RC, Wareham N, Aune D, Riboli E, Gunter MJ, Duell EJ, Brennan P, Ferrari P. Healthy lifestyle and the risk of pancreatic cancer in the EPIC study. Eur J Epidemiol. 2020;35:975-986.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 41]  [Article Influence: 8.2]  [Reference Citation Analysis (0)]
10.  Pereira SP, Oldfield L, Ney A, Hart PA, Keane MG, Pandol SJ, Li D, Greenhalf W, Jeon CY, Koay EJ, Almario CV, Halloran C, Lennon AM, Costello E. Early detection of pancreatic cancer. Lancet Gastroenterol Hepatol. 2020;5:698-710.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 254]  [Cited by in F6Publishing: 227]  [Article Influence: 56.8]  [Reference Citation Analysis (1)]
11.  Weissman S, Takakura K, Eibl G, Pandol SJ, Saruta M. The Diverse Involvement of Cigarette Smoking in Pancreatic Cancer Development and Prognosis. Pancreas. 2020;49:612-620.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 23]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
12.  Biller LH, Wolpin BM, Goggins M. Inherited Pancreatic Cancer Syndromes and High-Risk Screening. Surg Oncol Clin N Am. 2021;30:773-786.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 14]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
13.  Vietri MT, D'Elia G, Caliendo G, Albanese L, Signoriello G, Napoli C, Molinari AM. Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation. Genes (Basel). 2022;13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 11]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
14.  Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P, Stoffel EM, Gruber SB, Syngal S. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009;302:1790-1795.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 359]  [Cited by in F6Publishing: 341]  [Article Influence: 22.7]  [Reference Citation Analysis (0)]
15.  Saba H, Goggins M. Familial Pancreatic Cancer. Gastroenterol Clin North Am. 2022;51:561-575.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Reference Citation Analysis (0)]
16.  Walter FM, Mills K, Mendonça SC, Abel GA, Basu B, Carroll N, Ballard S, Lancaster J, Hamilton W, Rubin GP, Emery JD. Symptoms and patient factors associated with diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study): a prospective cohort study. Lancet Gastroenterol Hepatol. 2016;1:298-306.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 93]  [Article Influence: 11.6]  [Reference Citation Analysis (0)]
17.  Macdonald S, Macleod U, Campbell NC, Weller D, Mitchell E. Systematic review of factors influencing patient and practitioner delay in diagnosis of upper gastrointestinal cancer. Br J Cancer. 2006;94:1272-1280.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 108]  [Cited by in F6Publishing: 112]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
18.  Schmidt-Hansen M, Berendse S, Hamilton W. Symptoms of Pancreatic Cancer in Primary Care: A Systematic Review. Pancreas. 2016;45:814-818.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 32]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
19.  Chang VT, Sandifer C, Zhong F. GI Symptoms in Pancreatic Cancer. Clin Colorectal Cancer. 2023;22:24-33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
20.  Gobbi PG, Bergonzi M, Comelli M, Villano L, Pozzoli D, Vanoli A, Dionigi P. The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer. Cancer Epidemiol. 2013;37:186-190.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 64]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
21.  Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403-2413.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4270]  [Cited by in F6Publishing: 4057]  [Article Influence: 150.3]  [Reference Citation Analysis (0)]
22.  Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960-1966.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2755]  [Cited by in F6Publishing: 2685]  [Article Influence: 157.9]  [Reference Citation Analysis (0)]
23.  Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer;  PRODIGE Intergroup. FOLFIRINOX vs gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4838]  [Cited by in F6Publishing: 5161]  [Article Influence: 397.0]  [Reference Citation Analysis (1)]
24.  Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-1703.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4035]  [Cited by in F6Publishing: 4390]  [Article Influence: 399.1]  [Reference Citation Analysis (0)]
