Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade

Science Translational Medicine

Volumn 7, Issue 315, 2015, Pages

  Müller, Philipp ^a   Kreuzaler, Matthias ^a   Khan, Tarik ^b,j,k   Thommen, Daniela S ^a   Martin, Kea ^a   Glatz, Katharina ^c   Savic, Spasenija ^c   Harbeck, Nadia ^d,e   Nitz, Ulrike ^e,f,g   Gluz, Oleg ^e,g   Von Bergwelt Baildon, Michael ^h   Kreipe, Hans ^e,i   Reddy, Sai ^b   Christgen, Matthias ^e,i   Zippelius, Alfred ^a  

^a UNIVERSITY HOSPITAL BASEL   (Switzerland)

^b ETH ZURICH   (Switzerland)

^c UNIVERSITY HOSPITAL BASEL   (Switzerland)

^d UNIVERSITY OF MUNICH   (Germany)

^e West German Study Group   (Germany)

^f HEINRICH HEINE UNIVERSITY   (Germany)

^g Bethesda Monchengladbach GmbH   (Germany)

^h UNIVERSITY OF COLOGNE   (Germany)

ⁱ HANNOVER MEDICAL SCHOOL   (Germany)

^j F HOFFMANN LA ROCHE LTD   (Switzerland)

^k UNIVERSITY OF BASEL   (Switzerland)

more..

Author keywords

[No Author keywords available]

Indexed keywords

BLOCKING ANTIBODY; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; EPIDERMAL GROWTH FACTOR RECEPTOR 2; PROGRAMMED DEATH 1 RECEPTOR; PROGRAMMED DEATH PROTEIN 1 ANTIBODY; TRASTUZUMAB EMTANSINE; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; MAYTANSINE; MONOCLONAL ANTIBODY; PDCD1 PROTEIN, HUMAN;

ADAPTIVE IMMUNITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOIMMUNE DISEASE; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER RESISTANCE; CANCER SUSCEPTIBILITY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CLINICAL ARTICLE; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DRUG EFFICACY; EARLY CANCER; FEMALE; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOCOMPETENT CELL; INFLAMMATION; INNATE IMMUNITY; LYMPHOCYTE PROLIFERATION; LYMPHOCYTIC INFILTRATION; MONOTHERAPY; MOUSE; MULTICENTER STUDY; NONHUMAN; PHARMACOLOGICAL BLOCKING; POLARIZATION; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; T CELL DEPLETION; T LYMPHOCYTE ACTIVATION; TH1 CELL; TUMOR MODEL; TUMOR REJECTION; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; GENETICS; PROTO ONCOGENE;

ANIMALS; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; BREAST NEOPLASMS; CTLA-4 ANTIGEN; FEMALE; GENES, ERBB-2; HUMANS; MAYTANSINE; MICE; PROGRAMMED CELL DEATH 1 RECEPTOR;

EID: 84954457746     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aac4925     Document Type: Article

References (71)

