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Erschienen in: Cellular Oncology 5/2019

14.06.2019 | Review

Recent advances in the clinical development of immune checkpoint blockade therapy

verfasst von: Atefeh Ghahremanloo, Arash Soltani, Seyed Mohamad Sadegh Modaresi, Seyed Isaac Hashemy

Erschienen in: Cellular Oncology | Ausgabe 5/2019

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Abstract

Background

The discovery of immune checkpoint proteins and the mechanisms by which cancer cells utilize them to evade the immune system has transformed our approach to cancer immunotherapy. Checkpoint blockade antibodies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligands such as programmed cell death ligand 1 (PD-L1) have already revolutionized the treatment of multiple types of cancer and have significantly improved treatment and survival outcomes of patients affected by these malignancies.

Conclusions

Herein, we summarize current knowledge about the role of, and the mechanisms underlying PD-1/PD-L1 signaling pathways in antitumor immune responses, with particular emphasis on clinical studies evaluating the efficacy of anti-PD-1/PD-L1 blockade in various tumor types. Preliminary clinical investigations with immune-checkpoint blockers highlight broad opportunities with a high potential to enhance antitumor immunity and, as such, to generate significant clinical responses. These preliminary successes open up new avenues towards efficient therapeutics offered to patients.
Literatur
1.
Zurück zum Zitat K. Li, H. Tian, Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy. J. Drug Target 27, 244–256 (2019) K. Li, H. Tian, Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy. J. Drug Target 27, 244–256 (2019)
2.
Zurück zum Zitat D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)CrossRefPubMed D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)CrossRefPubMed
3.
Zurück zum Zitat G.P. Dunn, A.T. Bruce, H. Ikeda, L.J. Old, R.D. Schreiber, Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002)CrossRefPubMed G.P. Dunn, A.T. Bruce, H. Ikeda, L.J. Old, R.D. Schreiber, Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002)CrossRefPubMed
4.
Zurück zum Zitat R.A. Lake, B.W. Robinson, Immunotherapy and chemotherapy--a practical partnership. Nat. Rev. Cancer. 5, 397–405 (2005)CrossRefPubMed R.A. Lake, B.W. Robinson, Immunotherapy and chemotherapy--a practical partnership. Nat. Rev. Cancer. 5, 397–405 (2005)CrossRefPubMed
5.
Zurück zum Zitat I. Melero, G. Gaudernack, W. Gerritsen, C. Huber, G. Parmiani, S. Scholl, N. Thatcher, J. Wagstaff, C. Zielinski, I. Faulkner, H. Mellstedt, Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014)CrossRefPubMed I. Melero, G. Gaudernack, W. Gerritsen, C. Huber, G. Parmiani, S. Scholl, N. Thatcher, J. Wagstaff, C. Zielinski, I. Faulkner, H. Mellstedt, Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014)CrossRefPubMed
6.
Zurück zum Zitat M.M. Gubin, X. Zhang, H. Schuster, E. Caron, J.P. Ward, T. Noguchi, Y. Ivanova, J. Hundal, C.D. Arthur, W.J. Krebber, G.E. Mulder, M. Toebes, M.D. Vesely, S.S. Lam, A.J. Korman, J.P. Allison, G.J. Freeman, A.H. Sharpe, E.L. Pearce, T.N. Schumacher, R. Aebersold, H.G. Rammensee, C.J. Melief, E.R. Mardis, W.E. Gillanders, M.N. Artyomov, R.D. Schreiber, Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014)CrossRefPubMedPubMedCentral M.M. Gubin, X. Zhang, H. Schuster, E. Caron, J.P. Ward, T. Noguchi, Y. Ivanova, J. Hundal, C.D. Arthur, W.J. Krebber, G.E. Mulder, M. Toebes, M.D. Vesely, S.S. Lam, A.J. Korman, J.P. Allison, G.J. Freeman, A.H. Sharpe, E.L. Pearce, T.N. Schumacher, R. Aebersold, H.G. Rammensee, C.J. Melief, E.R. Mardis, W.E. Gillanders, M.N. Artyomov, R.D. Schreiber, Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014)CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat M.R. Zamani, S. Aslani, A. Salmaninejad, M.R. Javan, N. Rezaei, PD-1/PD-L and autoimmunity: A growing relationship. Cell. Immunol. 310, 27–41 (2016)CrossRefPubMed M.R. Zamani, S. Aslani, A. Salmaninejad, M.R. Javan, N. Rezaei, PD-1/PD-L and autoimmunity: A growing relationship. Cell. Immunol. 310, 27–41 (2016)CrossRefPubMed
8.
Zurück zum Zitat P. Sharma, K. Wagner, J.D. Wolchok, J.P. Allison, Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat. Rev. Cancer. 11, 805–812 (2011)CrossRefPubMedPubMedCentral P. Sharma, K. Wagner, J.D. Wolchok, J.P. Allison, Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat. Rev. Cancer. 11, 805–812 (2011)CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat P. Sharma, J.P. Allison, Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015)CrossRefPubMedPubMedCentral P. Sharma, J.P. Allison, Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015)CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat A. Hoos, Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016)CrossRefPubMed A. Hoos, Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016)CrossRefPubMed
12.
Zurück zum Zitat X. Zhang, J.-C.D. Schwartz, X. Guo, S. Bhatia, E. Cao, L. Chen, Z.-Y. Zhang, M.A. Edidin, S.G. Nathenson, S.C. Almo, Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20, 337–347 (2004)CrossRefPubMed X. Zhang, J.-C.D. Schwartz, X. Guo, S. Bhatia, E. Cao, L. Chen, Z.-Y. Zhang, M.A. Edidin, S.G. Nathenson, S.C. Almo, Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20, 337–347 (2004)CrossRefPubMed
13.
Zurück zum Zitat A.H. Sharpe, E.J. Wherry, R. Ahmed, G.J. Freeman, The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8, 239–245 (2007)CrossRefPubMed A.H. Sharpe, E.J. Wherry, R. Ahmed, G.J. Freeman, The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8, 239–245 (2007)CrossRefPubMed
15.
Zurück zum Zitat J. Chen, C.C. Jiang, L. Jin, X.D. Zhang, Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann. Oncol. 27, 409–416 (2016)CrossRefPubMed J. Chen, C.C. Jiang, L. Jin, X.D. Zhang, Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann. Oncol. 27, 409–416 (2016)CrossRefPubMed
16.
Zurück zum Zitat M. Ahmadzadeh, L.A. Johnson, B. Heemskerk, J.R. Wunderlich, M.E. Dudley, D.E. White, S.A. Rosenberg, Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537–1544 (2009)CrossRefPubMedPubMedCentral M. Ahmadzadeh, L.A. Johnson, B. Heemskerk, J.R. Wunderlich, M.E. Dudley, D.E. White, S.A. Rosenberg, Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537–1544 (2009)CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat N. Yaghoubi, A. Soltani, K. Ghazvini, S.M. Hassanian, S.I. Hashemy, PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. Biomed. Pharmacother. 110, 312–318 (2018)CrossRefPubMed N. Yaghoubi, A. Soltani, K. Ghazvini, S.M. Hassanian, S.I. Hashemy, PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. Biomed. Pharmacother. 110, 312–318 (2018)CrossRefPubMed
18.
Zurück zum Zitat H. Nishimura, Y. Agata, A. Kawasaki, M. Sato, S. Imamura, N. Minato, H. Yagita, T. Nakano, T. Honjo, Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4–CD8–) thymocytes. Int. Immunol. 8, 773–780 (1996)CrossRefPubMed H. Nishimura, Y. Agata, A. Kawasaki, M. Sato, S. Imamura, N. Minato, H. Yagita, T. Nakano, T. Honjo, Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4–CD8–) thymocytes. Int. Immunol. 8, 773–780 (1996)CrossRefPubMed
19.
Zurück zum Zitat M. Mahmoudi, A. Rezaiemanesh, A. Salmaninejad, S. Harsini, S. Poursani, T. Bahrami, F. Tahghighi, V. Ziaee, N. Rezaei, PDCD1 single nucleotide genes polymorphisms confer susceptibility to juvenile-onset systemic lupus erythematosus. Autoimmunity 48, 488–493 (2015)CrossRefPubMed M. Mahmoudi, A. Rezaiemanesh, A. Salmaninejad, S. Harsini, S. Poursani, T. Bahrami, F. Tahghighi, V. Ziaee, N. Rezaei, PDCD1 single nucleotide genes polymorphisms confer susceptibility to juvenile-onset systemic lupus erythematosus. Autoimmunity 48, 488–493 (2015)CrossRefPubMed
20.
Zurück zum Zitat M.E. Keir, M.J. Butte, G.J. Freeman, A.H. Sharpe, PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008)CrossRefPubMed M.E. Keir, M.J. Butte, G.J. Freeman, A.H. Sharpe, PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008)CrossRefPubMed
21.
Zurück zum Zitat Y. Agata, A. Kawasaki, H. Nishimura, Y. Ishida, T. Tsubata, H. Yagita, T. Honjo, Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996)CrossRefPubMed Y. Agata, A. Kawasaki, H. Nishimura, Y. Ishida, T. Tsubata, H. Yagita, T. Honjo, Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996)CrossRefPubMed
22.