25.  Chan KKW, Guo H, Cheng S, Beca JM, Redmond-Misner R, Isaranuwatchai W, Qiao L, Earle C, Berry SR, Biagi JJ, Welch S, Meyers BM, Mittmann N, Coburn N, Arias J, Schwartz D, Dai WF, Gavura S, McLeod R, Kennedy ED. Real-world outcomes of FOLFIRINOX vs gemcitabine and nab-paclitaxel in advanced pancreatic cancer: A population-based propensity score-weighted analysis. Cancer Med. 2020;9:160-169.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 50]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
26.  Wang Y, Camateros P, Cheung WY. A Real-World Comparison of FOLFIRINOX, Gemcitabine Plus nab-Paclitaxel, and Gemcitabine in Advanced Pancreatic Cancers. J Gastrointest Cancer. 2019;50:62-68.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 40]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
27.  Sohal DPS, Kennedy EB, Khorana A, Copur MS, Crane CH, Garrido-Laguna I, Krishnamurthi S, Moravek C, O'Reilly EM, Philip PA, Ramanathan RK, Ruggiero JT, Shah MA, Urba S, Uronis HE, Lau MW, Laheru D. Metastatic Pancreatic Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018;36:2545-2556.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 181]  [Cited by in F6Publishing: 176]  [Article Influence: 29.3]  [Reference Citation Analysis (0)]
28.  Paluri RK, Kasi A, Young C, Posey JA. Second-line treatment for metastatic pancreatic cancer. Clin Adv Hematol Oncol. 2020;18:106-115.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Petrelli F, Parisi A, Tomasello G, Mini E, Arru M, Russo A, Garrone O, Khakoo S, Ardito R, Ghidini M. Comparison of different second line treatments for metastatic pancreatic cancer: a systematic review and network meta-analysis. BMC Gastroenterol. 2023;23:212.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
30.  Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T, Yang W, Tian C, Miao Z, Wang T, Yang S. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther. 2021;6:201.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 473]  [Cited by in F6Publishing: 525]  [Article Influence: 175.0]  [Reference Citation Analysis (1)]
31.  Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2023 update. Pharmacol Res. 2023;187:106552.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 94]  [Article Influence: 94.0]  [Reference Citation Analysis (0)]
32.  Ayala-Aguilera CC, Valero T, Lorente-Macías Á, Baillache DJ, Croke S, Unciti-Broceta A. Small Molecule Kinase Inhibitor Drugs (1995-2021): Medical Indication, Pharmacology, and Synthesis. J Med Chem. 2022;65:1047-1131.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 110]  [Article Influence: 36.7]  [Reference Citation Analysis (0)]
33.  Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol. 2022;14:38-54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 4]  [Cited by in F6Publishing: 3]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
34.  Arpalahti L, Haglund C, Holmberg CI. Proteostasis Dysregulation in Pancreatic Cancer. Adv Exp Med Biol. 2020;1233:101-115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 8]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
35.  Alberts SR, Foster NR, Morton RF, Kugler J, Schaefer P, Wiesenfeld M, Fitch TR, Steen P, Kim GP, Gill S. PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann Oncol. 2005;16:1654-1661.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 84]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
36.  Kim A, Ha J, Kim J, Cho Y, Ahn J, Cheon C, Kim SH, Ko SG, Kim B. Natural Products for Pancreatic Cancer Treatment: From Traditional Medicine to Modern Drug Discovery. Nutrients. 2021;13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 29]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
37.  El-Khoueiry AB, Ramanathan RK, Yang DY, Zhang W, Shibata S, Wright JJ, Gandara D, Lenz HJ. A randomized phase II of gemcitabine and sorafenib vs sorafenib alone in patients with metastatic pancreatic cancer. Invest New Drugs. 2012;30:1175-1183.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 30]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
38.  Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz JF, Delpero JR, Turrini O, Viens P, Raoul JL. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23:2799-2805.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 165]  [Cited by in F6Publishing: 157]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
