Oncol Res Treat 2018;41:306-312
(DOI:10.1159/000488996)

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

Weber M.M. · Fottner C.

Author affiliations

Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, Mainz, Germany

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Article / Publication Details

First-Page Preview
Abstract of Review Article

Received: January 25, 2018
Accepted: April 05, 2018
Published online: April 26, 2018

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 2

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

For additional information: https://www.karger.com/ORT

Summary

Background: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Method: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Results: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Conclusion: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.

© 2018 S. Karger GmbH, Freiburg



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References

  1. Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A: Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61-72.
    External Resources
  2. Lloyd R, Osamura RY, Klöppel G, Rosai J: WHO classification of tumours of endocrine organs. Geneva, WHO, 2017.
  3. Pavel M, O'Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, Knigge U, Salazar R, Pape UF, Oberg K; Vienna Consensus Conference participants: ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016;103:172-185.
    External Resources
  4. Katz SC, Donkor C, Glasgow K, Pillarisetty VG, Gonen M, Espat NJ, Klimstra DS, D'Angelica MI, Allen PJ, Jarnagin W, Dematteo RP, Brennan MF, Tang LH: T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases. HPB (Oxford) 2010;12:674-683.
    External Resources
  5. Vikman S, Sommaggio R, De La Torre M, Oberg K, Essand M, Giandomenico V, Loskog A, Totterman TH: Midgut carcinoid patients display increased numbers of regulatory T cells in peripheral blood with infiltration into tumor tissue. Acta Oncol 2009;48:391-400.
    External Resources
  6. Ryschich E, Autschbach F, Eisold S, Klar E, Buchler MW, Schmidt J: Expression of HLA class I/II antigens and T cell immune response in human neuroendocrine tumors of the pancreas. Tissue Antigens 2003;62:48-54.
    External Resources
  7. Kasajima A, Ishikawa Y, Iwata A, Steiger K, Oka N, Ishida H, Sakurada A, Suzuki H, Kameya T, Konukiewitz B, Kloppel G, Okada Y, Sasano H, Weichert W: Inflammation and PD-L1 expression in pulmonary neuroendocrine tumors. Endocr Relat Cancer 2018;25:339-350.
    External Resources
  8. Vikman S, Giandomenico V, Sommaggio R, Oberg K, Essand M, Totterman TH: CD8+ T cells against multiple tumor-associated antigens in peripheral blood of midgut carcinoid patients. Cancer Immunol Immunother 2008;57:399-409.
    External Resources
  9. Schott M: Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers. Endocr Relat Cancer 2006;13:779-795.
    External Resources
  10. Raval RR, Sharabi AB, Walker AJ, Drake CG, Sharma P: Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer. J Immunother Cancer 2014;2:14.
    External Resources
  11. Ramsay AG: Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell immunity. Br J Haematol 2013;162:313-325.
    External Resources
  12. Beatty GL, Gladney WL: Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2015;21:687-692.
    External Resources
  13. Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara H, Signori E, Honoki K, Georgakilas AG, Amin A, Helferich WG, Boosani CS, Guha G, Ciriolo MR, Chen S, Mohammed SI, Azmi AS, Keith WN, Bilsland A, Bhakta D, Halicka D, Fujii H, Aquilano K, Ashraf SS, Nowsheen S, Yang X, Choi BK, Kwon BS: Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015;35(suppl):S185-S198.
    External Resources
  14. Keir ME, Butte MJ, Freeman GJ, Sharpe AH: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704.
    External Resources
  15. Su MY, Fisher DE: Immunotherapy in the precision medicine era: melanoma and beyond. PLoS Med 2016;13:e1002196.
    External Resources
  16. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ: Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007;27:111-122.
    External Resources
  17. Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-264.
    External Resources
  18. Kim ST, Ha SY, Lee S, Ahn S, Lee J, Park SH, Park JO, Lim HY, Kang WK, Kim KM, Park YS: The impact of PD-L1 expression in patients with metastatic GEP-NETs. J Cancer 2016;7:484-489.
    External Resources
