Immunotherapy of Malignant Peritoneal Mesothelioma and Pseudomyxoma Peritonei

  • Irina Zh. Zhubina
  • Irina O. Chikileva
  • Mikhail V. Kiselevskiy


Immunotherapy of malignant peritoneal mesothelioma and pseudomixoma peritonei is a promising method and is actively developed to treat patients with these malignancies. The approach includes methods of adoptive cellular immunotherapy with local infusions of autologic activated or genetically modified lymphocytes and target drugs based on monoclonal antibodies, including immune checkpoint inhibitors.


Immunotherapy LAK-cells CAR-T-cells Immune checkpoint inhibitors 


  1. 1.
    Zervos MD, Bizekis C, Pass HI (2008) Malignant mesothelioma 2008. Curr Opin Pulm Med 14(4):303–309CrossRefGoogle Scholar
  2. 2.
    Bononi A, Napolitano A, Pass H, Yang H, Carbone M (2015) Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies. Expert Rev Respir Med 9(5):633–654. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lai J, Zhou Z, Tang XJ, Gao ZB, Zhou J, Chen SQ (2016) A tumor-specific neo-antigen caused by a frameshift mutation in BAP1 is a potential personalized biomarker in malignant peritoneal mesothelioma. Int J Mol Sci 17(5):pii: E739. CrossRefGoogle Scholar
  4. 4.
    Vogelzang NJ, Rusthoven JJ, Symanowski J et al (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644CrossRefGoogle Scholar
  5. 5.
    Scherpereel A, Astoul P, Baas P et al. (2010) Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J 135(3):479–495CrossRefGoogle Scholar
  6. 6.
    Grégoire M (2010) What’s the place of immunotherapy in malignant mesothelioma treatments? Cell Adh Migr 4(1):153–161CrossRefGoogle Scholar
  7. 7.
    Goey SH, Eggermont AM, Punt CJ, Slingerland R, Gratama JW, Oosterom R, Oskam R, Bolhuis RL, Stoter G (1995) Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study. Br J Cancer 72(5):1283–1288CrossRefGoogle Scholar
  8. 8.
    Kiselevsky MV (ed) (2012) Malignant Effusions: Pleuritis, Ascites, Pericardites. Springer, Dordrecht/New York, p 156Google Scholar
  9. 9.
    Doherty M, Leighl NB, Feld R, Bradbury PA (1999) Phase I/II study of tumor-infiltrating lymphocyte (TIL) infusion and low-dose interleukin-2 (IL-2) in patients with advanced malignant pleural mesothelioma. Ann Surg Oncol 6(3):272–278CrossRefGoogle Scholar
  10. 10.
    Hegmans JP, Veltman JD, Lambers ME, de Vries IJ, Figdor CG, Hendriks RW, Hoogsteden HC, Lambrecht BN, Aerts JG (2010) Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am J Respir Crit Care Med 181(12):1383–1390CrossRefGoogle Scholar
  11. 11.
    Aerts J, Cornelissen R, Leest CVD et al (2017) OA13.06 autologous dendritic cells loaded with allogeneic tumor cell lysate (Pheralys®) in patients with mesothelioma: final results of a Phase I study. J Thorac Oncol 12(1):S295CrossRefGoogle Scholar
  12. 12.
    van den Ancker W, van Luijn MM, Westers TM et al (2010) Recent advances in antigen-loaded dendritic cell-based strategies for treatment of minimal residual disease in acute myeloid leukemia. Immunotherapy 2(1):69–83CrossRefGoogle Scholar
  13. 13.
    Cornelissen R, Lievense LA, Heuvers ME, Maat AP, Hendriks RW, Hoogsteden HC, Hegmans JP, Aerts JG (2012) Dendritic cell-based immunotherapy in mesothelioma Immunotherapy 4(10):1011–1022CrossRefGoogle Scholar
  14. 14.
    Baas P, Buikhuisen W, Dalesio O et al (2011) A multicenter, randomized Phase III maintenance study of thalidomide (arm A) versus observation (arm B) in patients with malignant pleural mesothelioma (MPM) after induction chemotherapy. J Clin Oncol 29(Suppl): Abstract 7006CrossRefGoogle Scholar
  15. 15.
    Jakobsen JN, Sørensen JB (2011) Review on clinical trials of targeted treatments in malignant mesothelioma. Cancer Chemother Pharmacol 68(1):1–15CrossRefGoogle Scholar
  16. 16.
    Dubey S, Jänne PA, Krug L, Pang H, Wang X, Heinze R, Watt C, Crawford J, Kratzke R, Vokes E, Kindler HL (2010) A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307. J Thorac Oncol 5(10):1655–1661CrossRefGoogle Scholar
  17. 17.
    Stevenson JP, Kindler HL, Papasavvas E et al (2013) Immunological effects of the TGFbeta-blocking antibody GC1008 in malignant pleural mesothelioma patients. Oncoimmunology 2(8):e26218CrossRefGoogle Scholar
  18. 18.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefGoogle Scholar
  19. 19.
    Cedres S, Ponce-Aix S, Zugazagoitia J et al (2015) Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM). PloS One 10(3):e0121071CrossRefGoogle Scholar
  20. 20.
    Calabro L, Morra A, Fonsatti E et al (2013) Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14(11):1104–1111CrossRefGoogle Scholar
  21. 21.
    Calabro L, Morra A, Fonsatti E et al (2015) Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med 3(4):301–309CrossRefGoogle Scholar
  22. 22.
    American Association for Cancer Research [No author listed] A Potential immune therapy for mesothelioma (2015) Cancer Discov Jul; 5(7)Google Scholar
