Skip to main content

Advertisement

SpringerLink
Log in

Immunothérapie anticancéreuse et cancers digestifs

Immunotherapy in gastro-intestinal malignacies

  • Dossier Thématique / Thematic File
  • Published:
Côlon & Rectum

Résumé

L’immunothérapie active n’a actuellement aucune place dans le traitement du cancer colorectal ni d’autres cancers digestifs. La principale voie de recherche clinique est l’utilisation d’anticorps ciblant les molécules de costimulation inhibitrices, notamment les anti-PD-1, qui ont fait leur preuve dans d’autres types de cancer. Si les premières données avec ces molécules étaient franchement décevantes, l’identification de réponses importantes chez les patients avec instabilité microsatellite a permis un regain d’intérêt pour ces traitements. Enfin, de nombreuses études pilotes ont été réalisées avec des stratégies d’immunothérapie non spécifiques ou spécifiques telles que vaccination ou transfert adoptif, avec parfois des résultats encourageants. Cependant ces traitements ont souvent été décevants lorsqu’ils ont été testés dans des phases plus avancées. Des progrès récents dans les biotechnologies, et la combinaison de plusieurs stratégies permettront peut-être d’optimiser ces stratégies. Enfin, il faudra intégrer ces traitements dans l’arsenal thérapeutique de routine, en tenant compte des effets immunologiques déjà connu des chimiothérapies cytotoxiques et anticorps monoclonaux.

Abstract

Despite a known immunosurveillance, Immunotherapy shows low activity in gastro-intestinal (GI) cancer. The most promising strategy could be the use of monoclonal antibodies blocking the immunomodulatory check-point inhibitor like anti-PD-1, which have been recently shown efficacy in several types of cancer. However in GI cancer, these molecules were disappointing considering the preliminary reports. But recently, high response rate was observed in patients with mismatch repair deficiency, leading to a regain of interest for the anti-PD1. Others strategies have been tested in colorectal and others GI cancer in pilot studies, with non-specific or specific immunotherapy with few promising results. However in latter phase of trial, results were often negative, or insufficient considering the complexity and the cost for adoptive therapy. Recent biotechnological progress and combination of several strategies may optimize these treatments. Finally, we will have to integrate these new treatments in our present therapeutic armament, taking into account the known immunomodulatory effect of cytotoxic chemotherapy or monoclonal antibodies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Références

  1. Obeid M, Tesniere A, Ghiringhelli F, et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 1:54–61

    Article  Google Scholar 

  2. Tesniere A, Schlemmer F, Boige V, et al (2009) Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 4:482–91

    Google Scholar 

  3. Vincent J, Mignot G, Chalmin F, et al (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 8:3052–61

    Article  Google Scholar 

  4. Terme M, Pernot S, Marcheteau E, et al (2013) VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 2:539–49

    Article  Google Scholar 

  5. Voron T, Colussi O, Marcheteau E, et al (2015) VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 2:139–48

    Article  Google Scholar 

  6. Mellor JD, Brown MP, Irving HR, et al (2013) A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol J Hematol Oncol 4:1

    Article  Google Scholar 

  7. Posner MC, Niedzwiecki D, Venook AP, et al (2008) A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: cancer and leukemia group B study 89903. Ann Surg Oncol 1:158–64

    Article  Google Scholar 

  8. Toubaji A, Achtar M, Provenzano M, et al (2008) Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol Immunother CII 9:1413–20

    Article  Google Scholar 

  9. Schulze T, Kemmner W, Weitz J, et al (2009) Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother CII 1:61–9

    Article  Google Scholar 

  10. Moulton HM, Yoshihara PH, Mason DH, et al (2002) Active specific immunotherapy with a beta-human chorionic gonadotropin peptide vaccine in patients with metastatic colorectal cancer: antibody response is associated with improved survival. Clin Cancer Res Off J Am Assoc Cancer Res 7:2044–51

    Google Scholar 

  11. Kibe S, Yutani S, Motoyama S, et al (2014) Phase II Study of Personalized Peptide Vaccination for Previously Treated Advanced Colorectal Cancer. Cancer Immunol Res 12:1154–62

