Advertisement

Immune Response and Immunotherapy in GIST

  • Gerardo A. Vitiello
  • Benjamin D. Medina
  • Ronald P. DeMatteoEmail author
Chapter

Abstract

Imatinib mesylate, a small molecule inhibitor of KIT and PDGFRA, dramatically improves the prognosis of patients with metastatic gastrointestinal stromal tumor (GIST) and serves as a paradigm for targeted molecular therapy. However, imatinib is rarely curative, and recurrent or resistant disease often develops. Immune-checkpoint blockade is a promising new approach to cancer therapy. Correlative research in human GIST specimens has suggested that certain characteristics of the immune infiltrate affect GIST prognosis. Using a genetically engineered mouse model of GIST, we have demonstrated that the therapeutic efficacy of imatinib is partially dependent on the immune system, and imatinib synergizes with multiple immunotherapies. In this chapter, we review the basics of current GIST therapy, detail the macrophage and T cell immune responses in GIST, summarize relevant preclinical GIST immunotherapy research, highlight ongoing and completed clinical trials with immunotherapeutic agents, and suggest future areas for immune therapy in GIST.

Keywords

Gastrointestinal stromal tumor Immunotherapy Imatinib CTLA-4 PD-1 PD-L1 CD40 

References

  1. 1.
    Chan KH, Chan CW, Chow WH, Kwan WK, Kong CK, Mak KF, et al. Gastrointestinal stromal tumors in a cohort of Chinese patients in Hong Kong. World J Gastroenterol. 2006;12(14):2223–8.CrossRefGoogle Scholar
  2. 2.
    Ducimetiere F, Lurkin A, Ranchere-Vince D, Decouvelaere AV, Peoc’h M, Istier L, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294.CrossRefGoogle Scholar
  3. 3.
    Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 2005;41(18):2868–72.CrossRefGoogle Scholar
  4. 4.
    Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005;103(4):821–9.CrossRefGoogle Scholar
  5. 5.
    Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.CrossRefGoogle Scholar
  6. 6.
    Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152(5):1259–69.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Cavnar MJ, Wang L, Balachandran VP, Antonescu CR, Tap WD, Keohan M, et al. Rectal gastrointestinal stromal tumor (GIST) in the era of imatinib: organ preservation and improved oncologic outcome. Ann Surg Oncol. 2017;24(13):3972–80.CrossRefGoogle Scholar
  8. 8.
    Joensuu H, DeMatteo RP. The management of gastrointestinal stromal tumors: a model for targeted and multidisciplinary therapy of malignancy. Annu Rev Med. 2012;63:247–58.CrossRefGoogle Scholar
  9. 9.
    Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708–10.CrossRefGoogle Scholar
  10. 10.
    Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865–78.CrossRefGoogle Scholar
  11. 11.
    Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001;61(22):8118–21.PubMedGoogle Scholar
  12. 12.
    Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33(5):466–77.CrossRefGoogle Scholar
  13. 13.
    DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231(1):51–8.CrossRefGoogle Scholar
  14. 14.
    Goss GAMP, Manola J, Singer S, Fletcher CD, Demetri GD. Clinical and pathologcial characteristics of gastrointestinal stromal tumors (GIST). Prog Proc Am Soc Clin Oncol. 2000;599a:19.Google Scholar
  15. 15.
    Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472–80.CrossRefGoogle Scholar
  16. 16.
    Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11(11):4182–90.CrossRefGoogle Scholar
  17. 17.
    Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26(4):620–5.CrossRefGoogle Scholar
  18. 18.
    Cohen NA, Zeng S, Seifert AM, Kim TS, Sorenson EC, Greer JB, et al. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors. Cancer Res. 2015;75(10):2061–70.CrossRefGoogle Scholar
  19. 19.
    Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007;26(27):3909–19.CrossRefGoogle Scholar
  20. 20.
    Takahashi T, Serada S, Ako M, Fujimoto M, Miyazaki Y, Nakatsuka R, et al. New findings of kinase switching in gastrointestinal stromal tumor under imatinib using phosphoproteomic analysis. Int J Cancer. 2013;133(11):2737–43.PubMedGoogle Scholar
  21. 21.
    Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127–34.CrossRefGoogle Scholar
  22. 22.
    Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295–302.CrossRefGoogle Scholar
  23. 23.
    Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38.CrossRefGoogle Scholar
  24. 24.
    McCarthy EF. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J. 2006;26:154–8.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432–3.CrossRefGoogle Scholar
  26. 26.
    Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98–106.CrossRefGoogle Scholar
  27. 27.
    Brahmer J, Horn L, Jackman D, Spigel D, Antonia S, Hellmann M, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): clinical characteristics of long-term survivors. Cancer Res. 2017;77(13 Supplement):CT077.CrossRefGoogle Scholar
  28. 28.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.CrossRefGoogle Scholar
  29. 29.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.CrossRefGoogle Scholar
  30. 30.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.CrossRefGoogle Scholar
  31. 31.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99.CrossRefGoogle Scholar
  32. 32.
    Sommer G, Agosti V, Ehlers I, Rossi F, Corbacioglu S, Farkas J, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci U S A. 2003;100(11):6706–11.CrossRefGoogle Scholar
  33. 33.
    Cavnar MJ, Zeng S, Kim TS, Sorenson EC, Ocuin LM, Balachandran VP, et al. KIT oncogene inhibition drives intratumoral macrophage M2 polarization. J Exp Med. 2013;210(13):2873–86.CrossRefGoogle Scholar
  34. 34.
    Cameron S, Gieselmann M, Blaschke M, Ramadori G, Fuzesi L. Immune cells in primary and metastatic gastrointestinal stromal tumors (GIST). Int J Clin Exp Pathol. 2014;7(7):3563–79.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Graeme-Cook F, Bhan AK, Harris NL. Immunohistochemical characterization of intraepithelial and subepithelial mononuclear cells of the upper airways. Am J Pathol. 1993;143(5):1416–22.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Radzun HJ, Hansmann ML, Heidebrecht HJ, Bodewadt-Radzun S, Wacker HH, Kreipe H, et al. Detection of a monocyte/macrophage differentiation antigen in routinely processed paraffin-embedded tissues by monoclonal antibody Ki-M1P. Lab Investig. 1991;65(3):306–15.PubMedGoogle Scholar
  37. 37.
    van Dongen M, Savage ND, Jordanova ES, Briaire-de Bruijn IH, Walburg KV, Ottenhoff TH, et al. Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors. Int J Cancer. 2010;127(4):899–909.PubMedGoogle Scholar
  38. 38.
    Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035–43.CrossRefGoogle Scholar
  39. 39.
    Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17(9):1094–100.CrossRefGoogle Scholar
  40. 40.
    Rusakiewicz S, Semeraro M, Sarabi M, Desbois M, Locher C, Mendez R, et al. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res. 2013;73(12):3499–510.CrossRefGoogle Scholar
  41. 41.
    Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34(3):137–43.CrossRefGoogle Scholar
  42. 42.
    Bertucci F, Finetti P, Mamessier E, Pantaleo MA, Astolfi A, Ostrowski J, et al. PDL1 expression is an independent prognostic factor in localized GIST. Oncoimmunology. 2015;4(5):e1002729.CrossRefGoogle Scholar
  43. 43.
    Blakely AM, Matoso A, Patil PA, Taliano R, Machan JT, Miner TJ, et al. Role of immune microenvironment in gastrointestinal stromal tumours. Histopathology. 2017;72(3):405–13.CrossRefGoogle Scholar
  44. 44.