  23. 23.
    Maio M, Scherpereel A, Calabrò L, Aerts J, Perez SC, Bearz A, et al (2017) Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol 18(9):1261–1273. Epub 2017 Jul 17CrossRefGoogle Scholar
  24. 24.
    Pastan I, Hassan R (2014) Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res 74(11):2907–2912CrossRefGoogle Scholar
  25. 25.
    Servais EL, Colovos C, Rodriguez L et al (2012) Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clin Cancer Res 18(9):2478–2489CrossRefGoogle Scholar
  26. 26.
    Hassan R, Schweizer C, Lu KF et al (2010) Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy. Lung Cancer 68(3):455–459CrossRefGoogle Scholar
  27. 27.
    Hassan R, Cohen SJ, Phillips M et al (2010) Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res 16(24):6132–6138CrossRefGoogle Scholar
  28. 28.
    Hassan R, Kindler HL, Jahan T et al (2014) Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin Cancer Res 20(23):5927–5936CrossRefGoogle Scholar
  29. 29.
    May RJ, Dao T, Pinilla-Ibarz J et al (2007) Peptide epitopes from the Wilms’ tumor 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells. Clin Cancer Res 13(15 Pt 1):4547–4555CrossRefGoogle Scholar
  30. 30.
    Zolot RS, Basu S, Million RP (2013) Antibody-drug conjugates. Nat Rev Drug Discov 12(4):259–260CrossRefGoogle Scholar
  31. 31.
    Hassan R, Lerner MR, Benbrook D et al (2002) Antitumor activity of SS(dsFv)PE38 and SS1(dsFv)PE38, recombinant antimesothelin immunotoxins against human gynecologic cancers grown in organotypic culture in vitro. Clin Cancer Res 8(11):3520–3526PubMedGoogle Scholar
  32. 32.
    Li Q, Verschraegen CF, Mendoza J, Hassan R (2004) Cytotoxic activity of the recombinant anti-mesothelin immunotoxin, SS1(dsFv)PE38, towards tumor cell lines established from ascites of patients with peritoneal mesotheliomas. Anticancer Res 24(3a):1327–1335PubMedGoogle Scholar
  33. 33.
    Hassan R, Bullock S, Premkumar A et al (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 13(17):5144–5149CrossRefGoogle Scholar
  34. 34.
    Kreitman RJ, Hassan R, Fitzgerald DJ, Pastan I (2009) Phase I trial of continuous infusion anti-mesothelin recombinant immunotoxin SS1P. Clin Cancer Res 15(16):5274–5279CrossRefGoogle Scholar
  35. 35.
    Hassan R, Sharon E, Thomas A et al (2014) Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. Cancer 120(21):3311–3319CrossRefGoogle Scholar
  36. 36.
    Hassan R, Miller AC, Sharon E et al (2013) Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med 5(208):208ra14CrossRefGoogle Scholar
  37. 37.
    Junghans RP (2017) The challenges of solid tumors for designer CAR-T therapies: a 25-year perspective. Cancer Gene Ther 24:89–99CrossRefGoogle Scholar
  38. 38.
    Adusumilli PS, Cherkassky L, Villena-Vargas J et al (2014) Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med 6(261):261ra151CrossRefGoogle Scholar
  39. 39.
    Mayor M, Zeltsman M, McGee E (2016) Adusumilli PS A regional approach for CAR T-cell therapy for mesothelioma: from mouse models to clinical trial. Immunotherapy 8(5):491–494CrossRefGoogle Scholar
  40. 40.
    Wang LC, Lo A, Scholler J et al (2014) Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2(2):154–166CrossRefGoogle Scholar
  41. 41.
    Rajasagi M, Shukla SA, Fritsch EF, Keskin DB, Deluca D, Carmona E, Zhang W, Sougnez C, Cibulskis K, Sidney J et al (2014) Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124:453–462CrossRefGoogle Scholar
  42. 42.
    Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS et al (2014) Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344:641–645. CrossRefPubMedGoogle Scholar
  43. 43.
    Huang J, El-Gamil M, Dudley ME, Li YF, Rosenberg SA, Robbins PF (2004) T cells associated with tumor regression recognize frameshifted products of the CDKN2A tumor suppressor gene locus and a mutated HLA class I gene product. J Immunol 172:6057–6064CrossRefGoogle Scholar
  44. 44.
    Hacohen N, Fritsch EF, Carter TA, Lander ES, Wu CJ (2013) Getting personal with neoantigen-based therapeutic cancer vaccines. Cancer Immunol Res 1:11–15CrossRefGoogle Scholar
  45. 45.
    Gauvrit A, Brandler S, Sapede-Peroz C, Boisgerault N, Tangy F, Gregoire M (2008) Measles virus induces oncolysis of mesothelioma cells and allows dendritic cells to cross-prime tumor-specific CD8 response. Cancer Res 68(12):4882–4892CrossRefGoogle Scholar
  46. 46.
    Shubina IZ, Blumenberg AG, Volkov SM, Demidov LV, Kiselevskiy MV (2007) Adoptive immunotherapy of malignant neoplasms. Vestnik RAMS 11:9–15Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Irina Zh. Zhubina
    • 1
  • Irina O. Chikileva
    • 1
  • Mikhail V. Kiselevskiy
    • 1
  1. 1.Laboratory of Cell ImmunityN.N. Blokhin National Medical Research CenterMoscowRussia

Personalised recommendations