An immune-active tumor microenvironment favors clinical response to ipilimumab
- 4.7k Downloads
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.
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.
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.
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.
KeywordsIpilimumab Metastatic melanoma Cytotoxic T lymphocyte antigen-4 Gene expression profiling Immunotherapy
We would like to thank Dr. Zenta Tsuchihashi for his contributions during design of the trial and initial data analysis, Drs. Julie Carman, Han Chang, Tai Wong, and Roumyana Yordanova for their guidance and critical review of the manuscript, and Ms. Beihong Hu and Aiqing He for technical support.
Conflict of interest
Rui-Ru Ji, Scott D. Chasalow, Lisu Wang, John Cogswell, Suresh Alaparthy, David Berman, Maria Jure-Kunkel, Nathan O. Siemers, Jeffrey R. Jackson, and Vafa Shahabi are employees of Bristol-Myers Squibb, the manufacturer of ipilimumab.
- 1.American Cancer Society (2009) Cancer facts and figures 2009. http://www.cancer.org/acs/groups/content/@nho/documents/document/500809webpdf.pdf
- 2.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
- 3.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):2105–2116PubMedGoogle Scholar
- 6.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):2517–2526Google Scholar
- 9.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):6895–6906PubMedCrossRefGoogle Scholar
- 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):2729–2734Google Scholar
- 12.Tarhini AA, Iqbal F (2010) CTLA-4 blockade: Therapeutic potential in cancer treatments. OncoTarg Ther 3:15–25Google Scholar
- 13.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):711–723Google Scholar
- 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 9:204Google Scholar
- 17.Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481Google Scholar
- 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):3005–3010Google Scholar
- 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):2009–2021PubMedCrossRefGoogle Scholar
- 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):929–938PubMedCrossRefGoogle Scholar
- 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–e94Google Scholar
- 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):3398–3403Google Scholar
- 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):6919–6923Google Scholar
- 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):1263–1271PubMedCrossRefGoogle Scholar
- 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):20410–20415Google Scholar
- 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):20429–20434Google Scholar
- 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 TreatGoogle Scholar
- 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):1960–1964PubMedCrossRefGoogle Scholar