39.  Sinn M, Liersch T, Riess H, Gellert K, Stübs P, Waldschmidt D, Lammert F, Maschmeyer G, Bechstein W, Bitzer M, Denzlinger C, Hofheinz R, Lindig U, Ghadimi M, Hinke A, Striefler JK, Pelzer U, Bischoff S, Bahra M, Oettle H. CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer - Final results. Eur J Cancer. 2020;138:172-181.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
40.  Blumenthal GM, Cortazar P, Zhang JJ, Tang S, Sridhara R, Murgo A, Justice R, Pazdur R. FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. Oncologist. 2012;17:1108-1113.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 100]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
41.  Damaskos C, Garmpis N, Karatzas T, Nikolidakis L, Kostakis ID, Garmpi A, Karamaroudis S, Boutsikos G, Damaskou Z, Kostakis A, Kouraklis G. Histone Deacetylase (HDAC) Inhibitors: Current Evidence for Therapeutic Activities in Pancreatic Cancer. Anticancer Res. 2015;35:3129-3135.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Li Y, Seto E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb Perspect Med. 2016;6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 539]  [Cited by in F6Publishing: 728]  [Article Influence: 91.0]  [Reference Citation Analysis (0)]
43.  Yousefi H, Yuan J, Keshavarz-Fathi M, Murphy JF, Rezaei N. Immunotherapy of cancers comes of age. Expert Rev Clin Immunol. 2017;13:1001-1015.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 55]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
44.  Menon S, Shin S, Dy G. Advances in Cancer Immunotherapy in Solid Tumors. Cancers (Basel). 2016;8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 119]  [Cited by in F6Publishing: 108]  [Article Influence: 13.5]  [Reference Citation Analysis (0)]
45.  Mukherji R, Debnath D, Hartley ML, Noel MS. The Role of Immunotherapy in Pancreatic Cancer. Curr Oncol. 2022;29:6864-6892.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 10]  [Reference Citation Analysis (0)]
46.  Balachandran VP, Beatty GL, Dougan SK. Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities. Gastroenterology. 2019;156:2056-2072.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 262]  [Cited by in F6Publishing: 276]  [Article Influence: 55.2]  [Reference Citation Analysis (0)]
47.  Li B, Chan HL, Chen P. Immune Checkpoint Inhibitors: Basics and Challenges. Curr Med Chem. 2019;26:3009-3025.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 122]  [Cited by in F6Publishing: 251]  [Article Influence: 50.2]  [Reference Citation Analysis (0)]
48.  Tison A, Garaud S, Chiche L, Cornec D, Kostine M. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat Rev Rheumatol. 2022;18:641-656.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 42]  [Reference Citation Analysis (0)]
49.  Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L, Wang S. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 2022;13:964442.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 96]  [Reference Citation Analysis (0)]
50.  Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA Jr, Donehower RC, Jaffee EM, Laheru DA. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36:382-389.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 362]  [Cited by in F6Publishing: 382]  [Article Influence: 34.7]  [Reference Citation Analysis (0)]
51.  Hopkins AC, Yarchoan M, Durham JN, Yusko EC, Rytlewski JA, Robins HS, Laheru DA, Le DT, Lutz ER, Jaffee EM. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight. 2018;3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 166]  [Cited by in F6Publishing: 165]  [Article Influence: 27.5]  [Reference Citation Analysis (0)]
52.  Kamath SD, Kalyan A, Kircher S, Nimeiri H, Fought AJ, Benson A 3rd, Mulcahy M. Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. Oncologist. 2020;25:e808-e815.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 105]  [Article Influence: 21.0]  [Reference Citation Analysis (0)]
53.  Aglietta M, Barone C, Sawyer MB, Moore MJ, Miller WH Jr, Bagalà C, Colombi F, Cagnazzo C, Gioeni L, Wang E, Huang B, Fly KD, Leone F. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol. 2014;25:1750-1755.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 144]  [Article Influence: 14.4]  [Reference Citation Analysis (0)]
54.  Renouf DJ, Loree JM, Knox JJ, Topham JT, Kavan P, Jonker D, Welch S, Couture F, Lemay F, Tehfe M, Harb M, Aucoin N, Ko YJ, Tang PA, Ramjeesingh R, Meyers BM, Kim CA, Du P, Jia S, Schaeffer DF, Gill S, Tu D, O'Callaghan CJ. The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma. Nat Commun. 2022;13:5020.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 34]  [Reference Citation Analysis (0)]
55.  Doi T, Muro K, Ishii H, Kato T, Tsushima T, Takenoyama M, Oizumi S, Gemmoto K, Suna H, Enokitani K, Kawakami T, Nishikawa H, Yamamoto N. A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors. Clin Cancer Res. 2019;25:6614-6622.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 75]  [Article Influence: 15.0]  [Reference Citation Analysis (0)]
56.  Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, Jackett L, Lum C, Scott C, Nagrial A, Behren A, So JY, Palmer J, Cebon J. Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers. Clin Cancer Res. 2020;26:4454-4459.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 95]  [Article Influence: 23.8]  [Reference Citation Analysis (0)]
57.  Reiss KA, Mick R, Teitelbaum U, O'Hara M, Schneider C, Massa R, Karasic T, Tondon R, Onyiah C, Gosselin MK, Donze A, Domchek SM, Vonderheide RH. Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomised, phase 1b/2 trial. Lancet Oncol. 2022;23:1009-1020.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 35]  [Article Influence: 17.5]  [Reference Citation Analysis (0)]
58.  Weiss GJ, Waypa J, Blaydorn L, Coats J, McGahey K, Sangal A, Niu J, Lynch CA, Farley JH, Khemka V. A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). Br J Cancer. 2017;117:33-40.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 95]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
59.  Weiss GJ, Blaydorn L, Beck J, Bornemann-Kolatzki K, Urnovitz H, Schütz E, Khemka V. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs. 2018;36:96-102.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 99]  [Cited by in F6Publishing: 92]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
60.  Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, Rugo HS, Cohen RB, O'Neil BH, Mehnert JM, Lopez J, Doi T, van Brummelen EMJ, Cristescu R, Yang P, Emancipator K, Stein K, Ayers M, Joe AK, Lunceford JK. T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028. J Clin Oncol. 2019;37:318-327.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 388]  [Cited by in F6Publishing: 563]  [Article Influence: 93.8]  [Reference Citation Analysis (0)]
61.  Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-413.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3799]  [Cited by in F6Publishing: 4392]  [Article Influence: 627.4]  [Reference Citation Analysis (0)]
62.  Hardwick NR, Carroll M, Kaltcheva T, Qian D, Lim D, Leong L, Chu P, Kim J, Chao J, Fakih M, Yen Y, Espenschied J, Ellenhorn JD, Diamond DJ, Chung V. p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T-cell responses. Clin Cancer Res. 2014;20:4459-4470.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 31]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
63.  Chung V, Kos FJ, Hardwick N, Yuan Y, Chao J, Li D, Waisman J, Li M, Zurcher K, Frankel P, Diamond DJ. Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers. Clin Transl Oncol. 2019;21:363-372.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 49]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
64.  Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5599]  [Cited by in F6Publishing: 5949]  [Article Influence: 495.8]  [Reference Citation Analysis (0)]
65.  Mehnert JM, Bergsland E, O'Neil BH, Santoro A, Schellens JHM, Cohen RB, Doi T, Ott PA, Pishvaian MJ, Puzanov I, Aung KL, Hsu C, Le Tourneau C, Hollebecque A, Élez E, Tamura K, Gould M, Yang P, Stein K, Piha-Paul SA. Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. Cancer. 2020;126:3021-3030.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 66]  [Article Influence: 16.5]  [Reference Citation Analysis (0)]