1. D. J. Slamon, G. M. Clark, S. G. Wong, W. J. Levin, A. Ullrich, W. L. McGuire, Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177-182 (1987).
2. S. Dawood, K. Broglio, A. U. Buzdar, G. N. Hortobagyi, S. H. Giordano, Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: An institutionalbased review. J. Clin. Oncol. 28, 92-98 (2010).
3. D. Slamon, W. Eiermann, N. Robert, T. Pienkowski, M. Martin, M. Press, J. Mackey, J. Glaspy, A. Chan, M. Pawlicki, T. Pinter, V. Valero, M.-C. Liu, G. Sauter, G. Von Minckwitz, F. Visco, V. Bee, M. Buyse, B. Bendahmane, I. Tabah-Fisch, M.-A. Lindsay, A. Riva, J. Crown; Breast Cancer International Research Group, Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365, 1273-1283 (2011).
4. M. J. Piccart-Gebhart, M. Procter, B. Leyland-Jones, A. Goldhirsch, M. Untch, I. Smith, L. Gianni, J. Baselga, R. Bell, C. Jackisch, D. Cameron, M. Dowsett, C. H. Barrios, G. Steger, C.-S. Huang, M. Andersson, M. Inbar, M. Lichinitser, I. Láng, U. Nitz, H. Iwata, C. Thomssen, C. Lohrisch, T. M. Suter, J. Rüschoff, T. Süto, V. Greatorex, C. Ward, C. Straehle, E. McFadden, M. S. Dolci, R. D. Gelber; Herceptin Adjuvant (HERA) Trial Study Team, Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659-1672 (2005).
5. D. J. Slamon, B. Leyland-Jones, S. Shak, H. Fuchs, V. Paton, A. Bajamonde, T. Fleming, W. Eiermann, J. Wolter, M. Pegram, J. Baselga, L. Norton, Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783-792 (2001).
6. S. M. Swain, S.-B. Kim, J. Cortés, J. Ro, V. Semiglazov, M. Campone, E. Ciruelos, J.-M. Ferrero, A. Schneeweiss, A. Knott, E. Clark, G. Ross, M. C. Benyunes, J. Baselga, Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 14, 461-471 (2013).
7. C. E. Geyer, J. Forster, D. Lindquist, S. Chan, C. G. Romieu, T. Pienkowski, A. Jagiello-Gruszfeld, J. Crown, A. Chan, B. Kaufman, D. Skarlos, M. Campone, N. Davidson, M. Berger, C. Oliva, S. D. Rubin, S. Stein, D. Cameron, Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733-2743 (2006).
8. J. Baselga, J. Cortés, S.-B. Kim, S.-A. Im, R. Hegg, Y.-H. Im, L. Roman, J. L. Pedrini, T. Pienkowski, A. Knott, E. Clark, M. C. Benyunes, G. Ross, S. M. Swain; CLEOPATRA Study Group, Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 366, 109-119 (2012).
9. D. Zardavas, J. Baselga, M. Piccart, Emerging targeted agents in metastatic breast cancer. Nat. Rev. Clin. Oncol. 10, 191-210 (2013).
10. P. M. LoRusso, D. Weiss, E. Guardino, S. Girish, M. X. Sliwkowski, Trastuzumab emtansine: A unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin. Cancer Res. 17, 6437-6447 (2011).
11. N. M. Okeley, S. C. Alley, P. D. Senter, Advancing antibody drug conjugation: From the laboratory to a clinically approved anticancer drug. Hematol. Oncol. Clin. North Am. 28, 13-25 (2014).
12. M. Barok, H. Joensuu, J. Isola, Trastuzumab emtansine: Mechanisms of action and drug resistance. Breast Cancer Res. 16, 209 (2014).
13. L. Amiri-Kordestani, G. M. Blumenthal, Q. C. Xu, L. Zhang, S. W. Tang, L. Ha, W. C. Weinberg, B. Chi, R. Candau-Chacon, P. Hughes, A. M. Russell, S. P. Miksinski, X. H. Chen, W. D. McGuinn, T. Palmby, S. J. Schrieber, Q. Liu, J. Wang, P. Song, N. Mehrotra, L. Skarupa, K. Clouse, A. Al-Hakim, R. Sridhara, A. Ibrahim, R. Justice, R. Pazdur, P. Cortazar, FDA approval: Adotrastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin. Cancer Res. 20, 4436-4441 (2014).