  19. Inamura K, Yokouchi Y, Kobayashi M, Ninomiya H, Sakakibara R, Nishio M, Okumura S, Ishikawa Y: Relationship of tumor PD-L1 (CD274) expression with lower mortality in lung high-grade neuroendocrine tumor. Cancer Med 2017;6:2347-2356.
    External Resources
  20. Grabowski P, Joehrens K, Arsenic R, Kaemmerer D, Hummel M, Scheibenbogen C, Busse A: Tumor infiltrating lymphocytes and PD-L1 expression differ in low and high grade neuroendocrine tumors. 12th Annual ENETS Conference 2015:abstr 1199.
  21. Li Z, Leng J, Wang H, Li S, Lu M, Zhou L, Huang X, Jia L, Kang Q, Li J, Shen L, Lin D: PD-L1 expression is associated with grade of neuroendocrine tumors. Neuroendocrinology 2016;103(suppl 1):39-40.
  22. Milione M, Pellegrinelli A, Centonze G, Dominoni F, Pusceddu S, Giacomelli L, Buzzoni R, Coppa J, Mazzaferro V, Anichin A, De Braud F: Distribution of T-cell infiltrate in G1, G2 and G3 NENs. 13th Annual ENETS Conference 2016;abstr 1448.
  23. Lamarca A, Nonaka D, Breitwieser W, Ashton G, Barriuso J, McNamara M, Moghadam S, Mansoor W, Hubner R, Clark C, Chakrabarty B, Valle JW: PD-1, PD-L1 and PD-L2 expression in well-differentiated small bowel gastrointestinal neuroendocrine tumours (Wd SB-NETs). 14th Annual ENETS Conference 2017;abstr H9.
  24. Saganas C, Blank A, Franzelli M, Marinoni I, Perren A: PD-L1 is expressed in a subset of pancreatic neuroendocrine tumors (pNET). 14th Annual ENETS Conference 2017;abstr 1780.
  25. Fan Y, Ma K, Wang C, Ning J, Hu Y, Dong D, Dong X, Geng Q, Li E, Wu Y: Prognostic value of PD-L1 and PD-1 expression in pulmonary neuroendocrine tumors. Onco Targets Ther 2016;9:6075-6082.
    External Resources
  26. Patel SP, Kurzrock R: PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015;14:847-856.
    External Resources
  27. Aguiar PN Jr, Santoro IL, Tadokoro H, de Lima Lopes G, Filardi BA, Oliveira P, Mountzios G, de Mello RA: The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. Immunotherapy 2016;8:479-488.
    External Resources
  28. Teng MW, Ngiow SF, Ribas A, Smyth MJ: Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 2015;75:2139-2145.
    External Resources
  29. Colle R, Cohen R, Cochereau D, Duval A, Lascols O, Lopez-Trabada D, Afchain P, Trouilloud I, Parc Y, Lefevre JH, Flejou JF, Svrcek M, Andre T: Immunotherapy and patients treated for cancer with microsatellite instability. Bull Cancer 2017;104:42-51.
    External Resources
  30. Sahnane N, Furlan D, Monti M, Romualdi C, Vanoli A, Vicari E, Solcia E, Capella C, Sessa F, La Rosa S: Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr Relat Cancer 2015;22:35-45.
    External Resources
  31. Mei M, Deng D, Liu TH, Sang XT, Lu X, Xiang HD, Zhou J, Wu H, Yang Y, Chen J, Lu CM, Chen YJ: Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas. J Clin Endocrinol Metab 2009;94:3448-3457.
    External Resources
  32. Arnason T, Sapp HL, Rayson D, Barnes PJ, Drewniak M, Nassar BA, Huang WY: Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors. Arch Pathol Lab Med 2011;135:1539-1544.
    External Resources
  33. Kidd M, Eick G, Shapiro MD, Camp RL, Mane SM, Modlin IM: Microsatellite instability and gene mutations in transforming growth factor-beta type II receptor are absent in small bowel carcinoid tumors. Cancer 2005;103:229-236.
    External Resources
  34. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G: Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214-218.
    External Resources
  35. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA: Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-128.
    External Resources
  36. Snyder A, Wolchok JD, Chan TA: Genetic basis for clinical response to CTLA-4 blockade. N Engl J Med 2015;372:783.
    External Resources
  37. Vollbrecht C, Werner R, Walter RF, Christoph DC, Heukamp LC, Peifer M, Hirsch B, Burbat L, Mairinger T, Schmid KW, Wohlschlaeger J, Mairinger FD: Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group. Br J Cancer 2015;113:1704-1711.
    External Resources
  38. Vijayvergia N, Boland PM, Handorf E, Gustafson KS, Gong Y, Cooper HS, Sheriff F, Astsaturov I, Cohen SJ, Engstrom PF: Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center pilot study. Br J Cancer 2016;115:564-570.
    External Resources
  39. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, Shih KC, Lebbe C, Linette GP, Milella M, Brownell I, Lewis KD, Lorch JH, Chin K, Mahnke L, von Heydebreck A, Cuillerot JM, Nghiem P: Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17:1374-1385.
    External Resources