66.  Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM, Golan T, Geva R, Borad MJ, Pedersen KS, Park JO, Ramirez RA, Abad DG, Feliu J, Muñoz A, Ponz-Sarvise M, Peled A, Lustig TM, Bohana-Kashtan O, Shaw SM, Sorani E, Chaney M, Kadosh S, Vainstein Haras A, Von Hoff DD, Hidalgo M. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020;26:878-885.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 275]  [Cited by in F6Publishing: 282]  [Article Influence: 70.5]  [Reference Citation Analysis (0)]
67.  Bockorny B, Macarulla T, Semenisty V, Borazanci E, Feliu J, Ponz-Sarvise M, Abad DG, Oberstein P, Alistar A, Muñoz A, Geva R, Guillén-Ponce C, Fernandez MS, Peled A, Chaney M, Gliko-Kabir I, Shemesh-Darvish L, Ickowicz D, Sorani E, Kadosh S, Vainstein-Haras A, Hidalgo M. Motixafortide and Pembrolizumab Combined to Nanoliposomal Irinotecan, Fluorouracil, and Folinic Acid in Metastatic Pancreatic Cancer: The COMBAT/KEYNOTE-202 Trial. Clin Cancer Res. 2021;27:5020-5027.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 34]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
68.  Hong D, Rasco D, Veeder M, Luke JJ, Chandler J, Balmanoukian A, George TJ, Munster P, Berlin JD, Gutierrez M, Mita A, Wakelee H, Samakoglu S, Guan S, Dimery I, Graef T, Borazanci E. A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors. Oncology. 2019;97:102-111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 42]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
69.  O'Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun W, Fisher G, Hezel A, Chang SC, Vlahovic G, Takahashi O, Yang Y, Fitts D, Philip PA. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5:1431-1438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 225]  [Cited by in F6Publishing: 387]  [Article Influence: 77.4]  [Reference Citation Analysis (0)]
70.  Mizugaki H, Yamamoto N, Murakami H, Kenmotsu H, Fujiwara Y, Ishida Y, Kawakami T, Takahashi T. Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors. Invest New Drugs. 2016;34:596-603.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 38]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
71.  Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, Cervantes A, Ochoa de Olza M, Marabelle A, Hodi FS, Ahn MJ, Emens LA, Barlesi F, Hamid O, Calvo E, McDermott D, Soliman H, Rhee I, Lin R, Pourmohamad T, Suchomel J, Tsuhako A, Morrissey K, Mahrus S, Morley R, Pirzkall A, Davis SL. Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors. Clin Cancer Res. 2019;25:3220-3228.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 161]  [Cited by in F6Publishing: 158]  [Article Influence: 31.6]  [Reference Citation Analysis (0)]
72.  DeSelm CJ, Tano ZE, Varghese AM, Adusumilli PS. CAR T-cell therapy for pancreatic cancer. J Surg Oncol. 2017;116:63-74.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 58]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
73.  Akce M, Zaidi MY, Waller EK, El-Rayes BF, Lesinski GB. The Potential of CAR T Cell Therapy in Pancreatic Cancer. Front Immunol. 2018;9:2166.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 83]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
74.  Sahlolbei M, Dehghani M, Kheiri Yeghane Azar B, Vafaei S, Roviello G, D'Angelo A, Madjd Z, Kiani J. Evaluation of targetable biomarkers for chimeric antigen receptor T-cell (CAR-T) in the treatment of pancreatic cancer: a systematic review and meta-analysis of preclinical studies. Int Rev Immunol. 2020;39:223-232.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
75.  O'Hara M, Stashwick C, Haas AR, Tanyi JL. Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy. Immunotherapy. 2016;8:449-460.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 56]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
76.  Wang J, Liu X, Ji J, Luo J, Zhao Y, Zhou X, Zheng J, Guo M, Liu Y. Orthotopic and Heterotopic Murine Models of Pancreatic Cancer Exhibit Different Immunological Microenvironments and Different Responses to Immunotherapy. Front Immunol. 2022;13:863346.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
77.  Beatty GL, O'Hara MH, Lacey SF, Torigian DA, Nazimuddin F, Chen F, Kulikovskaya IM, Soulen MC, McGarvey M, Nelson AM, Gladney WL, Levine BL, Melenhorst JJ, Plesa G, June CH. Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. Gastroenterology. 2018;155:29-32.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 248]  [Cited by in F6Publishing: 299]  [Article Influence: 49.8]  [Reference Citation Analysis (0)]