Zurück zum Zitat T. Yamazaki, H. Akiba, H. Iwai, H. Matsuda, M. Aoki, Y. Tanno, T. Shin, H. Tsuchiya, D.M. Pardoll, K. Okumura, M. Azuma, H. Yagita, Expression of programmed death 1 ligands by murine T cells and APC. J. Immunol. 169, 5538–5545 (2002)CrossRefPubMed T. Yamazaki, H. Akiba, H. Iwai, H. Matsuda, M. Aoki, Y. Tanno, T. Shin, H. Tsuchiya, D.M. Pardoll, K. Okumura, M. Azuma, H. Yagita, Expression of programmed death 1 ligands by murine T cells and APC. J. Immunol. 169, 5538–5545 (2002)CrossRefPubMed
23.
Zurück zum Zitat A.L. Kinter, E.J. Godbout, J.P. McNally, I. Sereti, G.A. Roby, M.A. O'Shea, A.S. Fauci, The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J. Immunol. 181, 6738–6746 (2008)CrossRefPubMed A.L. Kinter, E.J. Godbout, J.P. McNally, I. Sereti, G.A. Roby, M.A. O'Shea, A.S. Fauci, The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J. Immunol. 181, 6738–6746 (2008)CrossRefPubMed
24.
Zurück zum Zitat K.J. Oestreich, H. Yoon, R. Ahmed, J.M. Boss, NFATc1 regulates PD-1 expression upon T cell activation. J. Immunol. 181, 4832–4839 (2008)CrossRefPubMed K.J. Oestreich, H. Yoon, R. Ahmed, J.M. Boss, NFATc1 regulates PD-1 expression upon T cell activation. J. Immunol. 181, 4832–4839 (2008)CrossRefPubMed
25.
Zurück zum Zitat T. Watanabe, A. Bertoletti, T.A. Tanoto, PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J. Viral Hepat. 17, 453–458 (2010)CrossRefPubMed T. Watanabe, A. Bertoletti, T.A. Tanoto, PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J. Viral Hepat. 17, 453–458 (2010)CrossRefPubMed
26.
Zurück zum Zitat C.L. Day, D.E. Kaufmann, P. Kiepiela, J.A. Brown, E.S. Moodley, S. Reddy, E.W. Mackey, J.D. Miller, A.J. Leslie, C. DePierres, PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006)CrossRefPubMed C.L. Day, D.E. Kaufmann, P. Kiepiela, J.A. Brown, E.S. Moodley, S. Reddy, E.W. Mackey, J.D. Miller, A.J. Leslie, C. DePierres, PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006)CrossRefPubMed
27.
Zurück zum Zitat M.J. Butte, M.E. Keir, T.B. Phamduy, A.H. Sharpe, G.J. Freeman, Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007)CrossRefPubMedPubMedCentral M.J. Butte, M.E. Keir, T.B. Phamduy, A.H. Sharpe, G.J. Freeman, Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007)CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat X. Zhong, J.R. Tumang, W. Gao, C. Bai, T.L. Rothstein, PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for VH11/VH12 and phosphatidylcholine binding. Eur. J. Immunol. 37, 2405–2410 (2007)CrossRefPubMed X. Zhong, J.R. Tumang, W. Gao, C. Bai, T.L. Rothstein, PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for VH11/VH12 and phosphatidylcholine binding. Eur. J. Immunol. 37, 2405–2410 (2007)CrossRefPubMed
29.
Zurück zum Zitat C. Blank, T.F. Gajewski, A. Mackensen, Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol. Immunother. 54, 307–314 (2005)CrossRefPubMed C. Blank, T.F. Gajewski, A. Mackensen, Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol. Immunother. 54, 307–314 (2005)CrossRefPubMed
30.
Zurück zum Zitat A.M. Paterson, K.E. Brown, M.E. Keir, V.K. Vanguri, L.V. Riella, A. Chandraker, M.H. Sayegh, B.R. Blazar, G.J. Freeman, A.H. Sharpe, The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J. Immunol. 187, 1097–1105 (2011)CrossRefPubMed A.M. Paterson, K.E. Brown, M.E. Keir, V.K. Vanguri, L.V. Riella, A. Chandraker, M.H. Sayegh, B.R. Blazar, G.J. Freeman, A.H. Sharpe, The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J. Immunol. 187, 1097–1105 (2011)CrossRefPubMed
31.
Zurück zum Zitat J. Konishi, K. Yamazaki, M. Azuma, I. Kinoshita, H. Dosaka-Akita, M. Nishimura, B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin. Cancer. Res. 10, 5094–5100 (2004)CrossRefPubMed J. Konishi, K. Yamazaki, M. Azuma, I. Kinoshita, H. Dosaka-Akita, M. Nishimura, B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin. Cancer. Res. 10, 5094–5100 (2004)CrossRefPubMed
32.
Zurück zum Zitat J.A. Brown, D.M. Dorfman, F.R. Ma, E.L. Sullivan, O. Munoz, C.R. Wood, E.A. Greenfield, G.J. Freeman, Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257–1266 (2003)CrossRefPubMed J.A. Brown, D.M. Dorfman, F.R. Ma, E.L. Sullivan, O. Munoz, C.R. Wood, E.A. Greenfield, G.J. Freeman, Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257–1266 (2003)CrossRefPubMed
33.
Zurück zum Zitat H. Dong, S.E. Strome, D.R. Salomao, H. Tamura, F. Hirano, D.B. Flies, P.C. Roche, J. Lu, G. Zhu, K. Tamada, V.A. Lennon, E. Celis, L. Chen, Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002)CrossRefPubMed H. Dong, S.E. Strome, D.R. Salomao, H. Tamura, F. Hirano, D.B. Flies, P.C. Roche, J. Lu, G. Zhu, K. Tamada, V.A. Lennon, E. Celis, L. Chen, Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002)CrossRefPubMed
34.
Zurück zum Zitat R.H. Thompson, M.D. Gillett, J.C. Cheville, C.M. Lohse, H. Dong, W.S. Webster, K.G. Krejci, J.R. Lobo, S. Sengupta, L. Chen, H. Zincke, M.L. Blute, S.E. Strome, B.C. Leibovich, E.D. Kwon, Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. U. S. A. 101, 17174–17179 (2004)CrossRefPubMedPubMedCentral R.H. Thompson, M.D. Gillett, J.C. Cheville, C.M. Lohse, H. Dong, W.S. Webster, K.G. Krejci, J.R. Lobo, S. Sengupta, L. Chen, H. Zincke, M.L. Blute, S.E. Strome, B.C. Leibovich, E.D. Kwon, Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. U. S. A. 101, 17174–17179 (2004)CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat J. Bai, Z. Gao, X. Li, L. Dong, W. Han, J. Nie, Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget 8, 110693 (2017)PubMedPubMedCentral J. Bai, Z. Gao, X. Li, L. Dong, W. Han, J. Nie, Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget 8, 110693 (2017)PubMedPubMedCentral
36.
Zurück zum Zitat N. Selenko-Gebauer, O. Majdic, A. Szekeres, G. Hofler, E. Guthann, U. Korthauer, G. Zlabinger, P. Steinberger, W.F. Pickl, H. Stockinger, W. Knapp, J. Stockl, B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J. Immunol. 170, 3637–3644 (2003)CrossRefPubMed N. Selenko-Gebauer, O. Majdic, A. Szekeres, G. Hofler, E. Guthann, U. Korthauer, G. Zlabinger, P. Steinberger, W.F. Pickl, H. Stockinger, W. Knapp, J. Stockl, B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J. Immunol. 170, 3637–3644 (2003)CrossRefPubMed
37.
Zurück zum Zitat G.J. Freeman, A.J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L.J. Fitz, N. Malenkovich, T. Okazaki, M.C. Byrne, H.F. Horton, L. Fouser, L. Carter, V. Ling, M.R. Bowman, B.M. Carreno, M. Collins, C.R. Wood, T. Honjo, Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000)CrossRefPubMedPubMedCentral G.J. Freeman, A.J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L.J. Fitz, N. Malenkovich, T. Okazaki, M.C. Byrne, H.F. Horton, L. Fouser, L. Carter, V. Ling, M.R. Bowman, B.M. Carreno, M. Collins, C.R. Wood, T. Honjo, Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000)CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Y. Latchman, C.R. Wood, T. Chernova, D. Chaudhary, M. Borde, I. Chernova, Y. Iwai, A.J. Long, J.A. Brown, R. Nunes, E.A. Greenfield, K. Bourque, V.A. Boussiotis, L.L. Carter, B.M. Carreno, N. Malenkovich, H. Nishimura, T. Okazaki, T. Honjo, A.H. Sharpe, G.J. Freeman, PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001)CrossRefPubMed Y. Latchman, C.R. Wood, T. Chernova, D. Chaudhary, M. Borde, I. Chernova, Y. Iwai, A.J. Long, J.A. Brown, R. Nunes, E.A. Greenfield, K. Bourque, V.A. Boussiotis, L.L. Carter, B.M. Carreno, N. Malenkovich, H. Nishimura, T. Okazaki, T. Honjo, A.H. Sharpe, G.J. Freeman, PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001)CrossRefPubMed
39.
Zurück zum Zitat H. Dong, G. Zhu, K. Tamada, L. Chen, B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5, 1365 (1999)CrossRefPubMed H. Dong, G. Zhu, K. Tamada, L. Chen, B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5, 1365 (1999)CrossRefPubMed
40.
