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PD-1 immunotherapy in pancreatic cancer

current status

Pu, Ning MDa,b; Lou, Wenhui MD, PhDa,*; Yu, Jun MD, PhDb,*

doi: 10.1097/JP9.0000000000000010
Review Articles
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Pancreatic ductal adenocarcinoma is the known kind of tumor biologically featured as high malignant degree, lack of effective methods for diagnosis and treatment, which reflects its unpleasant prognosis. Recently, with the breakthrough of burgeoning therapeutic methods, the flush of dawn for pancreatic cancer nearly arrives. Nowadays, besides surgery, neoadjuvant chemoradiotherapy, tumor vaccine therapy, and immunotherapy all show their active situation and obtain certain clinical efficacy, but that is still limited to pancreatic cancer. However, the appearance and development of programmed cell death-1 (PD-1) immune checkpoint inhibitor may final improve survival of pancreatic cancer. This article aims to deeply understand the value of PD-1 immune checkpoint inhibitor in pancreatic cancer and validly provide the evidence for treatment by means of performing a systematic review on the current status in the fields of the mechanism and application of anti-PD-1 in pancreatic cancer, associations with surgery, PD-1-related side effects and prospections.

aDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China

bDepartment of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD

Corresponding author: Jun Yu, Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287 (e-mail: jyu41@jhmi.edu); Wenhui Lou, Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People's Republic of China (e-mail: lou.wenhui@zs-hospital.sh.cn)

How to cite this article: Pu N, Lou WH, Yu J. PD-1 immunotherapy in pancreatic cancer: current status. J Pancreatol 2019;00:00–00. doi: 10.1097/JP9.0000000000000010

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

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Introduction

Pancreatic ductal adenocarcinoma (PDAC) is world-widely considered as one of the most malignant tumors. Owing to a lack of methods for early detection and specific clinical characteristics, it is always too late to obtain radical resection when it confirms. Its total 5-year survival is still less than 8% regardless of combination with chemotherapy and radiotherapy.[1–4] Pancreatic cancer microenvironment is a dynamic network composed of highly fibrotic interstitium containing a large number of tumor cells, extracellular matrix components, and immune-inflammatory cells.[5] The treatment failure of PDAC is probably associated with tumor suppressive immune response and immune escape.[6]

The human immune system is the primary biological barrier and precise biological system that defends the body against the surrounding damages. It plays a vital role in the tumorigenesis and progression.[7] The activation of T cells is crucial in organismic immune response, whose primary signal comes from the binding of the peptide-major histocompatibility complex on the surface of antigen-presenting cells (APC) and T-cell receptor on T lymphocytes, and second signal generates from the interaction between the costimulatory molecules of T lymphocytes and APCs.[8] Costimulatory molecules on T lymphocytes are essential immune checkpoints including positive and negative molecules. Positive immune checkpoint, such as CD28, can produce a positive signal and promote lymphocytes proliferation, differentiation, and functions, while negative immune checkpoint, such as programmed cell death-1 (PD-1), can generate a negative signal and suppress lymphocytes functions leading to immunodeficiency or energy.[9,10]

PD-1 is widely confirmed its expression on activated T cells, B cells, NK cells, monocytes, and dendritic cells, while programed death-ligands (PD-Ls) is mostly located on solid tumors, tumor-infiltrating dendritic cells, and macrophages.[11–13] There is accumulating evidence that tumors exploit PD-1-dependent immune suppression for immune evasion. PD-1 is a member of the CD28 superfamily that interacts with its ligands, PD-L1 or PD-L2 to deliver negative signals. PD-1 and its 2 ligands are widely expressed and exert a broader range of immune suppression roles in activation of T cells. Subsequent studies showed that their interaction protected tissues from autoimmune attack and regulated the induction and maintenance of peripheral tolerance. PD-1 receptor-ligand binding was also involved in attenuating tumor immunity and infectious immunity and facilitating tumor progression and chronic infection.[14–16] Its potential molecular mechanism of immune inhibition was phosphorylated ITSM (TxYxxL)-associated SHP-1 or SHP-2, induced regulatory T cells (Tregs), and IL-2 production.[17–21]

The expression of PD-L1 and PD-L2 has been found on a wide variety of solid tumors and hematologic malignancies.[22–27] In addition, PD-1 expression on tumor-infiltrating lymphocytes (TILs) has been reported, suggesting that these T cells are functionally exhausted.[14,19] Strikingly, PD-Ls expression on tumor cells was strongly correlated to an unfavorable prognosis, which had been manifested in a variety of cancers containing pancreatic, bladder, gastric, kidney, esophageal, and ovarian cancers and melanoma.[28–34] The inhibition of local immune response can further promote tumor proliferation, extension, and metastasis.