78.  Li Z, Shao C, Liu X, Lu X, Jia X, Zheng X, Wang S, Zhu L, Li K, Pang Y, Xie F, Lu Y, Wang Y. Oncogenic ERBB2 aberrations and KRAS mutations cooperate to promote pancreatic ductal adenocarcinoma progression. Carcinogenesis. 2020;41:44-55.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
79.  Feng K, Liu Y, Guo Y, Qiu J, Wu Z, Dai H, Yang Q, Wang Y, Han W. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell. 2018;9:838-847.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 182]  [Article Influence: 26.0]  [Reference Citation Analysis (0)]
80.  Katari UL, Keirnan JM, Worth AC, Hodges SE, Leen AM, Fisher WE, Vera JF. Engineered T cells for pancreatic cancer treatment. HPB (Oxford). 2011;13:643-650.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 50]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
81.  Abate-Daga D, Lagisetty KH, Tran E, Zheng Z, Gattinoni L, Yu Z, Burns WR, Miermont AM, Teper Y, Rudloff U, Restifo NP, Feldman SA, Rosenberg SA, Morgan RA. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum Gene Ther. 2014;25:1003-1012.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 108]  [Cited by in F6Publishing: 118]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
82.  Posey AD Jr, Schwab RD, Boesteanu AC, Steentoft C, Mandel U, Engels B, Stone JD, Madsen TD, Schreiber K, Haines KM, Cogdill AP, Chen TJ, Song D, Scholler J, Kranz DM, Feldman MD, Young R, Keith B, Schreiber H, Clausen H, Johnson LA, June CH. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity. 2016;44:1444-1454.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 341]  [Cited by in F6Publishing: 407]  [Article Influence: 58.1]  [Reference Citation Analysis (0)]
83.  Chung MJ, Park JY, Bang S, Park SW, Song SY. Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer. Cancer Immunol Immunother. 2014;63:939-946.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 59]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
84.  Liu Y, Guo Y, Wu Z, Feng K, Tong C, Wang Y, Dai H, Shi F, Yang Q, Han W. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: A phase I clinical trial. Cytotherapy. 2020;22:573-580.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 87]  [Article Influence: 21.8]  [Reference Citation Analysis (0)]
85.  Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic cancer vaccines. Nat Rev Cancer. 2021;21:360-378.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 299]  [Cited by in F6Publishing: 561]  [Article Influence: 187.0]  [Reference Citation Analysis (0)]
86.  Jou J, Harrington KJ, Zocca MB, Ehrnrooth E, Cohen EEW. The Changing Landscape of Therapeutic Cancer Vaccines-Novel Platforms and Neoantigen Identification. Clin Cancer Res. 2021;27:689-703.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 93]  [Article Influence: 23.3]  [Reference Citation Analysis (0)]
87.  Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, Lillemoe KD, O'Reilly S, Abrams RA, Pardoll DM, Cameron JL, Yeo CJ. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol. 2001;19:145-156.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 438]  [Cited by in F6Publishing: 407]  [Article Influence: 17.7]  [Reference Citation Analysis (0)]
88.  Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, Hege K, Jaffee E. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res. 2008;14:1455-1463.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 250]  [Cited by in F6Publishing: 252]  [Article Influence: 15.8]  [Reference Citation Analysis (0)]
89.  Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, Sugar E, Piantadosi S, Cameron JL, Solt S, Onners B, Tartakovsky I, Choi M, Sharma R, Illei PB, Hruban RH, Abrams RA, Le D, Jaffee E, Laheru D. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg. 2011;253:328-335.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 287]  [Cited by in F6Publishing: 277]  [Article Influence: 21.3]  [Reference Citation Analysis (0)]
90.  Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, Solt S, Dorman A, Wamwea A, Yager A, Laheru D, Wolfgang CL, Wang J, Hruban RH, Anders RA, Jaffee EM, Zheng L. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res. 2014;2:616-631.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 365]  [Cited by in F6Publishing: 341]  [Article Influence: 34.1]  [Reference Citation Analysis (0)]
