nach oben

Erschienen in:

01.07.2012 | Original article

An immune-active tumor microenvironment favors clinical response to ipilimumab

verfasst von: Rui-Ru Ji, Scott D. Chasalow, Lisu Wang, Omid Hamid, Henrik Schmidt, John Cogswell, Suresh Alaparthy, David Berman, Maria Jure-Kunkel, Nathan O. Siemers, Jeffrey R. Jackson, Vafa Shahabi

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2012

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has been shown to improve overall survival in metastatic melanoma patients. As a consequence of CTLA-4 blockade, ipilimumab treatment is associated with proliferation and activation of peripheral T cells. To better understand various tumor-associated components that may influence the clinical outcome of ipilimumab treatment, gene expression profiles of tumors from patients treated with ipilimumab were characterized.

Experimental design

Gene expression profiling was performed on tumor biopsies collected from 45 melanoma patients before and 3 weeks after the start of treatment in a phase II clinical trial.

Results

Analysis of pre-treatment tumors indicated that patients with high baseline expression levels of immune-related genes were more likely to respond favorably to ipilimumab. Furthermore, ipilimumab appeared to induce two major changes in tumors from patients who exhibited clinical activity: genes involved in immune response showed increased expression, whereas expression of genes for melanoma-specific antigens and genes involved in cell proliferation decreased. These changes were associated with the total lymphocyte infiltrate in tumors, and there was a suggestion of association with prolonged overall survival in these patients. Many IFN-γ-inducible genes and Th1-associated markers showed increased expression after ipilimumab treatment, suggesting an accumulation of this particular type of T cell at the tumor sites, which might play an important role in mediating the antitumor activity of ipilimumab.

Conclusions

These results support the proposed mechanism of action of ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of ipilimumab.

Nur mit Berechtigung zugänglich

American Cancer Society (2009) Cancer facts and figures 2009. http://www.cancer.org/acs/groups/content/@nho/documents/document/500809webpdf.pdf

Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975–2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011

Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985, 1993. J Clin Oncol 17(7):2105–2116PubMed

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D et al (2011) Improved survival with vemurafenib in melanoma with braf v600e mutation. N Engl J Med 364(26):2507–2516PubMedCrossRef

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723PubMedCrossRef

Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok J (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526

Steer HJ, Lake RA, Nowak AK, Robinson BW (2010) Harnessing the immune response to treat cancer. Oncogene 29(48):6301–6313PubMedCrossRef

Chambers CA, Kuhns MS, Egen JG, Allison JP (2001) Ctla-4-mediated inhibition in regulation of t cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565–594PubMedCrossRef

Murillo O, Arina A, Hervas-Stubbs S, Gupta A, McCluskey B, Dubrot J, Palazon A, Azpilikueta A, Ochoa MC, Alfaro C, Solano S et al (2008) Therapeutic antitumor efficacy of anti-cd137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res 14(21):6895–6906PubMedCrossRef

10.

Chen H, Liakou CI, Kamat A, Pettaway C, Ward JF, Tang DN, Sun J, Jungbluth AA, Troncoso P, Logothetis C, Sharma P (2009) Anti-ctla-4 therapy results in higher cd4+ ICOShi t cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proceedings of the National Academy of Sciences of the United States of America 106(8):2729–2734

11.

Chambers CA, Krummel MF, Boitel B, Hurwitz A, Sullivan TJ, Fournier S, Cassell D, Brunner M, Allison JP (1996) The role of ctla-4 in the regulation and initiation of t-cell responses. Immunol Rev 153:27–46PubMedCrossRef

12.

Tarhini AA, Iqbal F (2010) CTLA-4 blockade: Therapeutic potential in cancer treatments. OncoTarg Ther 3:15–25

13.

14.

Harlin H, Kuna TV, Peterson AC, Meng Y, Gajewski TF (2006) Tumor progression despite massive influx of activated cd8(+) t cells in a patient with malignant melanoma ascites. Cancer Immunol Immunother 55(10):1185–1197PubMedCrossRef

15.

Kunz M, Toksoy A, Goebeler M, Engelhardt E, Brocker E, Gillitzer R (1999) Strong expression of the lymphoattractant c-x-c chemokine mig is associated with heavy infiltration of t cells in human malignant melanoma. J Pathol 189(4):552–558PubMedCrossRef

16.

Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gomez H, Bastholt L, Chasalow SD, Berman D (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Trans Med 9:204

17.

Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

18.

Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A et al (2008) Immunologic and clinical effects of antibody blockade of cytotoxic t lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proceedings of the National Academy of Sciences of the United States of America 105(8):3005–3010

19.

Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, Gladue RP, Lin W, Boyd JG, Moser B, Wood DE, Sahagan BG et al (1998) Interferon-inducible t cell alpha chemoattractant (i-tac): A novel non-elr cxc chemokine with potent activity on activated t cells through selective high affinity binding to cxcr3. J Exp Med 187(12):2009–2021PubMedCrossRef

20.

Liao F, Alkhatib G, Peden KW, Sharma G, Berger EA, Farber JM (1997) Strl33, a novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and t cell line-tropic HIV-1. J Exp Med 185(11):2015–2023PubMedCrossRef

21.

Du X, Poltorak A, Wei Y, Beutler B (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw 11(3):362–371PubMed

22.

Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (2004) Unc119, a novel activator of lck/fyn, is essential for t cell activation. J Exp Med 199(3):369–379PubMedCrossRef

23.

Mavoungou E, Georges-Courbot MC, Poaty-Mavoungou V, Nguyen HT, Yaba P, Delicat A, Georges AJ, Russo-Marie F (1997) HIV and SIV envelope glycoproteins induce phospholipase A2 activation in human and macaque lymphocytes. J Acquir Immune Defic Syndr Hum Retrovirol 16(1):1–9PubMedCrossRef

24.

Laabi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, Larsen CJ, Tsapis A (1992) A new gene, bcm, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant t cell lymphoma. EMBO J 11(11):3897–3904PubMed

25.

Tomlinson IM, Cook GP, Walter G, Carter NP, Riethman H, Buluwela L, Rabbitts TH, Winter G (1995) A complete map of the human immunoglobulin vh locus. Ann NY Acad Sci 764:43–46PubMedCrossRef

26.

Crouser ED, Culver DA, Knox KS, Julian MW, Shao G, Abraham S, Liyanarachchi S, Macre JE, Wewers MD, Gavrilin MA, Ross P et al (2009) Gene expression profiling identifies mmp-12 and adamdec1 as potential pathogenic mediators of pulmonary sarcoidosis. Am J Respir Crit Care Med 179(10):929–938PubMedCrossRef

27.

Bakos RM, Maier T, Besch R, Mestel DS, Ruzicka T, Sturm RA, Berking C Nestin and sox9 and sox10 transcription factors are coexpressed in melanoma. Exp Dermatol 19(8):e89–e94

28.

Yasumoto K, Yokoyama K, Shibata K, Tomita Y, Shibahara S (1994) Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol Cell Biol 14(12):8058–8070PubMed

29.

Hearing VJ (1973) Mammalian melanogenesis: tyrosinase versus peroxidase involvement, and activation mechanisms. Arch Biochem Biophys 158(2):720–725PubMedCrossRef

30.

Cheah MS, Wallace CD, Hoffman RM (1984) Hypomethylation of DNA in human cancer cells: a site-specific change in the c-myc oncogene. J Natl Cancer Inst 73(5):1057–1065PubMed

31.

Rao UN, Bakker A, Swalsky PA, Finkelstein SD (1999) Max interacting protein 1: loss of heterozygosity is frequent in desmoplastic melanoma. Mod Pathol 12(4):344–350PubMed

32.

Furlanetto RW, Harwell SE, Baggs RB (1993) Effects of insulin-like growth factor receptor inhibition on human melanomas in culture and in athymic mice. Cancer Res 53(11):2522–2526PubMed

33.

Rieber M, Rieber MS (1994) Cyclin-dependent kinase 2 and cyclin a interaction with e2f are targets for tyrosine induction of b16 melanoma terminal differentiation. Cell Growth Differ 5(12):1339–1346PubMed

34.

Draetta GF (1994) Mammalian g1 cyclins. Curr Opin Cell Biol 6(6):842–846PubMedCrossRef

35.

Schmollinger JC, Vonderheide RH, Hoar KM, Maecker B, Schultze JL, Hodi FS, Soiffer RJ, Jung K, Kuroda MJ, Letvin NL, Greenfield EA et al (2003) Melanoma inhibitor of apoptosis protein (ml-iap) is a target for immune-mediated tumor destruction. Proceedings of the National Academy of Sciences of the United States of America 100(6):3398–3403

36.

Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ (1998) Intracellular regulation of trail-induced apoptosis in human melanoma cells. J Immunol 161(6):2833–2840PubMed

37.

Chen YT, Gure AO, Tsang S, Stockert E, Jager E, Knuth A, Old LJ (1998) Identification of multiple cancer/testis antigens by allogeneic antibody screening of a melanoma cell line library. Proceedings of the National Academy of Sciences of the United States of America 95(12):6919–6923

38.

Parmiani G (2001) Melanoma antigens and their recognition by t cells. Keio J Med 50(2):86–90PubMedCrossRef

39.

Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101PubMedCrossRef

40.

Zeng W, Miyazato A, Chen G, Kajigaya S, Young NS, Maciejewski JP (2006) Interferon-gamma-induced gene expression in cd34 cells: Identification of pathologic cytokine-specific signature profiles. Blood 107(1):167–175PubMedCrossRef

41.