    Seifert AM, Zeng S, Zhang JQ, Kim TS, Cohen NA, Beckman MJ, et al. PD-1/PD-L1 blockade enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors. Clin Cancer Res. 2017;23(2):454–65.CrossRefGoogle Scholar
  45. 45.
    Katz SC, Burga RA, Naheed S, Licata LA, Thorn M, Osgood D, et al. Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor. J Transl Med. 2013;11:46.CrossRefGoogle Scholar
  46. 46.
    Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, Lyonnet L, et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med. 2011;17(6):700–7.CrossRefGoogle Scholar
  47. 47.
    Menard C, Blay JY, Borg C, Michiels S, Ghiringhelli F, Robert C, et al. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 2009;69(8):3563–9.CrossRefGoogle Scholar
  48. 48.
    Pautier P, Locher C, Robert C, Deroussent A, Flament C, Le Cesne A, et al. Phase I clinical trial combining imatinib mesylate and IL-2 in refractory cancer patients: IL-2 interferes with the pharmacokinetics of imatinib mesylate. Oncoimmunology. 2013;2(2):e23079.CrossRefGoogle Scholar
  49. 49.
    D’Angelo SP, Shoushtari AN, Keohan ML, Dickson MA, Gounder MM, Chi P, et al. Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas: a phase Ib study of dasatinib plus ipilimumab. Clin Cancer Res. 2017;23(12):2972–80.CrossRefGoogle Scholar
  50. 50.
    Reilley MJ, Bailey A, Subbiah V, Janku F, Naing A, Falchook G, et al. Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies. J Immunother Cancer. 2017;5:35.CrossRefGoogle Scholar
  51. 51.
    Chen LL, Chen X, Choi H, Sang H, Chen LC, Zhang H, et al. Exploiting antitumor immunity to overcome relapse and improve remission duration. Cancer Immunol Immunother. 2012;61(7):1113–24.CrossRefGoogle Scholar
  52. 52.
    Toulmonde M, Penel N, Adam J, Chevreau C, Blay J-Y, Le Cesne A, et al. Combination of pembrolizumab and metronomic cyclophosphamide in patients with advanced sarcomas and GIST: A French Sarcoma Group phase II trial. J Clin Oncol. 2017;35(15_suppl):11053.CrossRefGoogle Scholar
  53. 53.
    Komita H, Koido S, Hayashi K, Kan S, Ito M, Kamata Y, et al. Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression in human gastrointestinal stromal tumors. Oncol Rep. 2015;34(4):2099–105.CrossRefGoogle Scholar
  54. 54.
    Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother. 2016;65(10):1243–8.CrossRefGoogle Scholar
  55. 55.
    Knee DA, Hewes B, Brogdon JL. Rationale for anti-GITR cancer immunotherapy. Eur J Cancer. 2016;67:1–10.CrossRefGoogle Scholar
  56. 56.
    Messenheimer DJ, Jensen SM, Afentoulis ME, Wegmann KW, Feng Z, Friedman DJ, et al. Timing of PD-1 blockade is critical to effective combination immunotherapy with anti-OX40. Clin Cancer Res. 2017;23(20):6165–77.CrossRefGoogle Scholar
  57. 57.
    Huang Y, Ma Y, Gao P, Yao Z. Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy. J Thorac Dis. 2017;9(2):E168–74.CrossRefGoogle Scholar
  58. 58.
    Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One. 2015;10(9):e0137345.CrossRefGoogle Scholar
  59. 59.
    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.CrossRefGoogle Scholar
  60. 60.
    Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.CrossRefGoogle Scholar
  61. 61.
    Zhang JQ, Zeng S, Vitiello GA, Seifert AM, Medina BD, Beckman MJ, Loo JK, Santamaria-Barria J, Maltbaek JH, Param NJ, Moral JA, Zhao JN, Balachandran V, Rossi F, Antonescu CR, DeMatteo RP. Macrophages and CD8 T cells mediate the antitumor efficacy of combined CD40 ligation and imatinib therapy in gastrointestinal stromal tumors. Cancer Immunol Res. 2018;6(4):434–47.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Gerardo A. Vitiello
    • 1
  • Benjamin D. Medina
    • 1
  • Ronald P. DeMatteo
    • 2
    Email author
  1. 1.Department of SurgeryNew York University Langone Health SystemNew YorkUSA
  2. 2.Department of SurgeryHospital of the University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations