Wiener klinisches Magazin

, Volume 21, Issue 2, pp 80–85 | Cite as

Grundlagen der Krebsimmuntherapie

Tumorantigene und Impfung bei Krebs
Onkologie
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Zusammenfassung

Hintergrund

Tumoren können vom Immunsystem erkannt werden. Physiologische Mechanismen der immunologischen Toleranz und Ignoranz führen jedoch dazu, dass Tumoren trotzdem nicht abgestoßen werden. Der Weg von der Induktion einer Immunantwort bis zu einer Abstoßungsreaktion ist komplex und störanfällig, bildhaft dargestellt im Krebsimmunzyklus von Chen und Mellman.

Ergebnisse

Mit kontinuierlich verbesserter Methodik wurde eine Vielzahl von Antigenen unterschiedlicher Expressionsmuster identifiziert, die sich als Zielstrukturen für die Krebsimmuntherapie eignen. Es ist jetzt möglich, individuelle mutierte Neoantigene mit vertretbarem Aufwand zu identifizieren. Die therapeutische Impfung zielt ebenso wie die Checkpointblockade auf die Rekrutierung körpereigener Abwehrmechanismen. Die unzulänglichen Ergebnisse bisheriger Impfstudien werden v. a. damit erklärt, dass diese weder die Individualität der Tumor-Wirt-Interaktion noch immunologische Gegenregulation und die Durchbrechung tumoreigener Immunbarrieren in ausreichendem Maße beinhalteten. Die klinischen Erfolge der Checkpointblockade unterstreichen − wenn auch nur bei einer Subgruppe von Patienten mit nachhaltigem Effekt − das im körpereigenen Immunrepertoire liegende Potenzial.

Schlussfolgerungen

Technologische Fortschritte und eine enge Verzahnung von grundlagen- und anwendungsorientierter Forschung haben nahezu exponentiell wachsende Optionen für die Entwicklung neuer Immuntherapeutika geschaffen. Um dies nachhaltig und breit nutzen, ist es essenziell, immunologisch relevante prädiktive Biomarker zu entdecken und für den differenzierten Einsatz unterschiedlicher Immuntherapieverfahren und deren rationale Kombination auch mit nichtimmunologischen Therapien zu etablieren, um den Krebsimmunzyklus in Gang zu halten.

Schlüsselwörter

Tumorimmunität Prädiktive Biomarker Immunbarrieren Therapeutische Impfung Checkpointblockade 

Principles of cancer immunotherapy

Tumor antigens and vaccination in cancer

Abstract

Background

Tumors can be recognized by the immune system; however, physiological mechanisms of tolerance and ignorance regularly lead to tumors evading rejection. The way from induction of an immune response to final killing of cancer cells is complex and highly susceptible to failure, which is allegorized by the cancer immunity cycle described by Chen and Mellman.

Results

Continuous methodological progress has enabled the identification of a multitude of target antigens for cancer immunotherapy, with individual mutated neoantigens becoming increasingly popular. Therapeutic vaccination as well as checkpoint blockade aim at recruiting or enhancing anti-tumor responses from the patients’ own immune system. It is assumed that therapeutic vaccination has so far failed largely because the design of previous trials did not adequately consider the individuality of tumor/host interactions and did not include measures to circumvent counterregulation by the cellular immune system and to penetrate tumor immune barriers. This is supported by the clinical success of checkpoint blockade, which unequivocally demonstrates the potential of the patients’ immune repertoire, even though only a subset of patients experienced durable responses.

Conclusion

Continuous technical advancement and a close alliance between basic and applied research has generated almost exponentially growing options for the development of novel immunotherapeutic agents. To convert this into a permanent and broadly applicable clinical success, it will be of utmost importance to detect and establish immunologically relevant predictive biomarkers to guide the selective application of the different immunotherapy procedures and for evidence-based complementary combined approaches of any kind to keep the cancer immunity cycle moving.

Keywords

Tumor immunity Predictive biomarkers  Immune barriers Therapeutic vaccination Checkpoint blockade 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

T. Wölfel gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine noch nicht publizierten Daten aus Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Prehn RT, Main JM (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18:769–778PubMedGoogle Scholar
  2. 2.
    Old LJ, Boyse EA (1964) Immunology of experimental tumors. Annu Rev Med 15:167–186CrossRefPubMedGoogle Scholar
  3. 3.
    Willimsky G, Blankenstein T (2005) Sporadic immunogenic tumours avoid destruction by inducing T‑cell tolerance. Nature 437(7055):141–146CrossRefPubMedGoogle Scholar
  4. 4.
    Palucka AK, Coussens LM (2016) The basis of Oncoimmunology. Cell 164(6):1233–1247CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Di Marco M, Peper JK, Rammensee HG (2017) Identification of Immunogenic Epitopes by MS/MS. Cancer J 23(2):102–107CrossRefPubMedGoogle Scholar
  6. 6.
    Vormehr M et al (2016) Mutanome directed cancer immunotherapy. Curr Opin Immunol 39:14–22CrossRefPubMedGoogle Scholar
  7. 7.
    Shepard HM et al (2017) Developments in therapy with monoclonal antibodies and related proteins. Clin Med (Lond) 17(3):220–232CrossRefGoogle Scholar
  8. 8.
    Coulie PG et al (2014) Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14(2):135–146CrossRefPubMedGoogle Scholar
  9. 9.
    Schuler G (2010) Dendritic cells in cancer immunotherapy. Eur J Immunol 40(8):2123–2130CrossRefPubMedGoogle Scholar
  10. 10.
    Dunn GP et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998CrossRefPubMedGoogle Scholar
  11. 11.
    Joyce JA, Fearon DT (2015) T cell exclusion, immune privilege, and the tumor microenvironment. Science 348(6230):74–80CrossRefPubMedGoogle Scholar
  12. 12.
    Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2):205–214CrossRefPubMedGoogle Scholar
  13. 13.
    Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10CrossRefPubMedGoogle Scholar
  14. 14.
    Makkouk A, Weiner GJ (2015) Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res 75(1):5–10CrossRefPubMedGoogle Scholar
  15. 15.
    Finn OJ (2017) Human tumor antigens yesterday, today, and tomorrow. Cancer Immunol Res 5(5):347–354CrossRefPubMedGoogle Scholar
  16. 16.
    Boon T et al (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12(337):337–365CrossRefPubMedGoogle Scholar
  17. 17.
    Sahin U, Türeci O, Pfreundschuh M (1997) Serological identification of human tumor antigens. Curr Opin Oncol 9:709–716Google Scholar
  18. 18.
    Carter P, Smith L, Ryan M (2004) Identification and validation of cell surface antigens for antibody targeting in oncology. Endocr Relat Cancer 11(4):659–687CrossRefPubMedGoogle Scholar
  19. 19.
    Williamson NA, Rossjohn J, Purcell AW (2006) Tumors reveal their secrets to cytotoxic T cells. Proc Natl Acad Sci U S A 103(40):14649–14650CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yarchoan M et al (2017) Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer 17(4):209–222CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Batlevi CL et al (2016) Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol 13(1):25–40CrossRefPubMedGoogle Scholar
  22. 22.
    Zeltsman M et al (2017) CAR T‑cell therapy for lung cancer and malignant pleural mesothelioma. Transl Res.  https://doi.org/10.1016/j.trsl.2017.04.004 PubMedGoogle Scholar
  23. 23.
    Ku M, Chong G, Hawkes EA (2017) Tumour cell surface antigen targeted therapies in B‑cell lymphomas: Beyond rituximab. Blood Rev 31(1):23–35CrossRefPubMedGoogle Scholar
  24. 24.
    Lennerz V et al (2005) The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A 102(44):16013–16018CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lurquin C et al (2005) Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen. J Exp Med 201(2):249–257CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Linette GP et al (2013) Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122(6):863–871CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Morgan RA et al (2013) Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 36(2):133–151CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Walter S et al (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18(8):1254–1261CrossRefPubMedGoogle Scholar
  29. 29.
    Kvistborg P et al (2014) Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med 6(254):254–ra128CrossRefGoogle Scholar
  30. 30.
    June CH, Warshauer JT, Bluestone JA (2017) Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 23(5):540–547CrossRefPubMedGoogle Scholar
  31. 31.
    Michot JM et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148CrossRefPubMedGoogle Scholar
  32. 32.
    Hoos A (2016) Development of immuno-oncology drugs – from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov 15(4):235–247CrossRefPubMedGoogle Scholar
  33. 33.
    Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541(7637):321–330CrossRefPubMedGoogle Scholar
  34. 34.
    Kroemer G, Zitvogel L, Galluzzi L (2013) Victories and deceptions in tumor immunology: Stimuvax. Oncoimmunology 2(1):e23687CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    van der Burg SH et al (2016) Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer 16(4):219–233CrossRefPubMedGoogle Scholar
  36. 36.
    Patel A, Kaufman HL, Disis ML (2017) Next generation approaches for tumor vaccination. Chin Clin Oncol 6(2):19CrossRefPubMedGoogle Scholar
  37. 37.
    Hölzel M, Bovier A, Tüting T (2013) Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 13(5):365–376CrossRefPubMedGoogle Scholar
  38. 38.
    Schrörs B et al (2017) HLA class I loss in metachronous metastases prevents continuous T cell recognition of mutated neoantigens in a human melanoma model. Oncotarget 8(17):28312–28327CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.III. Medizinische Klinik, Universitäres Zentrum für Tumorerkrankungen, Forschungszentrum Immuntherapie, Deutsches Konsortium für Translationale Krebsforschung/Standort Frankfurt/MainzUniversitätsmedizin der Johannes Gutenberg-Universität MainzMainzDeutschland

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