Bosco A, McKenna KL, Devitt CJ, Firth MJ, Sly PD, Holt PG (2006) Identification of novel th2-associated genes in t memory responses to allergens. J Immunol 176(8):4766–4777PubMed

42.

Narayanan S, Silva R, Peruzzi G, Alvarez Y, Simhadri VR, Debell K, Coligan JE, Borrego F (2010) Human th1 cells that express cd300a are polyfunctional and after stimulation up-regulate the t-box transcription factor eomesodermin. PLoS One 5(5):e10636PubMedCrossRef

43.

Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F, Galon J (2011) Clinical impact of different classes of infiltrating t cytotoxic and helper cells (th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71(4):1263–1271PubMedCrossRef

44.

Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF (2009) Chemokine expression in melanoma metastases associated with cd8+ t-cell recruitment. Cancer Res 69(7):3077–3085PubMedCrossRef

45.

Kalinski P, Mailliard RB, Giermasz A, Zeh HJ, Basse P, Bartlett DL, Kirkwood JM, Lotze MT, Herberman RB (2005) Natural killer-dendritic cell cross-talk in cancer immunotherapy. Expert Opin Biol Ther 5(10):1303–1315PubMedCrossRef

46.

Yuan J, Gnjatic S, Li H, Powel S, Gallardo HF, Ritter E, Ku GY, Jungbluth AA, Segal NH, Rasalan TS, Manukian G et al (2008) Ctla-4 blockade enhances polyfunctional ny-eso-1 specific t cell responses in metastatic melanoma patients with clinical benefit. Proceedings of the National Academy of Sciences of the United States of America 105(51):20410–20415

47.

Ebrahimnejad A, Streichert T, Nollau P, Horst AK, Wagener C, Bamberger AM, Brummer J (2004) Ceacam1 enhances invasion and migration of melanocytic and melanoma cells. Am J Pathol 165(5):1781–1787PubMedCrossRef

48.

Winnepenninckx V, Lazar V, Michiels S, Dessen P, Stas M, Alonso SR, Avril MF, Ortiz Romero PL, Robert T, Balacescu O, Eggermont AM et al (2006) Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 98(7):472–482PubMedCrossRef

49.

Bogunovic D, O’Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S, Darvishian F, Berman R, Shapiro R, Pavlick AC, Lonardi S et al (2009) Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proceedings of the National Academy of Sciences of the United States of America 106(48):20429–20434

50.

Ascierto ML, Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang E, Ramakrishnan V, Wang XY, Bear HD et al (2011) A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat

51.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964PubMedCrossRef

Titel: An immune-active tumor microenvironment favors clinical response to ipilimumab
verfasst von: Rui-Ru Ji
Scott D. Chasalow
Lisu Wang
Omid Hamid
Henrik Schmidt
John Cogswell
Suresh Alaparthy
David Berman
Maria Jure-Kunkel
Nathan O. Siemers
Jeffrey R. Jackson
Vafa Shahabi
Publikationsdatum: 01.07.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 7/2012
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1172-6

Neu im Fachgebiet Onkologie

Mehr Lebenszeit mit Abemaciclib bei fortgeschrittenem Brustkrebs?

24.05.2024 Mammakarzinom Nachrichten

In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.

ADT zur Radiatio nach Prostatektomie: Wenn, dann wohl länger

24.05.2024 Prostatakarzinom Nachrichten

Welchen Nutzen es trägt, wenn die Strahlentherapie nach radikaler Prostatektomie um eine Androgendeprivation ergänzt wird, hat die RADICALS-HD-Studie untersucht. Nun liegen die Ergebnisse vor. Sie sprechen für länger dauernden Hormonentzug.

Das sind die führenden Symptome junger Darmkrebspatienten

23.05.2024 Leitsymptome in der Hausarztpraxis Nachrichten

Darmkrebserkrankungen in jüngeren Jahren sind ein zunehmendes Problem, das häufig längere Zeit übersehen wird, gerade weil die Patienten noch nicht alt sind. Welche Anzeichen Ärzte stutzig machen sollten, hat eine Metaanalyse herausgearbeitet.

„Überwältigende“ Evidenz für Tripeltherapie beim metastasierten Prostata-Ca.

22.05.2024 Prostatakarzinom Nachrichten

Patienten mit metastasiertem hormonsensitivem Prostatakarzinom sollten nicht mehr mit einer alleinigen Androgendeprivationstherapie (ADT) behandelt werden, mahnt ein US-Team nach Sichtung der aktuellen Datenlage. Mit einer Tripeltherapie haben die Betroffenen offenbar die besten Überlebenschancen.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

An immune-active tumor microenvironment favors clinical response to ipilimumab