Zurück zum Zitat D.M. Kuang, Q. Zhao, C. Peng, J. Xu, J.P. Zhang, C. Wu, L. Zheng, Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009)CrossRefPubMedPubMedCentral D.M. Kuang, Q. Zhao, C. Peng, J. Xu, J.P. Zhang, C. Wu, L. Zheng, Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009)CrossRefPubMedPubMedCentral
41.
Zurück zum Zitat L. Zhang, T.F. Gajewski, J. Kline, PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 114, 1545–1552 (2009)CrossRefPubMedPubMedCentral L. Zhang, T.F. Gajewski, J. Kline, PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 114, 1545–1552 (2009)CrossRefPubMedPubMedCentral
42.
Zurück zum Zitat J.M. Chemnitz, R.V. Parry, K.E. Nichols, C.H. June, J.L. Riley, SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004)CrossRefPubMed J.M. Chemnitz, R.V. Parry, K.E. Nichols, C.H. June, J.L. Riley, SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004)CrossRefPubMed
43.
Zurück zum Zitat R.V. Parry, J.M. Chemnitz, K.A. Frauwirth, A.R. Lanfranco, I. Braunstein, S.V. Kobayashi, P.S. Linsley, C.B. Thompson, J.L. Riley, CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005)CrossRefPubMedPubMedCentral R.V. Parry, J.M. Chemnitz, K.A. Frauwirth, A.R. Lanfranco, I. Braunstein, S.V. Kobayashi, P.S. Linsley, C.B. Thompson, J.L. Riley, CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005)CrossRefPubMedPubMedCentral
44.
Zurück zum Zitat K.-A. Sheppard, L.J. Fitz, J.M. Lee, C. Benander, J.A. George, J. Wooters, Y. Qiu, J.M. Jussif, L.L. Carter, C.R. Wood, PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574, 37–41 (2004)CrossRefPubMed K.-A. Sheppard, L.J. Fitz, J.M. Lee, C. Benander, J.A. George, J. Wooters, Y. Qiu, J.M. Jussif, L.L. Carter, C.R. Wood, PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574, 37–41 (2004)CrossRefPubMed
45.
Zurück zum Zitat A. Soltani, A. Bahreyni, N. Boroumand, M.K. Roshan, M. Khazaei, M. Ryzhikov, S. Soleimanpour, A. Avan, S.M. Hassanian, Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proinflammatory diseases, current status, and perspectives. J. Cell. Physiol. 233, 4783–4790 (2018)CrossRefPubMed A. Soltani, A. Bahreyni, N. Boroumand, M.K. Roshan, M. Khazaei, M. Ryzhikov, S. Soleimanpour, A. Avan, S.M. Hassanian, Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proinflammatory diseases, current status, and perspectives. J. Cell. Physiol. 233, 4783–4790 (2018)CrossRefPubMed
46.
Zurück zum Zitat I.A. Mayer, C.L. Arteaga, The PI3K/AKT Pathway as a target for cancer treatment. Annu. Rev. Med. 67, 11–28 (2016)CrossRefPubMed I.A. Mayer, C.L. Arteaga, The PI3K/AKT Pathway as a target for cancer treatment. Annu. Rev. Med. 67, 11–28 (2016)CrossRefPubMed
47.
Zurück zum Zitat N. Patsoukis, J. Brown, V. Petkova, F. Liu, L. Li and V.A. Boussiotis, Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 5, ra46 (2012) N. Patsoukis, J. Brown, V. Petkova, F. Liu, L. Li and V.A. Boussiotis, Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 5, ra46 (2012)
48.
Zurück zum Zitat N. Patsoukis, L. Li, D. Sari, V. Petkova, V.A. Boussiotis, PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol. Cell. Biol. 33, 3091–3098 (2013)CrossRefPubMedPubMedCentral N. Patsoukis, L. Li, D. Sari, V. Petkova, V.A. Boussiotis, PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol. Cell. Biol. 33, 3091–3098 (2013)CrossRefPubMedPubMedCentral
49.
Zurück zum Zitat F. Vazquez, S. Ramaswamy, N. Nakamura, W.R. Sellers, Phosphorylation of the PTEN tail regulates protein stability and function. Mol. Cell. Biol. 20, 5010–5018 (2000)CrossRefPubMedPubMedCentral F. Vazquez, S. Ramaswamy, N. Nakamura, W.R. Sellers, Phosphorylation of the PTEN tail regulates protein stability and function. Mol. Cell. Biol. 20, 5010–5018 (2000)CrossRefPubMedPubMedCentral
50.
Zurück zum Zitat J. Torres, R. Pulido, The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J. Biol. Chem. 276, 993–998 (2001)PubMed J. Torres, R. Pulido, The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J. Biol. Chem. 276, 993–998 (2001)PubMed
51.
Zurück zum Zitat T.G. Bivona, I. Perez De Castro, I.M. Ahearn, T.M. Grana, V.K. Chiu, P.J. Lockyer, P.J. Cullen, A. Pellicer, A.D. Cox, M.R. Philips, Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694–698 (2003)CrossRefPubMed T.G. Bivona, I. Perez De Castro, I.M. Ahearn, T.M. Grana, V.K. Chiu, P.J. Lockyer, P.J. Cullen, A. Pellicer, A.D. Cox, M.R. Philips, Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694–698 (2003)CrossRefPubMed
52.
Zurück zum Zitat J.O. Ebinu, D.A. Bottorff, E.Y. Chan, S.L. Stang, R.J. Dunn, J.C. Stone, RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science 280, 1082–1086 (1998)CrossRefPubMed J.O. Ebinu, D.A. Bottorff, E.Y. Chan, S.L. Stang, R.J. Dunn, J.C. Stone, RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science 280, 1082–1086 (1998)CrossRefPubMed
53.
Zurück zum Zitat J.O. Ebinu, S.L. Stang, C. Teixeira, D.A. Bottorff, J. Hooton, P.M. Blumberg, M. Barry, R.C. Bleakley, H.L. Ostergaard, J.C. Stone, RasGRP links T-cell receptor signaling to Ras. Blood 95, 3199–3203 (2000)PubMedCrossRef J.O. Ebinu, S.L. Stang, C. Teixeira, D.A. Bottorff, J. Hooton, P.M. Blumberg, M. Barry, R.C. Bleakley, H.L. Ostergaard, J.C. Stone, RasGRP links T-cell receptor signaling to Ras. Blood 95, 3199–3203 (2000)PubMedCrossRef
54.
Zurück zum Zitat P.A. Ott, F.S. Hodi, C. Robert, CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin. Cancer. Res. 19, 5300–5309 (2013)CrossRefPubMed P.A. Ott, F.S. Hodi, C. Robert, CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin. Cancer. Res. 19, 5300–5309 (2013)CrossRefPubMed
55.
Zurück zum Zitat D.M. Lussier, L. O'Neill, L.M. Nieves, M.S. McAfee, S.A. Holechek, A.W. Collins, P. Dickman, J. Jacobsen, P. Hingorani, J.N. Blattman, Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions. J. Immunother. 38, 96–106 (2015)CrossRefPubMedPubMedCentral D.M. Lussier, L. O'Neill, L.M. Nieves, M.S. McAfee, S.A. Holechek, A.W. Collins, P. Dickman, J. Jacobsen, P. Hingorani, J.N. Blattman, Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions. J. Immunother. 38, 96–106 (2015)CrossRefPubMedPubMedCentral
56.
Zurück zum Zitat R.S. Herbst, J.C. Soria, M. Kowanetz, G.D. Fine, O. Hamid, M.S. Gordon, J.A. Sosman, D.F. McDermott, J.D. Powderly, S.N. Gettinger, H.E. Kohrt, L. Horn, D.P. Lawrence, S. Rost, M. Leabman, Y. Xiao, A. Mokatrin, H. Koeppen, P.S. Hegde, I. Mellman, D.S. Chen, F.S. Hodi, Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014)CrossRefPubMedPubMedCentral R.S. Herbst, J.C. Soria, M. Kowanetz, G.D. Fine, O. Hamid, M.S. Gordon, J.A. Sosman, D.F. McDermott, J.D. Powderly, S.N. Gettinger, H.E. Kohrt, L. Horn, D.P. Lawrence, S. Rost, M. Leabman, Y. Xiao, A. Mokatrin, H. Koeppen, P.S. Hegde, I. Mellman, D.S. Chen, F.S. Hodi, Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014)CrossRefPubMedPubMedCentral
57.
Zurück zum Zitat C. Robert, G.V. Long, B. Brady, C. Dutriaux, M. Maio, L. Mortier, J.C. Hassel, P. Rutkowski, C. McNeil, E. Kalinka-Warzocha, K.J. Savage, M.M. Hernberg, C. Lebbe, J. Charles, C. Mihalcioiu, V. Chiarion-Sileni, C. Mauch, F. Cognetti, A. Arance, H. Schmidt, D. Schadendorf, H. Gogas, L. Lundgren-Eriksson, C. Horak, B. Sharkey, I.M. Waxman, V. Atkinson, P.A. Ascierto, Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015)CrossRefPubMed C. Robert, G.V. Long, B. Brady, C. Dutriaux, M. Maio, L. Mortier, J.C. Hassel, P. Rutkowski, C. McNeil, E. Kalinka-Warzocha, K.J. Savage, M.M. Hernberg, C. Lebbe, J. Charles, C. Mihalcioiu, V. Chiarion-Sileni, C. Mauch, F. Cognetti, A. Arance, H. Schmidt, D. Schadendorf, H. Gogas, L. Lundgren-Eriksson, C. Horak, B. Sharkey, I.M. Waxman, V. Atkinson, P.A. Ascierto, Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015)CrossRefPubMed
58.