  40. D'Angelo SP, Russell J, Hassel JC, Lebbe C, Chmielowski B, Rabinowits G, Terheyden P, Brownell I, Zwiener I, Bajars M, Hennessy M, Kaufman H: First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): preliminary data from an ongoing study. J Clin Oncol 2017;35(suppl):abstr 9530.
  41. Bavencio Summary of Product Characteristics. Darmstadt, Merck Serono, 2017.
  42. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, Lundgren L, Margolin K, Mitchell A, Olencki T, Pardoll DM, Reddy SA, Shantha EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA: PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016;374:2542-2552.
    External Resources
  43. Walocko FM, Scheier BY, Harms PW, Fecher LA, Lao CD: Metastatic Merkel cell carcinoma response to nivolumab. J Immunother Cancer 2016;4:79.
    External Resources
  44. Levra MG, Mazieres J, Valette CA, Molinier O, Planchard D, Frappat V, Ferrer L, Toffart AC, Moro-Sibilot D: Efficacy of immune checkpoint inhibitors in large cell neuroendocrine lung cancer: results from a French retrospective cohort. J Thoracic Oncol 2017;12:S702, abstr P701.707-012.
    External Resources
  45. Wang VE, Urisman A, Albacker L, Ali S, Miller V, Aggarwal R, Jablons D: Checkpoint inhibitor is active against large cell neuroendocrine carcinoma with high tumor mutation burden. J Immunother Cancer 2017;5:75.
    External Resources
  46. Paraghamian SE, Longoria TC, Eskander RN: Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report. Gynecol Oncol Res Pract 2017;4:3.
    External Resources
  47. Sharabi A, Kim SS, Kato S, Sanders PD, Patel SP, Sanghvi P, Weihe E, Kurzrock R: Exceptional response to nivolumab and stereotactic body radiation therapy (SBRT) in neuroendocrine cervical carcinoma with high tumor mutational burden: management considerations from the center for personalized cancer therapy at UC San Diego Moores Cancer Center. Oncologist 2017;22:631-637.
    External Resources
  48. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, Lehnert M, Iannone R, Tolcher AW: Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015;21:4286-4293.
    External Resources
  49. Naing A, Gelderblom H, Gainor JF, Forde PM, Butler M, Lin C-C, Sharma S, Ochoa de Olza M, Schellens JHM, Soria J-C, Taylor MH, Silva AP, Li Z, Bilic S, Cameron S, Infante JR: A first-in-human phase I study of the anti-PD-1 antibody PDR001 in patients with advanced solid tumors. J Clin Oncol 2016;34(suppl):3060.
  50. Mehnert JM, Rugo HS, O'Neil BH, Santoro A, Schellens JHM, Cohen RB, Doi T, Ott PA, Pishvaian MJ, Puzanov I, Aung KL, Hsu C, Le Tourneau C, Soria JC, Élez E, Tamura K, Gould M, Zaho G, Stein K, Piha-Paul SA: Pembrolizumab for patients with PD-L1-positive advanced carcinoids or pancreatic neuroendocrine tumors: results from the KEYNOTE-028 study. J Clin Oncol 2017;28(suppl 5):abstr 4270.
  51. Ugwu JK, Nwanyanwu C, Shelke AR: Dramatic response of a metastatic primary small-cell carcinoma of the pancreas to a trial of immunotherapy with nivolumab: a case report. Case Rep Oncol 2017;10:720-725.
    External Resources
  52. Stavrides-Eid M, Soo Rho Y, Barrera I, Kavan P: Case study: Immunotherapy in a young adult with atypical neuroendocrine tumour. 14th Annual ENETS Conference 2017;abstr Q30.
  53. Schmidt D, Wiedenmann B: Extremely long survival under combined immunotherapy in a metastatic functional neuroendocrine neoplasia patient. Neuroendocrinology 2017, DOI: 10.1159/000486417.
    External Resources
  54. Yao JC, Fazio N, Pavel M, Strosberg J, Bergsland E, Ruszniewski P, Voi M, Wu C, Degtyarev E, Aimone P, Singh S: An open-label phase II study to evaluate the efficacy and safety of PDR001 in patients with advanced well-differentiated non-functional NET of pancreatic, gastrointestinal (GI), or thoracic origin who have progressed on prior treatment. 14th Annual ENETS Conference 2017;abstr L19.
  55. Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J: Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer 2015;15:457-472.
    External Resources
  56. Brahmer JR, Pardoll DM: Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. Cancer Immunol Res 2013;1:85-91.
    External Resources

Article / Publication Details

First-Page Preview
Abstract of Review Article

Received: January 25, 2018
Accepted: April 05, 2018
Published online: April 26, 2018

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 2

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

For additional information: https://www.karger.com/ORT


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2018, Vol.41, No. 5

May 2018

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