Skip to main content
SpringerLink
Log in

Immuntherapie im unteren Gastrointestinaltrakt

Immunotherapy in lower gastrointestinal cancer

  • Schwerpunkt
  • Published:
Der Gastroenterologe Aims and scope

Zusammenfassung

Hintergrund

Die Immuntherapie ist von zunehmender Bedeutung bei vielen Krebserkrankungen. In den letzten Monaten erfolgten erste Zulassungen auch bei gastrointestinalen Tumoren.

Ziel der Arbeit

Die Übersicht soll den aktuellen Stellenwert von Inhibitoren gegen „programmed cell death protein 1“ (PD-1)/„programmed cell death ligand 1“ (PD-L1) und „cytotoxic T‑lymphocyte-associated protein 4“ (CTLA4) in der Therapie der unteren gastrointestinalen Tumoren beleuchten.

Material und Methoden

Publikationen aus MEDLINE® (U.S. National Library of Medicine®, Bethesda, MD, USA), der American Society of Clinical Oncology (ASCO) und der European Society for Medical Oncology (ESMO) aus den Jahren 2012–2020 wurden systematisch gesammelt und ausgewertet.

Ergebnisse

Die PD-1/-L1- und die CTLA4-Inhibition sind beim kolorektalen Karzinom (KRK) in kleinen, durch eine hohe Tumorlast gekennzeichneten Subgruppen mit defizientem „mismatch repair“ (dMMR) bzw. bei mikrosatelliteninstabilen (MSI-H-)Tumoren oder bei Tumoren mit Mutationen in der „polymerase epsilon proofreading domain“ (POLE) von Relevanz. Mit Pembrolizumab liegt die erste zugelassene Immuntherapie in der Erstlinientherapie des dMMR/MSI‑H KRK vor. Laufende Studien untersuchen den Einsatz der Immuntherapie in diesen Subgruppen in der (neo-)adjuvanten Situation. Jenseits dieser definierten Subgruppen sind die Ergebnisse aus Studien bislang nicht eindeutig. Beim Analkarzinom ist eine moderate immuntherapeutische Wirksamkeit in der fortgeschrittenen Situation gezeigt.

Diskussion

Die Hoffnung liegt auf laufenden Studienkonzepten, die mit Kombinationen und sequenziellen biomarkerbasierten Ansätzen die Immuntherapien einer größeren Gruppe der Patienten mit KRK zugänglich machen könnten.

Abstract

Background

Immunotherapy has gained increasing importance in the management of a variety of cancers. In recent months, the first agents were approved for gastrointestinal cancers.

Objectives

This review will highlight the current role of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T‑lymphocyte-associated protein 4 (CTLA4) inhibitors in lower gastrointestinal cancers.

Materials and methods

Publications from MEDLINE® (U.S. National Library of Medicine®, Bethesda, MD, USA), American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) from 2012–2020 were collected and evaluated.

Results

The relevance of PD-1/-L1 and CTLA4 inhibitors in colorectal cancer (CRC) is currently limited to small subgroups defined by a high tumor mutational burden (deficient mismatch repair [dMMR]/microsatellite instable [MSI-H] tumors or polymerase epsilon proofreading domain [POLE] mutated). Pembrolizumab is the first approved agent for first-line treatment of dMMR/MSI‑H CRC. Ongoing trials evaluated the role of immunotherapy in the neo-adjuvant setting. Beyond these defined subgroups, results from studies have been inconclusive to date. In advanced anal cancer, PD-1/L1 inhibition shows moderate efficacy.

Discussion

Ongoing trials evaluating combinations or sequential regimen with biomarker-based approaches may enable larger groups of patients access to immunotherapy.

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

Literatur

  1. Giannakis M et al (2016) Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep 17(4):1206

    Article  CAS  Google Scholar 

  2. Turajlic S et al (2017) Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol 18(8):1009–1021

    Article  CAS  Google Scholar 

  3. Llosa NJ et al (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5(1):43–51

    Article  CAS  Google Scholar 

  4. Rousseau BJ, Bieche I, Pasmant E (2020) High activity of nivolumab in patients with pathogenic exonucleasic domain POLE (edPOLE) mutated Mismatch Repair proficient (MMRp) advanced tumours. Ann Oncol 31:Abstract 5260

    Article  Google Scholar 

  5. Le DT et al (2015) PD‑1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520

    Article  CAS  Google Scholar 

  6. Le DT et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD‑1 blockade. Science 357(6349):409–413

    Article  CAS  Google Scholar 

  7. Overman MJ et al (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18(9):1182–1191

    Article  CAS  Google Scholar 

  8. Le DT et al (2020) Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: keynote-164. J Clin Oncol 38(1):11–19

    Article  CAS  Google Scholar 

  9. Andre T et al (2020) Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383(23):2207–2218

    Article  CAS  Google Scholar 

  10. Schrock AB et al (2019) Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol 30(7):1096–1103

    Article  CAS  Google Scholar 

  11. Overman MJ et al (2018) Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 36(8):773–779

    Article  CAS  Google Scholar 

  12. Lenz HJ, Van Cutsem E, Limon ML (2018) Durable clinical benefit with Nivolumab (NIVO) plus low-dose Ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer. ESMO LBA18_PR. Abstract ESMO