Zurück zum Zitat 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)CrossRefPubMedPubMedCentral 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)CrossRefPubMedPubMedCentral
59.
Zurück zum Zitat J. Brahmer, K.L. Reckamp, P. Baas, L. Crino, W.E. Eberhardt, E. Poddubskaya, S. Antonia, A. Pluzanski, E.E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J. Gainor, O. Aren Frontera, L. Havel, M. Steins, M.C. Garassino, J.G. Aerts, M. Domine, L. Paz-Ares, M. Reck, C. Baudelet, C.T. Harbison, B. Lestini, D.R. Spigel, Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015)CrossRefPubMedPubMedCentral J. Brahmer, K.L. Reckamp, P. Baas, L. Crino, W.E. Eberhardt, E. Poddubskaya, S. Antonia, A. Pluzanski, E.E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J. Gainor, O. Aren Frontera, L. Havel, M. Steins, M.C. Garassino, J.G. Aerts, M. Domine, L. Paz-Ares, M. Reck, C. Baudelet, C.T. Harbison, B. Lestini, D.R. Spigel, Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015)CrossRefPubMedPubMedCentral
60.
Zurück zum Zitat E.B. Garon, N.A. Rizvi, R. Hui, N. Leighl, A.S. Balmanoukian, J.P. Eder, A. Patnaik, C. Aggarwal, M. Gubens, L. Horn, E. Carcereny, M.J. Ahn, E. Felip, J.S. Lee, M.D. Hellmann, O. Hamid, J.W. Goldman, J.C. Soria, M. Dolled-Filhart, R.Z. Rutledge, J. Zhang, J.K. Lunceford, R. Rangwala, G.M. Lubiniecki, C. Roach, K. Emancipator, L. Gandhi, Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015)CrossRefPubMed E.B. Garon, N.A. Rizvi, R. Hui, N. Leighl, A.S. Balmanoukian, J.P. Eder, A. Patnaik, C. Aggarwal, M. Gubens, L. Horn, E. Carcereny, M.J. Ahn, E. Felip, J.S. Lee, M.D. Hellmann, O. Hamid, J.W. Goldman, J.C. Soria, M. Dolled-Filhart, R.Z. Rutledge, J. Zhang, J.K. Lunceford, R. Rangwala, G.M. Lubiniecki, C. Roach, K. Emancipator, L. Gandhi, Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015)CrossRefPubMed
61.
Zurück zum Zitat T. Powles, J.P. Eder, G.D. Fine, F.S. Braiteh, Y. Loriot, C. Cruz, J. Bellmunt, H.A. Burris, D.P. Petrylak, S.L. 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)CrossRefPubMed T. Powles, J.P. Eder, G.D. Fine, F.S. Braiteh, Y. Loriot, C. Cruz, J. Bellmunt, H.A. Burris, D.P. Petrylak, S.L. 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)CrossRefPubMed
62.
Zurück zum Zitat R.J. Motzer, B.I. Rini, D.F. McDermott, B.G. Redman, T.M. Kuzel, M.R. Harrison, U.N. Vaishampayan, H.A. Drabkin, S. George, T.F. Logan, K.A. Margolin, E.R. Plimack, A.M. Lambert, I.M. Waxman, H.J. Hammers, Nivolumab for metastatic renal cell carcinoma: Results of a randomized Phase II Trial. J. Clin. Oncol. 33, 1430–1437 (2015)CrossRefPubMed R.J. Motzer, B.I. Rini, D.F. McDermott, B.G. Redman, T.M. Kuzel, M.R. Harrison, U.N. Vaishampayan, H.A. Drabkin, S. George, T.F. Logan, K.A. Margolin, E.R. Plimack, A.M. Lambert, I.M. Waxman, H.J. Hammers, Nivolumab for metastatic renal cell carcinoma: Results of a randomized Phase II Trial. J. Clin. Oncol. 33, 1430–1437 (2015)CrossRefPubMed
63.
Zurück zum Zitat S.L. Topalian, M. Sznol, D.F. McDermott, H.M. Kluger, R.D. Carvajal, W.H. Sharfman, J.R. Brahmer, D.P. Lawrence, M.B. Atkins, J.D. Powderly, P.D. Leming, E.J. Lipson, I. Puzanov, D.C. Smith, J.M. Taube, J.M. Wigginton, G.D. Kollia, A. Gupta, D.M. Pardoll, J.A. Sosman, F.S. Hodi, Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014)CrossRefPubMedPubMedCentral S.L. Topalian, M. Sznol, D.F. McDermott, H.M. Kluger, R.D. Carvajal, W.H. Sharfman, J.R. Brahmer, D.P. Lawrence, M.B. Atkins, J.D. Powderly, P.D. Leming, E.J. Lipson, I. Puzanov, D.C. Smith, J.M. Taube, J.M. Wigginton, G.D. Kollia, A. Gupta, D.M. Pardoll, J.A. Sosman, F.S. Hodi, Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014)CrossRefPubMedPubMedCentral
64.
Zurück zum Zitat J. Naidoo, D.B. Page, B.T. Li, L.C. Connell, K. Schindler, M.E. Lacouture, M.A. Postow, J.D. Wolchok, Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann. Oncol. 26, 2375–2391 (2015)PubMedPubMedCentral J. Naidoo, D.B. Page, B.T. Li, L.C. Connell, K. Schindler, M.E. Lacouture, M.A. Postow, J.D. Wolchok, Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann. Oncol. 26, 2375–2391 (2015)PubMedPubMedCentral
65.
Zurück zum Zitat M.E. Valsecchi, Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270 (2015)CrossRefPubMed M.E. Valsecchi, Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270 (2015)CrossRefPubMed
66.
Zurück zum Zitat J.S. Weber, S.P. D’Angelo, D. Minor, F.S. Hodi, R. Gutzmer, B. Neyns, C. Hoeller, N.I. Khushalani, W.H. Miller Jr., C.D. Lao, G.P. Linette, L. Thomas, P. Lorigan, K.F. Grossmann, J.C. Hassel, M. Maio, M. Sznol, P.A. Ascierto, P. Mohr, B. Chmielowski, A. Bryce, I.M. Svane, J.J. Grob, A.M. Krackhardt, C. Horak, A. Lambert, A.S. Yang, J. Larkin, Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375–384 (2015)CrossRefPubMed J.S. Weber, S.P. D’Angelo, D. Minor, F.S. Hodi, R. Gutzmer, B. Neyns, C. Hoeller, N.I. Khushalani, W.H. Miller Jr., C.D. Lao, G.P. Linette, L. Thomas, P. Lorigan, K.F. Grossmann, J.C. Hassel, M. Maio, M. Sznol, P.A. Ascierto, P. Mohr, B. Chmielowski, A. Bryce, I.M. Svane, J.J. Grob, A.M. Krackhardt, C. Horak, A. Lambert, A.S. Yang, J. Larkin, Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375–384 (2015)CrossRefPubMed
67.
Zurück zum Zitat N.H. Segal, S.H.I. Ou, A.S. Balmanoukian, M.G. Fury, E. Massarelli, J.R. Brahmer, J. Weiss, P. Schoffski, S.J. Antonia, C. Massard, D.P. Zandberg, S. Khleif, X. Li, M. Rebelatto, K. Steele, P.B. Robbins, J.A. Blake-Haskins, M.O. Butler, Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. J. Clin. Oncol. 33 (2015) N.H. Segal, S.H.I. Ou, A.S. Balmanoukian, M.G. Fury, E. Massarelli, J.R. Brahmer, J. Weiss, P. Schoffski, S.J. Antonia, C. Massard, D.P. Zandberg, S. Khleif, X. Li, M. Rebelatto, K. Steele, P.B. Robbins, J.A. Blake-Haskins, M.O. Butler, Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. J. Clin. Oncol. 33 (2015)
68.
Zurück zum Zitat 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)CrossRefPubMedPubMedCentral 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)CrossRefPubMedPubMedCentral
69.
Zurück zum Zitat D.S. Chen, B.A. Irving, F.S. Hodi, Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer. Res. 18, 6580–6587 (2012)CrossRefPubMed D.S. Chen, B.A. Irving, F.S. Hodi, Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer. Res. 18, 6580–6587 (2012)CrossRefPubMed
70.
72.
Zurück zum Zitat J. Polivka Jr., F. Janku, Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 142, 164–175 (2014)CrossRefPubMed J. Polivka Jr., F. Janku, Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 142, 164–175 (2014)CrossRefPubMed
74.