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Overview of PD-1 research in PDAC

Based on the previous introduction on PD-1/PD-L1, treatment targeting PD-1/PD-L1 in PDAC showed no apparent therapeutic effects. The majority of PDAC excluding mismatch repair deficiencies are regarded as resistant or immune-quiescent tumors and are non-responsive to single checkpoint treatment, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-PD-1.[35] However, some advances have already been achieved in combination with anti-PD-1 treatment for PDAC. Soares et al[36] reported in preclinical murine research that the cure rate under combination GM-CSF cell-based vaccines (GVAX) and anti-transforming growth factor-β therapy was about 30% and additional association with anti-PD-1 antibodies came up to 50%. In addition, Arce Vargas et al[37] found that Fc-optimized anti-CD25 treatment could deplete tumor-infiltrating Tregs and synergize with anti-PD-1 antagonists to eradicate solid cancers. In another preclinical research, researchers observed that CD25, transforming growth factor-β blockade combined with anti-PD-1 therapy had a higher cure rate in a murine model than previous research, and it was up to 80%.[2] Concomitantly, 1 more preclinical study confirmed that combining CSF1R blockade with anti-PD-1 and anti-CTLA-4 blockade showed a more evident tumor suppressive effect than with anti-PD-1 and anti-CTLA-4 blockade, independent of gemcitabine, which indicated that a CSF1R blockade might stimulate the response of PDAC to immune checkpoint blockade therapy.[38]

In PDAC, the human PD-1-antibody drugs now tested in clinical trials are Pidilizumab, Nivolumab, and Pembrolizumab.[39] In PDAC patients with previous chemotherapy treatment, a 2-armed, 1:1 randomized, phase II study of cyclophosphamide-GVAX-vaccine (CY/GVAX) and CRS-207 (a live-attenuated Listeria monocytogene-expressing mesothelin drug) was reported to be conducted with or without Nivolumab. Patients who received 2 doses of CY/GVAX and Nivolumab and 4 doses of CRS-207 and Nivolumab (Arm A) would be compared with patients who received 2 doses of CY/GVAX and 4 doses of CRS-207 (Arm B). Overall survival was the primary assessment of this study. This combination therapy with Nivolumab may result in priming tumor antigen-specific T lymphocytes and blocking immune checkpoints simultaneously. In this study, CY/GVAX-vaccine and CRS-207 were to prime tumor antigen-specific T lymphocytes.[40] In an ASCO symposium, Firdaus et al[41] presented a 2-armed, 2-part, phase I study of Nivolumab and Nab-paclitaxel-cytostatic with and without Gemcitabine in advanced PDAC patients. Patients were administered with 3 mg/kg Nivolumab and125 mg/m2 Nab-paclitaxel (Arm A) compared with patients who were administered with 3 mg/kg Nivolumab, 125 mg/m2 Nab-paclitaxel and 1000 mg/m2 Gemcitabine (Arm B). In this still recruiting clinical trial, evaluation of dose-limiting toxicity (Part I), in concomitance with evaluation of the safety of Nab-paclitaxel/Nivolumab combination (Parts I and II) were the primary objectives.

A phase I trial had enrolled 32 patients and included only 1 pancreatic cancer patient. The trial was performed to confirm the maximum tolerated dose, safety, anti-tumor response and pharmacokinetics, and pharmacodynamics of Pembrolizumab (MK-3475) in advanced solid tumor patients. The PDAC patient was stabilized as the best response to MK-3475 who showed disease-free progression for 20 weeks after anti-PD-1 treatment.[42] In another clinical trial of 2-part immunotherapies, Pembrolizumab and Pexidartinib, a colony-stimulating factor 1 receptor inhibitor were tested in patients with PDAC, as well as other solid tumors. Pharmacokinetic and pharmacodynamic effects, safety, and efficacy, were to be evaluated. Pexidartinib was expected to target myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) because MDSCs could inhibit tumor surveillance and cause resistance to PD-1 antagonists and TAMs could contribute to tumor growth and promote tumor resistance to radiochemotherapy.[43] Weiss et al[44] reported that gemcitabine, nab-paclitaxel, and pembrolizumab could be safely given to chemotherapy-naive PDAC patients. Efficacy appeared to be slightly improved over previously reported results for standard weekly ×3 every 28-day gemcitabine and nab-paclitaxel dosing. Table 1 shows the latest clinical trials concerning anti-PD-1 therapy in PDAC.

Table 1

Table 1

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PD-1 immunotherapy and surgery

Recently, large amounts of researches confirmed that a significant promotion on overall outcomes was found in PDAC patients with perioperative chemoradiotherapies.[45,46] However, there remains a lack of random, multicenter clinical researches to assess the safety and efficiency of PD-1 immunotherapy during perioperative. In the latest retrospective research, 17 enrolled patients who were diagnosed with melanoma (n = 14), renal cell carcinoma (n = 2), and urothelial carcinoma (n = 1) received perioperative immune checkpoint therapy in 22 operations. Perioperative immune checkpoint therapies included pembrolizumab (n = 10), ipilimumab (n = 5), atezolizumab (n = 5), and ipilimumab/nivolumab (n = 2). The results showed no Grades III-IV Clavien–Dindo complications and only 1 death secondary to ventricular fibrillation in the setting of coronary artery disease. Immune checkpoint inhibitors appeared to be safe in the perioperative settings including multiple different types of surgery and were not probably necessary to be stopped in the perioperative settings.[46] In an early lung cancer clinical research, Nivolumab was administrated to patients at 2 and 4 weeks before surgery. As a result, there were no delayed operations, or serious postoperative side effects occurred.[47] Many prospective still enrolling clinical studies are being conducted in multiple solid tumors with perioperative PD-1 immunotherapy.[48–52] The perioperative PD-1 immunotherapy has not yet been reported in PDAC. It will be a profound exploration of whether PDAC patients obtain excellent benefits from the PD-1 immunotherapy during perioperative periods.

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PD-1 immunotherapy related side effects

It has been reported that the main side effects of immune checkpoint inhibitors are closely associated with the immune response to normal cells, which is considered as immune-related adverse events (irAE), such as rashes, encephalitis, colitis, endocrine diseases, and hepatitis.[53,54] Therefore, dose control and pharmacokinetic assessment are crucial, and the application of immune checkpoint inhibitors is often accompanied by risk warnings about severe or even fatal irAEs resulting from T-cell activation and proliferation. Prasanna et al[55] reported a case of isolated immune-related pancreatic exocrine insufficiency after pembrolizumab treatment in metastatic melanoma. In addition, Costa et al[56] reported an extremely rapid pneumonitis within 24 hours after use of Nivolumab for PDAC. As more and more clinical researches conducted in PDAC patients, much unpredictable response towards PD-1 immunotherapy may occur and more attention needs to be paid in the administration of patients.

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Prospection

Now, we are still facing with a critical issue that effective immune therapies are only used for patients with advanced cancers. When other therapies fail, the immune system of patients may also be damaged. Therefore, if we can interfere with immunotherapies early, over 50% of patients may benefit. However, it is still impossible owing to a lack of robust clinical evidence confirming its superiority. Some researchers even said immune checkpoint therapies, such as PD-1, had no benefit to solid tumor containing PDAC, which was probably owing to the tumor mutational burden, levels of PD-L1 expression, microsatellite instability, DNA mismatch repair deficiency, or TILs.[57,58]

However, it is critical for immune checkpoint molecules in regulating the immune system. PD-1 immune checkpoint molecule is one of the most popular markers of T lymphocytes in the tumor microenvironment. PD-1 single immunotherapy to PDAC may show no good results, but a combination with other immunotherapies, chemotherapies or radiotherapies may obtain a wide room. Concomitantly, in-depth study of the molecular mechanism of the microenvironment in PDAC regulating changes of immune checkpoint molecule is conducive to intervene to its upstream and solve current limitations of immunotherapy for PDAC. PD-1 blockade is a method that makes the immunolocalization, so further studies towards microenvironment may finally impact the efficiency of PD-1 immunotherapy and improve the prognosis of PDAC.

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Acknowledgments

None.

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Author contributions

None.

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Financial support

None.

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Conflicts of interest

The authors declare no conflicts of interest.

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Keywords:

Checkpoint inhibitor; Immunotherapy; Pancreatic cancer; PD-1; Prognosis

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