14. T. T. Junttila, G. Li, K. Parsons, G. L. Phillips, M. X. Sliwkowski, Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res. Treat. 128, 347-356 (2011).
15. S. Verma, D. Miles, L. Gianni, I. E. Krop, M. Welslau, J. Baselga, M. Pegram, D.-Y. Oh, V. Diéras, E. Guardino, L. Fang, M. W. Lu, S. Olsen, K. Blackwell; EMILIA Study Group, Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783-1791 (2012).
16. P. F. Peddi, S. A. Hurvitz, Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: Latest evidence and clinical potential. Ther. Adv. Med. Oncol. 6, 202-209 (2014).
17. A. E. Prota, K. Bargsten, J. F. Diaz, M. Marsh, C. Cuevas, M. Liniger, C. Neuhaus, J. M. Andreu, K.-H. Altmann, M. O. Steinmetz, A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proc. Natl. Acad. Sci. U. S. A. 111, 13817-13821 (2014).
18. M. Lopus, E. Oroudjev, L. Wilson, S. Wilhelm, W. Widdison, R. Chari, M. A. Jordan, Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol. Cancer Ther. 9, 2689-2699 (2010).
19. K. Okamoto, K. Harada, S. Ikeyama, S. Iwasa, Therapeutic effect of ansamitocin targeted to tumor by a bispecific monoclonal antibody. Jpn. J. Cancer Res. 83, 761-768 (1992).
20. R. V. J. Chari, B. A. Martell, J. L. Gross, S. B. Cook, S. A. Shah, W. A. Blättler, S. J. McKenzie, V. S. Goldmacher, Immunoconjugates containing novel maytansinoids: Promising anticancer drugs. Cancer Res. 52, 127-131 (1992).
21. K. Martin, P. Müller, J. Schreiner, S. S. Prince, D. Lardinois, V. A. Heinzelmann-Schwarz, D. S. Thommen, A. Zippelius, The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity. Cancer Immunol. Immunother. 63, 925-938 (2014).
22. P. Müller, K. Martin, S. Theurich, J. Schreiner, S. Savic, G. Terszowski, D. Lardinois, V. A. Heinzelmann-Schwarz, M. Schlaak, H.-M. Kvasnicka, G. Spagnoli, S. Dirnhofer, D. E. Speiser, M. Von Bergwelt-Baildon, A. Zippelius, Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol. Res. 2, 741-755 (2014).
23. P. Müller, K. Martin, S. Theurich, M. Von Bergwelt-Baildon, A. Zippelius, Cancer chemotherapy agents targets intratumoral dendritic cells to potentiate antitumor immunity. Oncoimmunology 3, e954460 (2014).
24. A. Younes, A. K. Gopal, S. E. Smith, S. M. Ansell, J. D. Rosenblatt, K. J. Savage, R. Ramchandren, N. L. Bartlett, B. D. Cheson, S. De Vos, A. Forero-Torres, C. H. Moskowitz, J. M. Connors, A. Engert, E. K. Larsen, D. A. Kennedy, E. L. Sievers, R. Chen, Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J. Clin. Oncol. 30, 2183-2189 (2012).
25. S. Theurich, J. Malcher, K. Wennhold, A. Shimabukuro-Vornhagen, J. Chemnitz, U. Holtick, A. Krause, C. Kobe, D. Kahraman, A. Engert, C. Scheid, G. Chakupurakal, M. Hallek, M. Von Bergwelt-Baildon, Brentuximab vedotin combined with donor lymphocyte infusions for early relapse of Hodgkin lymphoma after allogeneic stem-cell transplantation induces tumor-specific immunity and sustained clinical remission. J. Clin. Oncol. 31, e59-e63 (2013).
26. D. Hofmann, U. Nitz, O. Gluz, R. E. Kates, T. Schinkoethe, P. Staib, N. Harbeck, WSG ADAPT-adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: Study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial. Trials 14, 261 (2013).
27. R. Salgado, C. Denkert, S. Demaria, N. Sirtaine, F. Klauschen, G. Pruneri, S. Wienert, G. Van Den Eynden, F. L. Baehner, F. Penault-Llorca, E. A. Perez, E. A. Thompson, W. F. Symmans, A. L. Richardson, J. Brock, C. Criscitiello, H. Bailey, M. Ignatiadis, G. Floris, J. Sparano, Z. Kos, T. Nielsen, D. L. Rimm, K. H. Allison, J. S. Reis-Filho, S. Loibl, C. Sotiriou, G. Viale, S. Badve, S. Adams, K. Willard-Gallo, S. Loi, The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259-271 (2015).
28. M.-Y. Polley, S. C. Y. Leung, L. M. McShane, D. Gao, J. C. Hugh, M. G. Mastropasqua, G. Viale, L. A. Zabaglo, F. Penault-Llorca, J. M. S. Bartlett, A. M. Gown, W. F. Symmans, T. Piper, E. Mehl, R. A. Enos, D. F. Hayes, M. Dowsett, T. O. Nielsen; International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group, An international Ki67 reproducibility study. J. Natl. Cancer Inst. 105, 1897-1906 (2013).
29. S. Loi, S. Michiels, R. Salgado, N. Sirtaine, V. Jose, D. Fumagalli, P.-L. Kellokumpu-Lehtinen, P. Bono, V. Kataja, C. Desmedt, M. J. Piccart, S. Loibl, C. Denkert, M. J. Smyth, H. Joensuu, C. Sotiriou, Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: Results from the FinHER trial. Ann. Oncol. 25, 1544-1550 (2014).
30. H. P. Sinn, H. Schmid, H. Junkermann, J. Huober, G. Leppien, M. Kaufmann, G. Bastert, H. F. Otto, Histologic regression of breast cancer after primary (neoadjuvant) chemotherapy. Geburtshilfe Frauenheilkd 54, 552-558 (1994).
31. D. Finkle, Z. R. Quan, V. Asghari, J. Kloss, N. Ghaboosi, E. Mai, W. L. Wong, P. Hollingshead, R. Schwall, H. Koeppen, S. Erickson, HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin. Cancer Res. 10, 2499-2511 (2004).
32. P. A. Prieto, J. C. Yang, R. M. Sherry, M. S. Hughes, U. S. Kammula, D. E. White, C. L. Levy, S. A. Rosenberg, G. Q. Phan, CTLA-4 blockade with ipilimumab: Long-term follow-up of 177 patients with metastatic melanoma. Clin. Cancer Res. 18, 2039-2047 (2012).
33. J. R. Brahmer, S. S. Tykodi, L. Q. M. Chow, W.-J. Hwu, S. L. Topalian, P. Hwu, C. G. Drake, L. H. Camacho, J. Kauh, K. Odunsi, H. C. Pitot, O. Hamid, S. Bhatia, R. Martins, K. Eaton, S. Chen, T. M. Salay, S. Alaparthy, J. F. Grosso, A. J. Korman, S. M. Parker, S. Agrawal, S. M. Goldberg, D. M. Pardoll, A. Gupta, J. M. Wigginton, Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455-2465 (2012).
34. T. Powles, J. P. Eder, G. D. Fine, F. S. Braiteh, Y. Loriot, C. Cruz, J. Bellmunt, H. A. Burris, D. P. Petrylak, S.-. Teng, X. Shen, Z. Boyd, P. S. Hegde, D. S. Chen, N. J. Vogelzang, MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558-562 (2014).
35. J. D. Wolchok, H. Kluger, M. K. Callahan, M. A. Postow, N. A. Rizvi, A. M. Lesokhin, N. H. Segal, C. E. Ariyan, R.-A. Gordon, K. Reed, M. M. Burke, A. Caldwell, S. A. Kronenberg, B. U. Agunwamba, X. Zhang, I. Lowy, H. D. Inzunza, W. Feely, C. E. Horak, Q. Hong, A. J. Korman, J. M. Wigginton, A. Gupta, M. Sznol, Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122-133 (2013).
36. S. Gill, A. E. Vasey, A. De Souza, J. Baker, A. T. Smith, H. E. Kohrt, M. Florek, K. D. Gibbs Jr., K. Tate, D. S. Ritchie, R. S. Negrin, Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells. Blood 119, 5758-5768 (2012).
37. A. Zippelius, J. Schreiner, P. Herzig, P. Müller, Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol. Res. 3, 236-244 (2015).
38. J. Duraiswamy, K. M. Kaluza, G. J. Freeman, G. Coukos, Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591-3603 (2013).
39. M. A. Curran, W. Montalvo, H. Yagita, J. P. Allison, PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl. Acad. Sci. U. S. A. 107, 4275-4280 (2010).