Zurück zum Zitat W. Peng, J.Q. Chen, C. Liu, S. Malu, C. Creasy, M.T. Tetzlaff, C. Xu, J.A. McKenzie, C. Zhang, X. Liang, L.J. Williams, W. Deng, G. Chen, R. Mbofung, A.J. Lazar, C.A. Torres-Cabala, Z.A. Cooper, P.L. Chen, T.N. Tieu, S. Spranger, X. Yu, C. Bernatchez, M.A. Forget, C. Haymaker, R. Amaria, J.L. McQuade, I.C. Glitza, T. Cascone, H.S. Li, L.N. Kwong, T.P. Heffernan, J. Hu, R.L. Bassett Jr., M.W. Bosenberg, S.E. Woodman, W.W. Overwijk, G. Lizee, J. Roszik, T.F. Gajewski, J.A. Wargo, J.E. Gershenwald, L. Radvanyi, M.A. Davies, P. Hwu, Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016)CrossRefPubMed W. Peng, J.Q. Chen, C. Liu, S. Malu, C. Creasy, M.T. Tetzlaff, C. Xu, J.A. McKenzie, C. Zhang, X. Liang, L.J. Williams, W. Deng, G. Chen, R. Mbofung, A.J. Lazar, C.A. Torres-Cabala, Z.A. Cooper, P.L. Chen, T.N. Tieu, S. Spranger, X. Yu, C. Bernatchez, M.A. Forget, C. Haymaker, R. Amaria, J.L. McQuade, I.C. Glitza, T. Cascone, H.S. Li, L.N. Kwong, T.P. Heffernan, J. Hu, R.L. Bassett Jr., M.W. Bosenberg, S.E. Woodman, W.W. Overwijk, G. Lizee, J. Roszik, T.F. Gajewski, J.A. Wargo, J.E. Gershenwald, L. Radvanyi, M.A. Davies, P. Hwu, Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016)CrossRefPubMed
75.
Zurück zum Zitat S. Spranger, R. Bao, T.F. Gajewski, Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015)CrossRefPubMed S. Spranger, R. Bao, T.F. Gajewski, Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015)CrossRefPubMed
76.
Zurück zum Zitat R.F. Sweis, S. Spranger, R. Bao, G.P. Paner, W.M. Stadler, G. Steinberg, T.F. Gajewski, Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol. Res. 4, 563–568 (2016)CrossRefPubMedPubMedCentral R.F. Sweis, S. Spranger, R. Bao, G.P. Paner, W.M. Stadler, G. Steinberg, T.F. Gajewski, Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol. Res. 4, 563–568 (2016)CrossRefPubMedPubMedCentral
77.
Zurück zum Zitat S. Hu-Lieskovan, S. Mok, B. Homet Moreno, J. Tsoi, L. Robert, L. Goedert, E.M. Pinheiro, R.C. Koya, T.G. Graeber, B. Comin-Anduix, A. Ribas, Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci. Transl. Med. 7, 279ra241 (2015)CrossRef S. Hu-Lieskovan, S. Mok, B. Homet Moreno, J. Tsoi, L. Robert, L. Goedert, E.M. Pinheiro, R.C. Koya, T.G. Graeber, B. Comin-Anduix, A. Ribas, Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci. Transl. Med. 7, 279ra241 (2015)CrossRef
78.
Zurück zum Zitat W. Hugo, H. Shi, L. Sun, M. Piva, C. Song, X. Kong, G. Moriceau, A. Hong, K.B. Dahlman, D.B. Johnson, J.A. Sosman, A. Ribas, R.S. Lo, Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162, 1271–1285 (2015)CrossRefPubMedPubMedCentral W. Hugo, H. Shi, L. Sun, M. Piva, C. Song, X. Kong, G. Moriceau, A. Hong, K.B. Dahlman, D.B. Johnson, J.A. Sosman, A. Ribas, R.S. Lo, Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162, 1271–1285 (2015)CrossRefPubMedPubMedCentral
79.
Zurück zum Zitat L. Liu, P.A. Mayes, S. Eastman, H. Shi, S. Yadavilli, T. Zhang, J. Yang, L. Seestaller-Wehr, S.Y. Zhang, C. Hopson, L. Tsvetkov, J. Jing, S. Zhang, J. Smothers, A. Hoos, The BRAF and MEK inhibitors Dabrafenib and Trametinib: Effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin. Cancer Res. 21, 1639–1651 (2015)CrossRefPubMed L. Liu, P.A. Mayes, S. Eastman, H. Shi, S. Yadavilli, T. Zhang, J. Yang, L. Seestaller-Wehr, S.Y. Zhang, C. Hopson, L. Tsvetkov, J. Jing, S. Zhang, J. Smothers, A. Hoos, The BRAF and MEK inhibitors Dabrafenib and Trametinib: Effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin. Cancer Res. 21, 1639–1651 (2015)CrossRefPubMed
80.
Zurück zum Zitat P.C. Tumeh, C.L. Harview, J.H. Yearley, I.P. Shintaku, E.J. Taylor, L. Robert, B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A.N. West, M. Carmona, C. Kivork, E. Seja, G. Cherry, A.J. Gutierrez, T.R. Grogan, C. Mateus, G. Tomasic, J.A. Glaspy, R.O. Emerson, H. Robins, R.H. Pierce, D.A. Elashoff, C. Robert, A. Ribas, PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014)CrossRefPubMedPubMedCentral P.C. Tumeh, C.L. Harview, J.H. Yearley, I.P. Shintaku, E.J. Taylor, L. Robert, B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A.N. West, M. Carmona, C. Kivork, E. Seja, G. Cherry, A.J. Gutierrez, T.R. Grogan, C. Mateus, G. Tomasic, J.A. Glaspy, R.O. Emerson, H. Robins, R.H. Pierce, D.A. Elashoff, C. Robert, A. Ribas, PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014)CrossRefPubMedPubMedCentral
81.
Zurück zum Zitat J.M. Zaretsky, A. Garcia-Diaz, D.S. Shin, H. Escuin-Ordinas, W. Hugo, S. Hu-Lieskovan, D.Y. Torrejon, G. Abril-Rodriguez, S. Sandoval, L. Barthly, J. Saco, B.H. Moreno, R. Mezzadra, B. Chmielowski, K. Ruchalski, I.P. Shintaku, P.J. Sanchez, C. Puig-Saus, G. Cherry, E. Seja, X. Kong, J. Pang, B. Berent-Maoz, B. Comin-Anduix, T.G. Graeber, P.C. Tumeh, T.N. Schumacher, R.S. Lo, A. Ribas, Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N. Engl. J. Med. 375, 819–829 (2016)CrossRefPubMedPubMedCentral J.M. Zaretsky, A. Garcia-Diaz, D.S. Shin, H. Escuin-Ordinas, W. Hugo, S. Hu-Lieskovan, D.Y. Torrejon, G. Abril-Rodriguez, S. Sandoval, L. Barthly, J. Saco, B.H. Moreno, R. Mezzadra, B. Chmielowski, K. Ruchalski, I.P. Shintaku, P.J. Sanchez, C. Puig-Saus, G. Cherry, E. Seja, X. Kong, J. Pang, B. Berent-Maoz, B. Comin-Anduix, T.G. Graeber, P.C. Tumeh, T.N. Schumacher, R.S. Lo, A. Ribas, Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N. Engl. J. Med. 375, 819–829 (2016)CrossRefPubMedPubMedCentral
82.
Zurück zum Zitat J. Gao, L.Z. Shi, H. Zhao, J. Chen, L. Xiong, Q. He, T. Chen, J. Roszik, C. Bernatchez, S.E. Woodman, P.L. Chen, P. Hwu, J.P. Allison, A. Futreal, J.A. Wargo, P. Sharma, Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397–404 (2016)CrossRefPubMedPubMedCentral J. Gao, L.Z. Shi, H. Zhao, J. Chen, L. Xiong, Q. He, T. Chen, J. Roszik, C. Bernatchez, S.E. Woodman, P.L. Chen, P. Hwu, J.P. Allison, A. Futreal, J.A. Wargo, P. Sharma, Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397–404 (2016)CrossRefPubMedPubMedCentral
83.
Zurück zum Zitat J.L. Benci, B. Xu, Y. Qiu, T.J. Wu, H. Dada, C. Twyman-Saint Victor, L. Cucolo, D.S.M. Lee, K.E. Pauken, A.C. Huang, T.C. Gangadhar, R.K. Amaravadi, L.M. Schuchter, M.D. Feldman, H. Ishwaran, R.H. Vonderheide, A. Maity, E.J. Wherry, A.J. Minn, Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554 (2016)CrossRefPubMedPubMedCentral J.L. Benci, B. Xu, Y. Qiu, T.J. Wu, H. Dada, C. Twyman-Saint Victor, L. Cucolo, D.S.M. Lee, K.E. Pauken, A.C. Huang, T.C. Gangadhar, R.K. Amaravadi, L.M. Schuchter, M.D. Feldman, H. Ishwaran, R.H. Vonderheide, A. Maity, E.J. Wherry, A.J. Minn, Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554 (2016)CrossRefPubMedPubMedCentral
84.
Zurück zum Zitat L.C. Platanias, Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005)CrossRefPubMed L.C. Platanias, Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005)CrossRefPubMed
86.
Zurück zum Zitat J.E. Darnell Jr., I.M. Kerr, G.R. Stark, Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994)CrossRefPubMed J.E. Darnell Jr., I.M. Kerr, G.R. Stark, Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994)CrossRefPubMed
87.