    Article  Google Scholar 

  12. Vermorken JB, Claessen AM, van Tinteren H, et al (1999) Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. The Lancet 9150:345–50

    Article  Google Scholar 

  13. Harris JE, Ryan L, Hoover HC Jr, et al (2000) Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol Off J Am Soc Clin Oncol 1:148–57

    Google Scholar 

  14. Uyl-de Groot CA, Vermorken JB, Hanna MG Jr, et al (2005) Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits. Vaccine 17–18:2379–87

    Article  Google Scholar 

  15. Liu Y, Zhang W, Zhang B, et al (2013) DC vaccine therapy combined concurrently with oral capecitabine in metastatic colorectal cancer patients. Hepatogastroenterology 121:23–7

    Google Scholar 

  16. Lesterhuis WJ, de Vries IJM, Aarntzen EA, et al (2010) A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients. Br J Cancer 9:1415–21

    Article  Google Scholar 

  17. Morse MA, Niedzwiecki D, Marshall JL, et al (2013) A Randomized Phase II Study of Immunization With Dendritic Cells Modified With Poxvectors Encoding CEA and MUC1 Compared With the Same Poxvectors Plus GM-CSF for Resected Metastatic Colorectal Cancer. Ann Surg. 7 mai

    Google Scholar 

  18. Kavanagh B, Ko A, Venook A, et al (2007) Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides. J Immunother Hagerstown Md 7:762–72

    Article  Google Scholar 

  19. Burgdorf. Clinical responses in patients with advanced colorectal cancer to a dendritic cell based vaccine. Oncol Rep [Internet] 1 janv 1994 [cité 20 oct 2013] Disponible sur: http://www.spandidos-publications.com.gate2.inist.fr/or/20/6/1305

    Google Scholar 

  20. Tartour E, Benchetrit F, Haicheur N, et al (2002) Synthetic and natural non-live vectors: rationale for their clinical development in cancer vaccine protocols. Vaccine 20 Suppl 4:A32–9

    Article  CAS  PubMed  Google Scholar 

  21. Morse MA, Nair SK, Mosca PJ, et al (2003) Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA. Cancer Invest 3:341–9

    Article  Google Scholar 

  22. Barth RJ Jr, Fisher DA, Wallace PK, et al (2010) A randomized trial of ex vivo CD40L activation of a dendritic cell vaccine in colorectal cancer patients: tumor-specific immune responses are associated with improved survival. Clin Cancer Res Off J Am Assoc Cancer Res 22:5548–56

    Article  Google Scholar 

  23. Karlsson M, Marits P, Dahl K, et al (2010) Pilot study of sentinel-node-based adoptive immunotherapy in advanced colorectal cancer. Ann Surg Oncol 7:1747–57

    Article  Google Scholar 

  24. Zhen YH, Liu XH, Yang Y, et al (2015) Phase I/II study of adjuvant immunotherapy with sentinel lymph node T lymphocytes in patients with colorectal cancer. Cancer Immunol Immunother CII 9:1083–93

    Article  Google Scholar 

  25. Gao D, Li C, Xie X, et al (2014) Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients. PloS One 4):e93886

    Article  Google Scholar 

  26. Correale P, Rotundo MS, Botta C, et al (2011) Chemoimmunotherapy with gemcitabine + FOLFOX followed by granulocyte-macrophage colony stimulating factor and low dose aldesleukine (GOLFIG regimen) is a highly active frontline treatment for advanced colorectal carcinoma: Results from the GOLFIG/2 phase III trial. Proc 102nd Annu Meet Am Assoc Cancer Res 2011 Apr 2–6 Orlando Fla Phila PA AACR 2011 Abstr Nr 5511

    Google Scholar 

  27. Schmoll HJ, Wittig B, Arnold D, et al (2014) Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial. J Cancer Res Clin Oncol 9:1615–24

    Article  Google Scholar 

  28. Chung KY, Gore I, Fong L, et al (2010) Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 21:3485–90

    Article  Google Scholar 

  29. Brahmer JR, Drake CG, Wollner I, et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol Off J Am Soc Clin Oncol 19:3167–75