40. G. D. Lewis Phillips, G. Li, D. L. Dugger, L. M. Crocker, K. L. Parsons, E. Mai, W. A. Blättler, J. M. Lambert, R. V. J. Chari, R. J. Lutz, W. L. T. Wong, F. S. Jacobson, H. Koeppen, R. H. Schwall, S. R. Kenkare-Mitra, S. D. Spencer, M. X. Sliwkowski, Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280-9290 (2008).
41. Q.-B. She, S. Chandarlapaty, Q. Ye, J. Lobo, K. M. Haskell, K. R. Leander, D. DeFeo-Jones, H. E. Huber, N. Rosen, Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLOS One 3, e3065 (2008).
42. D. J. L. Wong, S. A. Hurvitz, Recent advances in the development of anti-HER2 antibodies and antibody-drug conjugates. Ann. Transl. Med. 2, 122 (2014).
43. L. A. Emens, Breast cancer immunobiology driving immunotherapy: Vaccines and immune checkpoint blockade. Expert Rev. Anticancer Ther. 12, 1597-1611 (2012).
44. C. Denkert, S. Loibl, A. Noske, M. Roller, B. M. Müller, M. Komor, J. Budczies, S. Darb-Esfahani, R. Kronenwett, C. Hanusch, C. Von Törne, W. Weichert, K. Engels, C. Solbach, I. Schrader, M. Dietel, G. Von Minckwitz, Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28, 105-113 (2010).
45. S. Loi, N. Sirtaine, F. Piette, R. Salgado, G. Viale, F. Van Eenoo, G. Rouas, P. Francis, J. P. A. Crown, E. Hitre, E. De Azambuja, E. Quinaux, A. Di Leo, S. Michiels, M. J. Piccart, C. Sotiriou, Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J. Clin. Oncol. 31, 860-867 (2013).
46. I. Péguillet, M. Milder, D. Louis, A. Vincent-Salomon, T. Dorval, S. Piperno-Neumann, S. M. Scholl, O. Lantz, High numbers of differentiated effector CD4 T cells are found in patients with cancer and correlate with clinical response after neoadjuvant therapy of breast cancer. Cancer Res. 74, 2204-2216 (2014).
47. Y. Issa-Nummer, S. Darb-Esfahani, S. Loibl, G. Kunz, V. Nekljudova, I. Schrader, B. V. Sinn, H.-U. Ulmer, R. Kronenwett, M. Just, T. Kühn, K. Diebold, M. Untch, F. Holms, J.-U. Blohmer, J.-O. Habeck, M. Dietel, F. Overkamp, P. Krabisch, G. Von Minckwitz, C. Denkert, Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer-a substudy of the neoadjuvant GeparQuinto trial. PLOS One 8, e79775 (2013).
48. M. L. Disis, S. E. Stanton, Triple-negative breast cancer: Immune modulation as the new treatment paradigm. Am. Soc. Clin. Oncol. Educ. Book. 35, e25-e30 (2015).
49. E. A. Perez, E. A. Thompson, K. V. Ballman, S. K. Anderson, Y. W. Asmann, K. R. Kalari, J. E. Eckel-Passow, A. C. Dueck, K. S. Tenner, J. Jen, J.-B. Fan, X. J. Geiger, A. E. McCullough, B. Chen, R. B. Jenkins, G. W. Sledge, E. P. Winer, J. R. Gralow, M. M. Reinholz, Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial. J. Clin. Oncol. 33, 701-708 (2015).
50. H. Nishikawa, S. Sakaguchi, Regulatory T cells in cancer immunotherapy. Curr. Opin. Immunol. 27, 1-7 (2014).
51. G. J. Bates, S. B. Fox, C. Han, R. D. Leek, J. F. Garcia, A. L. Harris, A. H. Banham, Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 24, 5373-5380 (2006).
52. S. Ladoire, L. Arnould, G. Mignot, B. Coudert, C. Rébé, F. Chalmin, J. Vincent, M. Bruchard, B. Chauffert, F. Martin, P. Fumoleau, F. Ghiringhelli, Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res. Treat. 125, 65-72 (2011).
53. S. L. Topalian, F. S. Hodi, J. R. Brahmer, S. N. Gettinger, D. C. Smith, D. F. McDermott, J. D. Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, P. D. Leming, D. R. Spigel, S. J. Antonia, L. Horn, C. G. Drake, D. M. Pardoll, L. Chen, W. H. Sharfman, R. A. Anders, J. M. Taube, T. L. McMiller, H. Xu, A. J. Korman, M. Jure-Kunkel, S. Agrawal, D. McDonald, G. D. Kollia, A. Gupta, J. M. Wigginton, M. Sznol, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443-2454 (2012).