Zurück zum Zitat M. Marzec, Q. Zhang, A. Goradia, P.N. Raghunath, X. Liu, M. Paessler, H.Y. Wang, M. Wysocka, M. Cheng, B.A. Ruggeri, M.A. Wasik, Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc. Natl. Acad. Sci. U. S. A. 105, 20852–20857 (2008)CrossRefPubMedPubMedCentral M. Marzec, Q. Zhang, A. Goradia, P.N. Raghunath, X. Liu, M. Paessler, H.Y. Wang, M. Wysocka, M. Cheng, B.A. Ruggeri, M.A. Wasik, Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc. Natl. Acad. Sci. U. S. A. 105, 20852–20857 (2008)CrossRefPubMedPubMedCentral
88.
Zurück zum Zitat S. Alas, B. Bonavida, Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin. Cancer Res. 9, 316–326 (2003)PubMed S. Alas, B. Bonavida, Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin. Cancer Res. 9, 316–326 (2003)PubMed
89.
Zurück zum Zitat D.S. Shin, J.M. Zaretsky, H. Escuin-Ordinas, A. Garcia-Diaz, S. Hu-Lieskovan, A. Kalbasi, C.S. Grasso, W. Hugo, S. Sandoval, D.Y. Torrejon, N. Palaskas, G.A. Rodriguez, G. Parisi, A. Azhdam, B. Chmielowski, G. Cherry, E. Seja, B. Berent-Maoz, I.P. Shintaku, D.T. Le, D.M. Pardoll, L.A. Diaz Jr., P.C. Tumeh, T.G. Graeber, R.S. Lo, B. Comin-Anduix, A. Ribas, Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017)CrossRefPubMed D.S. Shin, J.M. Zaretsky, H. Escuin-Ordinas, A. Garcia-Diaz, S. Hu-Lieskovan, A. Kalbasi, C.S. Grasso, W. Hugo, S. Sandoval, D.Y. Torrejon, N. Palaskas, G.A. Rodriguez, G. Parisi, A. Azhdam, B. Chmielowski, G. Cherry, E. Seja, B. Berent-Maoz, I.P. Shintaku, D.T. Le, D.M. Pardoll, L.A. Diaz Jr., P.C. Tumeh, T.G. Graeber, R.S. Lo, B. Comin-Anduix, A. Ribas, Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017)CrossRefPubMed
90.
Zurück zum Zitat M.H. Kaplan, A.L. Wurster, M.J. Grusby, A signal transducer and activator of transcription (Stat)4-independent pathway for the development of T helper type 1 cells. J. Exp. Med. 188, 1191–1196 (1998)CrossRefPubMedPubMedCentral M.H. Kaplan, A.L. Wurster, M.J. Grusby, A signal transducer and activator of transcription (Stat)4-independent pathway for the development of T helper type 1 cells. J. Exp. Med. 188, 1191–1196 (1998)CrossRefPubMedPubMedCentral
91.
Zurück zum Zitat D.S. Shin, A. Ribas, The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr. Opin. Immunol. 33, 23–35 (2015)CrossRefPubMed D.S. Shin, A. Ribas, The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr. Opin. Immunol. 33, 23–35 (2015)CrossRefPubMed
92.
Zurück zum Zitat C. Meyer, L. Cagnon, C.M. Costa-Nunes, P. Baumgaertner, N. Montandon, L. Leyvraz, O. Michielin, E. Romano, D.E. Speiser, Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63, 247–257 (2014)CrossRefPubMed C. Meyer, L. Cagnon, C.M. Costa-Nunes, P. Baumgaertner, N. Montandon, L. Leyvraz, O. Michielin, E. Romano, D.E. Speiser, Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63, 247–257 (2014)CrossRefPubMed
93.
Zurück zum Zitat S.L. Highfill, Y. Cui, A.J. Giles, J.P. Smith, H. Zhang, E. Morse, R.N. Kaplan, C.L. Mackall, Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl. Med. 6, 237ra267 (2014)CrossRef S.L. Highfill, Y. Cui, A.J. Giles, J.P. Smith, H. Zhang, E. Morse, R.N. Kaplan, C.L. Mackall, Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl. Med. 6, 237ra267 (2014)CrossRef
94.
Zurück zum Zitat S.M. Steinberg, T.B. Shabaneh, P. Zhang, V. Martyanov, Z. Li, B.T. Malik, T.A. Wood, A. Boni, A. Molodtsov, C.V. Angeles, T.J. Curiel, M.L. Whitfield, M.J. Turk, Myeloid cells that impair immunotherapy are restored in melanomas with acquired resistance to BRAF inhibitors. Cancer Res. 77, 1599–1610 (2017)CrossRefPubMedPubMedCentral S.M. Steinberg, T.B. Shabaneh, P. Zhang, V. Martyanov, Z. Li, B.T. Malik, T.A. Wood, A. Boni, A. Molodtsov, C.V. Angeles, T.J. Curiel, M.L. Whitfield, M.J. Turk, Myeloid cells that impair immunotherapy are restored in melanomas with acquired resistance to BRAF inhibitors. Cancer Res. 77, 1599–1610 (2017)CrossRefPubMedPubMedCentral
95.
Zurück zum Zitat S. Sakaguchi, T. Yamaguchi, T. Nomura, M. Ono, Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008)CrossRefPubMed S. Sakaguchi, T. Yamaguchi, T. Nomura, M. Ono, Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008)CrossRefPubMed
96.
Zurück zum Zitat K.G. Elpek, C. Lacelle, N.P. Singh, E.S. Yolcu, H. Shirwan, CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model. J. Immunol. 178, 6840–6848 (2007)CrossRefPubMed K.G. Elpek, C. Lacelle, N.P. Singh, E.S. Yolcu, H. Shirwan, CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model. J. Immunol. 178, 6840–6848 (2007)CrossRefPubMed
97.
Zurück zum Zitat E. Bettelli, Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner, V.K. Kuchroo, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)CrossRefPubMed E. Bettelli, Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner, V.K. Kuchroo, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)CrossRefPubMed
98.
Zurück zum Zitat F.A. Vargas, A.J.S. Furness, I. Solomon, K. Joshi, L. Mekkaoui, M.H. Lesko, E.M. Rota, R. Dahan, A. Georgiou, A. Sledzinska, A.B. Aissa, D. Franz, M.W. Sunderland, Y.N.S. Wong, J.Y. Henry, T. O'Brien, D. Nicol, B. Challacombe, S.A. Beers, S. Turajlic, M. Gore, J. Larkin, C. Swanton, K.A. Chester, M. Pule, J.V. Ravetch, T. Marafioti, K.S. Peggs, S.A. Quezada, Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity 46, 577–586 (2017)CrossRef F.A. Vargas, A.J.S. Furness, I. Solomon, K. Joshi, L. Mekkaoui, M.H. Lesko, E.M. Rota, R. Dahan, A. Georgiou, A. Sledzinska, A.B. Aissa, D. Franz, M.W. Sunderland, Y.N.S. Wong, J.Y. Henry, T. O'Brien, D. Nicol, B. Challacombe, S.A. Beers, S. Turajlic, M. Gore, J. Larkin, C. Swanton, K.A. Chester, M. Pule, J.V. Ravetch, T. Marafioti, K.S. Peggs, S.A. Quezada, Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity 46, 577–586 (2017)CrossRef
99.
Zurück zum Zitat N.A. Taylor, S.C. Vick, M.D. Iglesia, W.J. Brickey, B.R. Midkiff, K.P. McKinnon, S. Reisdorf, C.K. Anders, L.A. Carey, J.S. Parker, C.M. Perou, B.G. Vincent, J.S. Serody, Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer. J. Clin. Invest. 127, 3472–3483 (2017)CrossRefPubMedPubMedCentral N.A. Taylor, S.C. Vick, M.D. Iglesia, W.J. Brickey, B.R. Midkiff, K.P. McKinnon, S. Reisdorf, C.K. Anders, L.A. Carey, J.S. Parker, C.M. Perou, B.G. Vincent, J.S. Serody, Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer. J. Clin. Invest. 127, 3472–3483 (2017)CrossRefPubMedPubMedCentral
100.
Zurück zum Zitat J.J. Lebrun, The dual role of TGFbeta in human cancer: From tumor suppression to cancer metastasis. ISRN Mol. Biol. 2012, 381428 (2012)PubMedPubMedCentral J.J. Lebrun, The dual role of TGFbeta in human cancer: From tumor suppression to cancer metastasis. ISRN Mol. Biol. 2012, 381428 (2012)PubMedPubMedCentral
101.
Zurück zum Zitat C. Vanpouille-Box, J.M. Diamond, K.A. Pilones, J. Zavadil, J.S. Babb, S.C. Formenti, M.H. Barcellos-Hoff, S. Demaria, TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 75, 2232–2242 (2015)CrossRefPubMedPubMedCentral C. Vanpouille-Box, J.M. Diamond, K.A. Pilones, J. Zavadil, J.S. Babb, S.C. Formenti, M.H. Barcellos-Hoff, S. Demaria, TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 75, 2232–2242 (2015)CrossRefPubMedPubMedCentral
102.