    Article  Google Scholar 

  30. Topalian SL, Hodi FS, Brahmer JR, et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 26:2443–54

    Article  Google Scholar 

  31. Brahmer JR, Tykodi SS, Chow LQM, et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 26:2455–65

    Article  Google Scholar 

  32. Galon J, Costes A, Sanchez-Cabo F, et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 5795:1960–4

    Article  Google Scholar 

  33. Pagès F, Berger A, Camus M, et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 25:2654–66

    Article  Google Scholar 

  34. Pagès F, Kirilovsky A, Mlecnik B, et al (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 35:5944–51

    Article  Google Scholar 

  35. Kroemer G, Galluzzi L, Zitvogel L, et al (2015) Colorectal cancer: the first neoplasia found to be under immunosurveillance and the last one to respond to immunotherapy? Onco-immunology 7: e1058597 Collection 2015

    Google Scholar 

  36. Le DT, Uram JN, Wang H, et al (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 26:2509–20

    Article  Google Scholar 

  37. Wörmann SM, Diakopoulos KN, Lesina M, et al (2014) The immune network in pancreatic cancer development and progression. Oncogene 23:2956–67

    Article  Google Scholar 

  38. Le DT, Wang-Gillam A, Picozzi V, et al (2015) Safety and survival with GVAX pancreas prime and Listeria Monocytogenesexpressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol Off J Am Soc Clin Oncol 12:1325–33

    Article  Google Scholar 

  39. Lutz ER, Wu AA, Bigelow E, et al (2014) Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res 7:616–31

    Article  Google Scholar 

  40. Bang YJ. (2015) Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: Interim results of KEYNOTE-028. ESMO, Vienna

    Google Scholar 

  41. Doi T, Piha-Paul SA, Jalal SI, et al (2015) Pembrolizumab (MK-3475) for patients (pts) with advanced esophageal carcinoma: Preliminary results from KEYNOTE-028. J Clin Oncol 33 (suppl; abstr 4010)

  42. Bang YJ, Chung HC, Shankaran V, et al Relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in keynote-012. J Clin Oncol [Internet] [cité 28 juin 2015]; Disponible sur: http://meetinglibrary.asco.org/content/150958-156

    Google Scholar 

  43. Buonaguro L (2015) HEPAVAC Consortium. Developments in cancer vaccines for hepatocellular carcinoma. Cancer Immunol Immunother CII. 21 juin Epub ahead of print

    Google Scholar 

  44. Takayama T, Sekine T, Makuuchi M, et al (2000) Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet Lond Engl 9232:802–7

    Article  Google Scholar 

  45. El-Khoueriry AB, Melero I, Crocenzi TS, et al (2015) Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 33 (suppl; abstr LBA101)

  46. Kenter GG, Welters MJP, Valentijn ARPM, et al (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med 19:1838–47

    Article  Google Scholar 

  47. Kenter GG, Welters MJP, Valentijn ARPM, et al (2008) Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity. Clin Cancer Res Off J Am Assoc Cancer Res 1:169–77

    Article  Google Scholar 

  48. Welters MJP, Kenter GG, Piersma SJ, et al (2008) Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res Off J Am Assoc Cancer Res 1:178–87

    Article  Google Scholar 

  49. Fox PA, Nathan M, Francis N, et al (2010) A double-blind, randomized controlled trial of the use of imiquimod cream for the treatment of anal canal high-grade anal intraepithelial neoplasia in HIV-positive MSM on HAART, with long-term follow-up data including the use of open-label imiquimod. AIDS Lond Engl 15:2331–5

    Google Scholar 

  50. Ott P. (2015) Pembrolizumab (MK-3475) for PD-L1-positive squamous cell carcinoma (SCC) of the anal canal: Preliminary safety and efficacy results from keynote-028. A. 500. ESMO, Vienna

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Service d’hépato-gastroentérologie et oncologie digestive, Hôpital Européen Georges Pompidou, Université Paris Descartes, Paris-Sorbonne Cité, 75006, Paris, France

    S. Pernot & J. Taieb

Authors
  1. S. Pernot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Taieb
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Taieb.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pernot, S., Taieb, J. Immunothérapie anticancéreuse et cancers digestifs. Colon Rectum 9, 201–209 (2015). https://doi.org/10.1007/s11725-015-0606-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11725-015-0606-2

Mots clés

Keywords

Search

Navigation