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Emerging developments in immune checkpoint inhibitor therapy for gastroenteropancreatic neuroendocrine neoplasm
Received date: 2022-11-07
Online published: 2023-08-18
Immunotherapies targeting immune checkpoints have undergone rapid evolution, and have been preliminary explored in treatment of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) in recent years. However, their potential to deliver tangible clinical benefits remains uncertain. In this article, we systematically reviewed the current status and efficacy of clinical trials, which evaluated immune checkpoint inhibitor (ICI) as monotherapy or in dual-ICI therapy for GEP-NEN. Despite lacking substantial breakthroughs in GEP-NEN treatment, ICI demonstrated some antitumor activity and safety in treating recurrent or metastatic GEP-NEN, albeit with a generally low objective response rate (ORR). The ORR of ICI in GEP-NEN treatment exhibited a negative correlation with tumor differentiation, suggesting that poorly diffe-rentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) might achieve better clinical responses. Disease control rate of dual-ICI therapy was higher than that of monotherapy. However, dual-ICI also got more severe side effects. Given the rarity of mismatch repair gene defects and high microsatellite instability (dMMR/MSI-H) in GEP-NEN, patients with high tumor mutational burden (TMB-H≥10 muts/Mb) could get potentially benefit from ICI therapy. In the future, it is expected to further explore the synergistic combined application of ICI with chemotherapy, radiotherapy, and antiangiogenic drugs in GEP-NEN, which may enhance its antitumor efficacy. Clinically, the benefit groups of ICI immunotherapy should be evaluated comprehensively according to pathological grading, immune markers, disease progression, and patient's physical condition.
HAN Xu, WANG Wenquan, LOU Wenhui, LIU Liang . Emerging developments in immune checkpoint inhibitor therapy for gastroenteropancreatic neuroendocrine neoplasm[J]. Journal of Surgery Concepts & Practice, 2023 , 28(03) : 267 -272 . DOI: 10.16139/j.1007-9610.2023.03.015
| [1] | POLEé I N, HERMANS B C M, VAN DER ZWAN J M, et al. Long-term survival in patients with gastroenteropancreatic neuroendocrine neoplasms: a population-based study[J]. Eur J Cancer, 2022, 172:252-263. |
| [2] | OTT P A, ELEZ E, HIRET S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ⅰb KEYNOTE-028 study[J]. J Clin Oncol, 2017, 35(34):3823-3829. |
| [3] | WEBER M M, FOTTNER C. Immune checkpoint inhibitors in the treatment of patients with neuroendocrine neoplasia[J]. Oncol Res Treat, 2018, 41(5):306-312. |
| [4] | VIJAYVERGIA N, DASARI A, DENG M, et al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials[J]. Br J Cancer, 2020, 122(9):1309-1314. |
| [5] | STROSBERG J, MIZUNO N, DOI T, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase Ⅱ KEYNOTE-158 study[J]. Clin Cancer Res,2020,26(9):2124-2130. |
| [6] | PATEL S P, OTHUS M, CHAE Y K, et al. A phase Ⅱ basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors[J]. Clin Cancer Res, 2020, 26(10):2290-2296. |
| [7] | PATEL S P, MAYERSON E, CHAE Y K, et al. A phase Ⅱ basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: high-grade neuroendocrine neoplasm cohort[J]. Cancer, 2021, 127(17):3194-3201. |
| [8] | LU M, ZHANG P, ZHANG Y, et al. Efficacy, safety, and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase Ⅰb trial[J]. Clin Cancer Res, 2020, 26(10):2337-2345. |
| [9] | KLEIN O, KEE D, MARKMAN B, et al. Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers[J]. Clin Cancer Res, 2020, 26(17):4454-4459. |
| [10] | MEHNERT J M, BERGSLAND E, O'NEIL B H, et al. Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: results from the KEYNOTE-028 study[J]. Cancer, 2020, 126(13):3021-3030. |
| [11] | YAO J C, STROSBERG J, FAZIO N, et al. Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms[J]. Endocr Relat Cancer, 2021:ERC-20-0382.R1. |
| [12] | B?SCH F, BRüWER K, ALTENDORF-HOFMANN A, et al. Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia[J]. Endocr Relat Cancer, 2019, 26(3):293-301. |
| [13] | O'DONNELL J S, TENG M W L, SMYTH M J. Cancer immunoediting and resistance to T cell-based immunotherapy[J]. Nat Rev Clin Oncol, 2019, 16(3):151-167. |
| [14] | 楼文晖, 韩序. 胃肠胰神经内分泌肿瘤新辅助治疗及转化治疗的策略[J]. 中华消化外科杂志, 2022, 21(4):465-469. |
| [14] | LOU W H, HAN X. Strategies of neoadjuvant and conversion therapy for gastroenteropancreatic neuroendocrine neoplasms[J]. Chin J Dig Surg, 2022, 21(4):465-469. |
| [15] | OVCINNIKOVS V, ROSS E M, PETERSONE L, et al. CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells[J]. Sci Immunol, 2019, 4(35):eaaw0902. |
| [16] | TEKGUC M, WING J B, OSAKI M, et al. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells[J]. Proc Natl Acad Sci U S A, 2021, 118(30):e2023739118. |
| [17] | ARNASON T, SAPP H L, RAYSON D, et al. Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors[J]. Arch Pathol Lab Med, 2011, 135(12):1539-1544. |
| [18] | YOUNG K, LAWLOR R T, RAGULAN C, et al. Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours[J]. Gut, 2021, 70(10):1904-1913. |
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