Zurück zum Zitat Q. Yu, E. Sicinska, Y. Geng, M. Ahnstrom, A. Zagozdzon, Y. Kong, H. Gardner, H. Kiyokawa, L.N. Harris, O. Stal, P. Sicinski, Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23–32 (2006)CrossRefPubMed Q. Yu, E. Sicinska, Y. Geng, M. Ahnstrom, A. Zagozdzon, Y. Kong, H. Gardner, H. Kiyokawa, L.N. Harris, O. Stal, P. Sicinski, Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23–32 (2006)CrossRefPubMed
103.
Zurück zum Zitat Y.J. Choi, X. Li, P. Hydbring, T. Sanda, J. Stefano, A.L. Christie, S. Signoretti, A.T. Look, A.L. Kung, H. von Boehmer, P. Sicinski, The requirement for cyclin D function in tumor maintenance. Cancer Cell 22, 438–451 (2012)CrossRefPubMedPubMedCentral Y.J. Choi, X. Li, P. Hydbring, T. Sanda, J. Stefano, A.L. Christie, S. Signoretti, A.T. Look, A.L. Kung, H. von Boehmer, P. Sicinski, The requirement for cyclin D function in tumor maintenance. Cancer Cell 22, 438–451 (2012)CrossRefPubMedPubMedCentral
104.
Zurück zum Zitat J.L. Adams, J. Smothers, R. Srinivasan, A. Hoos, Big opportunities for small molecules in immuno-oncology. Nat. Rev. Drug Discov. 14, 603–622 (2015)CrossRefPubMed J.L. Adams, J. Smothers, R. Srinivasan, A. Hoos, Big opportunities for small molecules in immuno-oncology. Nat. Rev. Drug Discov. 14, 603–622 (2015)CrossRefPubMed
105.
Zurück zum Zitat A.D. Wells, P.A. Morawski, New roles for cyclin-dependent kinases in T cell biology: linking cell division and differentiation. Nat. Rev. Immunol. 14, 261–270 (2014)CrossRefPubMed A.D. Wells, P.A. Morawski, New roles for cyclin-dependent kinases in T cell biology: linking cell division and differentiation. Nat. Rev. Immunol. 14, 261–270 (2014)CrossRefPubMed
106.
Zurück zum Zitat S. Goel, M.J. DeCristo, A.C. Watt, H. BrinJones, J. Sceneay, B.B. Li, N. Khan, J.M. Ubellacker, S. Xie, O. Metzger-Filho, J. Hoog, M.J. Ellis, C.X. Ma, S. Ramm, I.E. Krop, E.P. Winer, T.M. Roberts, H.J. Kim, S.S. McAllister, J.J. Zhao, CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471–475 (2017)CrossRefPubMedPubMedCentral S. Goel, M.J. DeCristo, A.C. Watt, H. BrinJones, J. Sceneay, B.B. Li, N. Khan, J.M. Ubellacker, S. Xie, O. Metzger-Filho, J. Hoog, M.J. Ellis, C.X. Ma, S. Ramm, I.E. Krop, E.P. Winer, T.M. Roberts, H.J. Kim, S.S. McAllister, J.J. Zhao, CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471–475 (2017)CrossRefPubMedPubMedCentral
107.
Zurück zum Zitat L. Jerby-Arnon, P. Shah, M.S. Cuoco, C. Rodman, M.J. Su, J.C. Melms, R. Leeson, A. Kanodia, S. Mei, J.R. Lin, S. Wang, B. Rabasha, D. Liu, G. Zhang, C. Margolais, O. Ashenberg, P.A. Ott, E.I. Buchbinder, R. Haq, F.S. Hodi, G.M. Boland, R.J. Sullivan, D.T. Frederick, B. Miao, T. Moll, K.T. Flaherty, M. Herlyn, R.W. Jenkins, R. Thummalapalli, M.S. Kowalczyk, I. Canadas, B. Schilling, A.N.R. Cartwright, A.M. Luoma, S. Malu, P. Hwu, C. Bernatchez, M.A. Forget, D.A. Barbie, A.K. Shalek, I. Tirosh, P.K. Sorger, K. Wucherpfennig, E.M. Van Allen, D. Schadendorf, B.E. Johnson, A. Rotem, O. Rozenblatt-Rosen, L.A. Garraway, C.H. Yoon, B. Izar, A. Regev, A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997 (2018)CrossRefPubMedPubMedCentral L. Jerby-Arnon, P. Shah, M.S. Cuoco, C. Rodman, M.J. Su, J.C. Melms, R. Leeson, A. Kanodia, S. Mei, J.R. Lin, S. Wang, B. Rabasha, D. Liu, G. Zhang, C. Margolais, O. Ashenberg, P.A. Ott, E.I. Buchbinder, R. Haq, F.S. Hodi, G.M. Boland, R.J. Sullivan, D.T. Frederick, B. Miao, T. Moll, K.T. Flaherty, M. Herlyn, R.W. Jenkins, R. Thummalapalli, M.S. Kowalczyk, I. Canadas, B. Schilling, A.N.R. Cartwright, A.M. Luoma, S. Malu, P. Hwu, C. Bernatchez, M.A. Forget, D.A. Barbie, A.K. Shalek, I. Tirosh, P.K. Sorger, K. Wucherpfennig, E.M. Van Allen, D. Schadendorf, B.E. Johnson, A. Rotem, O. Rozenblatt-Rosen, L.A. Garraway, C.H. Yoon, B. Izar, A. Regev, A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997 (2018)CrossRefPubMedPubMedCentral
108.
Zurück zum Zitat M.B. Atkins, R. Reiney, K.M. Sznol, D.F. McDermott, M. Lotem, J. Schachter, J.D. Wolchok, W.J. Urba, T. Kuzel, L.M. Schuchter, C.L. Slingluff, M.S. Ernstoff, J.W. Fay, P.A. Friedlander, T. Gajewski, H.M. Zarour, R. Rotem-Yehudar, J.A. Sosman, Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma. J. Clin. Oncol. 32 (2014) M.B. Atkins, R. Reiney, K.M. Sznol, D.F. McDermott, M. Lotem, J. Schachter, J.D. Wolchok, W.J. Urba, T. Kuzel, L.M. Schuchter, C.L. Slingluff, M.S. Ernstoff, J.W. Fay, P.A. Friedlander, T. Gajewski, H.M. Zarour, R. Rotem-Yehudar, J.A. Sosman, Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma. J. Clin. Oncol. 32 (2014)
109.
Zurück zum Zitat R. Berger, R. Rotem-Yehudar, G. Slama, S. Landes, A. Kneller, M. Leiba, M. Koren-Michowitz, A. Shimoni, A. Nagler, Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer. Res. 14, 3044–3051 (2008)CrossRefPubMed R. Berger, R. Rotem-Yehudar, G. Slama, S. Landes, A. Kneller, M. Leiba, M. Koren-Michowitz, A. Shimoni, A. Nagler, Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer. Res. 14, 3044–3051 (2008)CrossRefPubMed
110.
Zurück zum Zitat J.R. Westin, F. Chu, M. Zhang, L.E. Fayad, L.W. Kwak, N. Fowler, J. Romaguera, F. Hagemeister, M. Fanale, F. Samaniego, L. Feng, V. Baladandayuthapani, Z. Wang, W. Ma, Y. Gao, M. Wallace, L.M. Vence, L. Radvanyi, T. Muzzafar, R. Rotem-Yehudar, R.E. Davis, S.S. Neelapu, Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 15, 69–77 (2014)CrossRefPubMed J.R. Westin, F. Chu, M. Zhang, L.E. Fayad, L.W. Kwak, N. Fowler, J. Romaguera, F. Hagemeister, M. Fanale, F. Samaniego, L. Feng, V. Baladandayuthapani, Z. Wang, W. Ma, Y. Gao, M. Wallace, L.M. Vence, L. Radvanyi, T. Muzzafar, R. Rotem-Yehudar, R.E. Davis, S.S. Neelapu, Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 15, 69–77 (2014)CrossRefPubMed
111.
Zurück zum Zitat A. Patnaik, S.P. Kang, D. Rasco, K.P. Papadopoulos, J. Elassaiss-Schaap, M. Beeram, R. Drengler, C. Chen, L. Smith, G. Espino, K. Gergich, L. Delgado, A. Daud, J.A. Lindia, X.N. Li, R.H. Pierce, J.H. Yearley, D. Wu, O. Laterza, M. Lehnert, R. Iannone, A.W. Tolcher, Phase I study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in patients with advanced solid tumors. Clin. Cancer Res. 21, 4286–4293 (2015)CrossRefPubMed A. Patnaik, S.P. Kang, D. Rasco, K.P. Papadopoulos, J. Elassaiss-Schaap, M. Beeram, R. Drengler, C. Chen, L. Smith, G. Espino, K. Gergich, L. Delgado, A. Daud, J.A. Lindia, X.N. Li, R.H. Pierce, J.H. Yearley, D. Wu, O. Laterza, M. Lehnert, R. Iannone, A.W. Tolcher, Phase I study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in patients with advanced solid tumors. Clin. Cancer Res. 21, 4286–4293 (2015)CrossRefPubMed
112.