54. O. Hamid, C. Robert, A. Daud, F. S. Hodi, W.-J. Hwu, R. Kefford, J. D. Wolchok, P. Hersey, R. W. Joseph, J. S. Weber, R. Dronca, T. C. Gangadhar, A. Patnaik, H. Zarour, A. M. Joshua, K. Gergich, J. Elassaiss-Schaap, A. Algazi, C. Mateus, P. Boasberg, P. C. Tumeh, B. Chmielowski, S. W. Ebbinghaus, X. N. Li, S. P. Kang, A. Ribas, Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134-144 (2013).
55. J. W. Hodge, A. Ardiani, B. Farsaci, A. R. Kwilas, S. R. Gameiro, The tipping point for combination therapy: Cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin. Oncol. 39, 323-339 (2012).
56. C. U. Blank, The perspective of immunotherapy: New molecules and new mechanisms of action in immune modulation. Curr. Opin. Oncol. 26, 204-214 (2014).
57. L. Zitvogel, L. Galluzzi, M. J. Smyth, G. Kroemer, Mechanism of action of conventional and targeted anticancer therapies: Reinstating immunosurveillance. Immunity 39, 74-88 (2013).
58. + regulatory T cells. Clin. Cancer Res. 14, 2413-2420 (2008).
59. N. Oda, K. Shimazu, Y. Naoi, K. Morimoto, A. Shimomura, M. Shimoda, N. Kagara, N. Maruyama, S. J. Kim, S. Noguchi, Intratumoral regulatory T cells as an independent predictive factor for pathological complete response to neoadjuvant paclitaxel followed by 5-FU/epirubicin/cyclophosphamide in breast cancer patients. Breast Cancer Res. Treat. 136, 107-116 (2012).
60. M. A. Koch, G. Tucker-Heard, N. R. Perdue, J. R. Killebrew, K. B. Urdahl, D. J. Campbell, The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595-602 (2009).
61. V. Lazarevic, L. H. Glimcher, T-bet in disease. Nat. Immunol. 12, 597-606 (2011).
62. + Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor β2. Immunity 37, 501-510 (2012).
63. + regulatory T cell-depleted mice. Cancer Res. 65, 8471-8478 (2005).
64. + T helper cells and hindered by naturally occurring T regulatory cells. J. Immunol. 174, 2591-2601 (2005).
65. M. J. Selby, J. J. Engelhardt, M. Quigley, K. A. Henning, T. Chen, M. Srinivasan, A. J. Korman, Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32-42 (2013).
66. T. R. Simpson, F. Li, W. Montalvo-Ortiz, M. A. Sepulveda, K. Bergerhoff, F. Arce, C. Roddie, J. Y. Henry, H. Yagita, J. D. Wolchok, K. S. Peggs, J. V. Ravetch, J. P. Allison, S. A. Quezada, Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695-1710 (2013).
67. E. Romano, M. Kusio-Kobialka, P. G. Foukas, P. Baumgaertner, C. Meyer, P. Ballabeni, O. Michielin, B. Weide, P. Romero, D. E. Speiser, Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl. Acad. Sci. U. S. A. 112, 6140-6145 (2015).
68. A. J. Furness, F. A. Vargas, K. S. Peggs, S. A. Quezada, Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies. Trends Immunol. 35, 290-298 (2014).
69. T. F. Gajewski, H. Schreiber, Y.-X. Fu, Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014-1022 (2013).
70. D. T. Utzschneider, A. Legat, S. A. Fuertes Marraco, L. Carrié, I. Luescher, D. E. Speiser, D. Zehn, T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat. Immunol. 14, 603-610 (2013).
71. O. Gluz, D. Hofmann, R. E. Kates, N. Harbeck, U. Nitz, ADAPT - Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer. Cancer Res. 72, OT3-3-02 (2012).