91.  Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL, Onners B, Uram JN, Laheru DA, Lutz ER, Solt S, Murphy AL, Skoble J, Lemmens E, Grous J, Dubensky T Jr, Brockstedt DG, Jaffee EM. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33:1325-1333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 386]  [Cited by in F6Publishing: 419]  [Article Influence: 46.6]  [Reference Citation Analysis (0)]
92.  Le DT, Picozzi VJ, Ko AH, Wainberg ZA, Kindler H, Wang-Gillam A, Oberstein P, Morse MA, Zeh HJ 3rd, Weekes C, Reid T, Borazanci E, Crocenzi T, LoConte NK, Musher B, Laheru D, Murphy A, Whiting C, Nair N, Enstrom A, Ferber S, Brockstedt DG, Jaffee EM. Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). Clin Cancer Res. 2019;25:5493-5502.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 140]  [Article Influence: 28.0]  [Reference Citation Analysis (0)]
93.  Le DT, Brockstedt DG, Nir-Paz R, Hampl J, Mathur S, Nemunaitis J, Sterman DH, Hassan R, Lutz E, Moyer B, Giedlin M, Louis JL, Sugar EA, Pons A, Cox AL, Levine J, Murphy AL, Illei P, Dubensky TW Jr, Eiden JE, Jaffee EM, Laheru DA. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin Cancer Res. 2012;18:858-868.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 276]  [Cited by in F6Publishing: 251]  [Article Influence: 20.9]  [Reference Citation Analysis (0)]
94.  Rossi GR, Mautino MR, Unfer RC, Seregina TM, Vahanian N, Link CJ. Effective treatment of preexisting melanoma with whole cell vaccines expressing alpha(1,3)-galactosyl epitopes. Cancer Res. 2005;65:10555-10561.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 62]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
95.  Hardacre JM, Mulcahy M, Small W, Talamonti M, Obel J, Krishnamurthi S, Rocha-Lima CS, Safran H, Lenz HJ, Chiorean EG. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg. 2013;17:94-100; discussion p. 100.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 134]  [Cited by in F6Publishing: 130]  [Article Influence: 11.8]  [Reference Citation Analysis (0)]
96.  Hewitt DB, Nissen N, Hatoum H, Musher B, Seng J, Coveler AL, Al-Rajabi R, Yeo CJ, Leiby B, Banks J, Balducci L, Vaccaro G, LoConte N, George TJ, Brenner W, Elquza E, Vahanian N, Rossi G, Kennedy E, Link C, Lavu H. A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer. Ann Surg. 2022;275:45-53.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 42]  [Article Influence: 21.0]  [Reference Citation Analysis (0)]
97.  Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Gedde-Dahl T 3rd, Stokke KT, Sølheim BG, Egge TS, Søreide O, Thorsby E, Gaudernack G. Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study. Int J Cancer. 1996;65:450-453.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 2]  [Reference Citation Analysis (0)]
98.  Gjertsen MK, Bjorheim J, Saeterdal I, Myklebust J, Gaudernack G. Cytotoxic CD4+ and CD8+ T lymphocytes, generated by mutant p21-ras (12Val) peptide vaccination of a patient, recognize 12Val-dependent nested epitopes present within the vaccine peptide and kill autologous tumour cells carrying this mutation. Int J Cancer. 1997;72:784-790.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 2]  [Reference Citation Analysis (0)]
99.  Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Søreide O, Thorsby E, Gaudernack G. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet. 1995;346:1399-1400.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 150]  [Cited by in F6Publishing: 154]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
100.  Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Søreide O, Eriksen JA, Møller M, Baksaas I, Lothe RA, Saeterdal I, Gaudernack G. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer. 2001;92:441-450.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 190]  [Cited by in F6Publishing: 187]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
101.  Wedén S, Klemp M, Gladhaug IP, Møller M, Eriksen JA, Gaudernack G, Buanes T. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer. 2011;128:1120-1128.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 129]  [Cited by in F6Publishing: 120]  [Article Influence: 8.6]  [Reference Citation Analysis (0)]