  13. Chalabi M et al (2020) Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 26(4):566–576

    Article  CAS  Google Scholar 

  14. Ludford K et al (2021) Pathological tumor response following immune checkpoint blockade for deficient mismatch repair advanced colorectal cancer. J Natl Cancer Inst 113(2):208–211

    Article  Google Scholar 

  15. Overman M, Kopetz ES, McDermott R (2016) Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. J Clin Oncol 34(suppl):abstr 3501

    Article  Google Scholar 

  16. Chen EX et al (2020) Effect of combined immune checkpoint inhibition vs best supportive care alone in patients with advanced colorectal cancer: the Canadian cancer trials group CO.26 study. JAMA Oncol 6(6):831–838

    Article  Google Scholar 

  17. Mettu NB, Twohy E, Ou F‑S (2019) BACCI: A phase II randomized, double-blind, multicenter, placebocontrolled study of capecitabine (C) bevacizumab (B) plus atezolizumab (A) or placebo (P) in refractory metastatic colorectal cancer (mCRC): An ACCRU network study. Ann Oncol 30:533PD

    Article  Google Scholar 

  18. Grothey A, Tabernero J, Arnold D (2018) Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): Findings from Cohort 2 of MODUL. Ann Oncol (suppl). ESMO abstract

  19. Ebert PJ et al (2016) MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44(3):609–621

    Article  CAS  Google Scholar 

  20. Bendell J, Kim TW, Goh BC (2016) Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol 34(suppl):abstr 3502

    Article  Google Scholar 

  21. Eng C et al (2019) Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 20(6):849–861

    Article  CAS  Google Scholar 

  22. Fukuoka S et al (2020) Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (Regonivo, Epoc1603). J Clin Oncol 38(18):2053–2061

    Article  CAS  Google Scholar 

  23. Cousin S, Bellera CA, Guegan JP (2020) Regomune: A phase II study of regorafenib plus avelumab in solid tumors—Results of the non-MSI‑H metastatic colorectal cancer (mCRC) cohort. J Clin Oncol 38:abstr. 4019

    Article  Google Scholar 

  24. Kim R (2020) Phase I/IB study of regorafenib and nivolumab inmismatch repair (MMR) proficient advanced refractory colorectal cancer. In: Proceedings of the ESMOWorld GI 2020—Virtual Barcelona, 1–4 July 2020

    Google Scholar 

  25. Stein A, Binder M, Goekkurt E (2020) Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): Final results of the phase II AVETUX trial (AIO-KRK-0216). J Clin Oncol 38(96). ASCO GI Abstr

  26. Martinelli E, Martini G, Troiani T (2020) Avelumab plus cetuximab in pre-treated RAS wild type metastatic colorectal cancer patients as a rechallenge strategy: The phase II CAVE (cetuximab-avelumab) mCRC study. Ann Oncol 31(397). ESMO abstract

  27. Segal NH, Kemeny N, Cercek A (2016) Non-randomized phase II study to assess the efficacy of pembrolizumab (Pem) plus radiotherapy (RT) or ablation in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) patients. J Clin Oncol 34(suppl). ASCO abstr

  28. Ott PA et al (2017) Safety and antitumor activity of the anti-PD‑1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol 28(5):1036–1041

    Article  CAS  Google Scholar 

  29. Morris VK et al (2017) Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol 18(4):446–453

    Article  CAS  Google Scholar 

  30. Lonardi S, Pietrantonio F, Prete AA (2020) Final results of the CARACAS study: Randomized phase II trial of avelumab alone or with cetuximab for unresectable, locally advanced or metastatic squamous cell anal carcinoma progressed to at least one line of treatment. Ann Oncol 31:S412

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hämatologisch-Onkologische Praxis Eppendorf, Universitäres Cancer Center Hamburg, Eppendorfer Landstraße 42, 20249, Hamburg, Deutschland

    Alexander Stein

Authors
  1. Alexander Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Stein.

Ethics declarations

Interessenkonflikt

A. Stein gibt institutionelle Forschungsunterstützung von BMS und Merck sowie Honorare für die Teilnahme an Advisory Boards oder für Vorträge von Astra Zeneca, BMS, Merck, MSD und Roche an.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

T. Seufferlein, Ulm

N. P. Malek, Tübingen

figure qr

QR-Code scannen & Beitrag online lesen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stein, A. Immuntherapie im unteren Gastrointestinaltrakt. Gastroenterologe 16, 257–263 (2021). https://doi.org/10.1007/s11377-021-00534-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11377-021-00534-2

Schlüsselwörter

Keywords

Search

Navigation