102.  Abou-Alfa GK, Chapman PB, Feilchenfeldt J, Brennan MF, Capanu M, Gansukh B, Jacobs G, Levin A, Neville D, Kelsen DP, O'Reilly EM. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Am J Clin Oncol. 2011;34:321-325.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 76]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
103.  Ramanathan RK, Lee KM, McKolanis J, Hitbold E, Schraut W, Moser AJ, Warnick E, Whiteside T, Osborne J, Kim H, Day R, Troetschel M, Finn OJ. Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunol Immunother. 2005;54:254-264.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 153]  [Cited by in F6Publishing: 142]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
104.  Kaufman HL, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo KS, Kim DW, Marshall J. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med. 2007;5:60.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 80]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
105.  Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, Geller BA, Schmotzer A, Potter DP, Whiteside T, Finn OJ, Ramanathan RK. A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 2008;6:955-964.  [PubMed]  [DOI]  [Cited in This Article: ]
106.  Brett BT, Smith SC, Bouvier CV, Michaeli D, Hochhauser D, Davidson BR, Kurzawinski TR, Watkinson AF, Van Someren N, Pounder RE, Caplin ME. Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J Clin Oncol. 2002;20:4225-4231.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 88]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
107.  Gilliam AD, Broome P, Topuzov EG, Garin AM, Pulay I, Humphreys J, Whitehead A, Takhar A, Rowlands BJ, Beckingham IJ. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas. 2012;41:374-379.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 59]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
108.  Bernhardt SL, Gjertsen MK, Trachsel S, Møller M, Eriksen JA, Meo M, Buanes T, Gaudernack G. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer. 2006;95:1474-1482.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 208]  [Cited by in F6Publishing: 197]  [Article Influence: 10.9]  [Reference Citation Analysis (0)]
109.  Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, Coxon F, Ross P, Madhusudan S, Roques T, Cunningham D, Falk S, Wadd N, Harrison M, Corrie P, Iveson T, Robinson A, McAdam K, Eatock M, Evans J, Archer C, Hickish T, Garcia-Alonso A, Nicolson M, Steward W, Anthoney A, Greenhalf W, Shaw V, Costello E, Naisbitt D, Rawcliffe C, Nanson G, Neoptolemos J. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 2014;15:829-840.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 265]  [Cited by in F6Publishing: 245]  [Article Influence: 24.5]  [Reference Citation Analysis (0)]
110.  Staff C, Mozaffari F, Frödin JE, Mellstedt H, Liljefors M. Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients. Int J Oncol. 2014;45:1293-1303.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 48]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
111.  Kimura Y, Tsukada J, Tomoda T, Takahashi H, Imai K, Shimamura K, Sunamura M, Yonemitsu Y, Shimodaira S, Koido S, Homma S, Okamoto M. Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Pancreas. 2012;41:195-205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 99]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
112.  Mehrotra S, Britten CD, Chin S, Garrett-Mayer E, Cloud CA, Li M, Scurti G, Salem ML, Nelson MH, Thomas MB, Paulos CM, Salazar AM, Nishimura MI, Rubinstein MP, Li Z, Cole DJ. Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer. J Hematol Oncol. 2017;10:82.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 100]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
113.  Jiang N, Qiao G, Wang X, Morse MA, Gwin WR, Zhou L, Song Y, Zhao Y, Chen F, Zhou X, Huang L, Hobeika A, Yi X, Xia X, Guan Y, Song J, Ren J, Lyerly HK. Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study. Clin Cancer Res. 2017;23:5066-5073.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 51]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
114.  Yanagisawa R, Koizumi T, Koya T, Sano K, Koido S, Nagai K, Kobayashi M, Okamoto M, Sugiyama H, Shimodaira S. WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study. Anticancer Res. 2018;38:2217-2225.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 25]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]