Zurück zum Zitat C. Robert, A. Ribas, J.D. Wolchok, F.S. Hodi, O. Hamid, R. Kefford, J.S. Weber, A.M. Joshua, W.J. Hwu, T.C. Gangadhar, A. Patnaik, R. Dronca, H. Zarour, R.W. Joseph, P. Boasberg, B. Chmielowski, C. Mateus, M.A. Postow, K. Gergich, J. Elassaiss-Schaap, X.N. Li, R. Iannone, S.W. Ebbinghaus, S.P. Kang, A. Daud, Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014)CrossRefPubMed C. Robert, A. Ribas, J.D. Wolchok, F.S. Hodi, O. Hamid, R. Kefford, J.S. Weber, A.M. Joshua, W.J. Hwu, T.C. Gangadhar, A. Patnaik, R. Dronca, H. Zarour, R.W. Joseph, P. Boasberg, B. Chmielowski, C. Mateus, M.A. Postow, K. Gergich, J. Elassaiss-Schaap, X.N. Li, R. Iannone, S.W. Ebbinghaus, S.P. Kang, A. Daud, Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014)CrossRefPubMed
113.
Zurück zum Zitat A. Ribas, I. Puzanov, R. Dummer, D. Schadendorf, O. Hamid, C. Robert, F.S. Hodi, J. Schachter, A.C. Pavlick, K.D. Lewis, L.D. Cranmer, C.U. Blank, S.J. O'Day, P.A. Ascierto, A.K. Salama, K.A. Margolin, C. Loquai, T.K. Eigentler, T.C. Gangadhar, M.S. Carlino, S.S. Agarwala, S.J. Moschos, J.A. Sosman, S.M. Goldinger, R. Shapira-Frommer, R. Gonzalez, J.M. Kirkwood, J.D. Wolchok, A. Eggermont, X.N. Li, W. Zhou, A.M. Zernhelt, J. Lis, S. Ebbinghaus, S.P. Kang, A. Daud, Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 16, 908–918 (2015)CrossRefPubMedPubMedCentral A. Ribas, I. Puzanov, R. Dummer, D. Schadendorf, O. Hamid, C. Robert, F.S. Hodi, J. Schachter, A.C. Pavlick, K.D. Lewis, L.D. Cranmer, C.U. Blank, S.J. O'Day, P.A. Ascierto, A.K. Salama, K.A. Margolin, C. Loquai, T.K. Eigentler, T.C. Gangadhar, M.S. Carlino, S.S. Agarwala, S.J. Moschos, J.A. Sosman, S.M. Goldinger, R. Shapira-Frommer, R. Gonzalez, J.M. Kirkwood, J.D. Wolchok, A. Eggermont, X.N. Li, W. Zhou, A.M. Zernhelt, J. Lis, S. Ebbinghaus, S.P. Kang, A. Daud, Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 16, 908–918 (2015)CrossRefPubMedPubMedCentral
114.
Zurück zum Zitat C. Robert, J. Schachter, G.V. Long, A. Arance, J.J. Grob, L. Mortier, A. Daud, M.S. Carlino, C. McNeil, M. Lotem, J. Larkin, P. Lorigan, B. Neyns, C.U. Blank, O. Hamid, C. Mateus, R. Shapira-Frommer, M. Kosh, H. Zhou, N. Ibrahim, S. Ebbinghaus, A. Ribas, Pembrolizumab versus Ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015)CrossRefPubMed C. Robert, J. Schachter, G.V. Long, A. Arance, J.J. Grob, L. Mortier, A. Daud, M.S. Carlino, C. McNeil, M. Lotem, J. Larkin, P. Lorigan, B. Neyns, C.U. Blank, O. Hamid, C. Mateus, R. Shapira-Frommer, M. Kosh, H. Zhou, N. Ibrahim, S. Ebbinghaus, A. Ribas, Pembrolizumab versus Ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015)CrossRefPubMed
115.
Zurück zum Zitat R.S. Herbst, P. Baas, D.-W. Kim, E. Felip, J.L. Pérez-Gracia, J.-Y. Han, J. Molina, J.-H. Kim, C.D. Arvis, M.-J. Ahn, Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. The Lancet 387, 1540–1550 (2016)CrossRef R.S. Herbst, P. Baas, D.-W. Kim, E. Felip, J.L. Pérez-Gracia, J.-Y. Han, J. Molina, J.-H. Kim, C.D. Arvis, M.-J. Ahn, Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. The Lancet 387, 1540–1550 (2016)CrossRef
116.
Zurück zum Zitat J. Sul, G.M. Blumenthal, X. Jiang, K. He, P. Keegan, R. Pazdur, FDA approval summary: Pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist 21, 643–650 (2016)CrossRefPubMedPubMedCentral J. Sul, G.M. Blumenthal, X. Jiang, K. He, P. Keegan, R. Pazdur, FDA approval summary: Pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist 21, 643–650 (2016)CrossRefPubMedPubMedCentral
117.
Zurück zum Zitat E.R. Plimack, J. Bellmunt, S. Gupta, R. Berger, R.B. Montgomery, K. Heath, J. Juco, K. Emancipator, K. Pathiraja, J.K. Lunceford, R.F. Perini, P.H. O'Donnell, Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J. Clin. Oncol. 33, 4502–4502 (2015)CrossRef E.R. Plimack, J. Bellmunt, S. Gupta, R. Berger, R.B. Montgomery, K. Heath, J. Juco, K. Emancipator, K. Pathiraja, J.K. Lunceford, R.F. Perini, P.H. O'Donnell, Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J. Clin. Oncol. 33, 4502–4502 (2015)CrossRef
118.
Zurück zum Zitat A.V. Balar, D. Castellano, P.H. O'Donnell, P. Grivas, J. Vuky, T. Powles, E.R. Plimack, N.M. Hahn, R. de Wit, L. Pang, M.J. Savage, R.F. Perini, S.M. Keefe, D. Bajorin, J. Bellmunt, First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 1483–1492 (2017)CrossRefPubMed A.V. Balar, D. Castellano, P.H. O'Donnell, P. Grivas, J. Vuky, T. Powles, E.R. Plimack, N.M. Hahn, R. de Wit, L. Pang, M.J. Savage, R.F. Perini, S.M. Keefe, D. Bajorin, J. Bellmunt, First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 1483–1492 (2017)CrossRefPubMed
119.
Zurück zum Zitat J. Bellmunt, R. de Wit, D.J. Vaughn, Y. Fradet, J.L. Lee, L. Fong, N.J. Vogelzang, M.A. Climent, D.P. Petrylak, T.K. Choueiri, A. Necchi, W. Gerritsen, H. Gurney, D.I. Quinn, S. Culine, C.N. Sternberg, Y. Mai, C.H. Poehlein, R.F. Perini, D.F. Bajorin, Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017)CrossRefPubMedPubMedCentral J. Bellmunt, R. de Wit, D.J. Vaughn, Y. Fradet, J.L. Lee, L. Fong, N.J. Vogelzang, M.A. Climent, D.P. Petrylak, T.K. Choueiri, A. Necchi, W. Gerritsen, H. Gurney, D.I. Quinn, S. Culine, C.N. Sternberg, Y. Mai, C.H. Poehlein, R.F. Perini, D.F. Bajorin, Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017)CrossRefPubMedPubMedCentral
120.
Zurück zum Zitat T.Y. Seiwert, R.I. Haddad, S. Gupta, R. Mehra, M. Tahara, R. Berger, S.-H. Lee, B. Burtness, D.T. Le, K. Heath, A. Blum, M. Dolled-Filhart, K. Emancipator, K. Pathiraja, J.D. Cheng, L.Q. Chow, Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J. Clin. Oncol. 33, LBA6008–LBA6008 (2015)CrossRef T.Y. Seiwert, R.I. Haddad, S. Gupta, R. Mehra, M. Tahara, R. Berger, S.-H. Lee, B. Burtness, D.T. Le, K. Heath, A. Blum, M. Dolled-Filhart, K. Emancipator, K. Pathiraja, J.D. Cheng, L.Q. Chow, Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J. Clin. Oncol. 33, LBA6008–LBA6008 (2015)CrossRef
121.
Zurück zum Zitat J.R. Brahmer, C.G. Drake, I. Wollner, J.D. Powderly, J. Picus, W.H. Sharfman, E. Stankevich, A. Pons, T.M. Salay, T.L. McMiller, M.M. Gilson, C. Wang, M. Selby, J.M. Taube, R. Anders, L. Chen, A.J. Korman, D.M. Pardoll, I. Lowy, S.L. Topalian, Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010)CrossRefPubMedPubMedCentral J.R. Brahmer, C.G. Drake, I. Wollner, J.D. Powderly, J. Picus, W.H. Sharfman, E. Stankevich, A. Pons, T.M. Salay, T.L. McMiller, M.M. Gilson, C. Wang, M. Selby, J.M. Taube, R. Anders, L. Chen, A.J. Korman, D.M. Pardoll, I. Lowy, S.L. Topalian, Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010)CrossRefPubMedPubMedCentral
122.
Zurück zum Zitat J.D. Wolchok, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J.J. Grob, C.L. Cowey, C.D. Lao, J. Wagstaff, D. Schadendorf, P.F. Ferrucci, M. Smylie, R. Dummer, A. Hill, D. Hogg, J. Haanen, M.S. Carlino, O. Bechter, M. Maio, I. Marquez-Rodas, M. Guidoboni, G. McArthur, C. Lebbe, P.A. Ascierto, G.V. Long, J. Cebon, J. Sosman, M.A. Postow, M.K. Callahan, D. Walker, L. Rollin, R. Bhore, F.S. Hodi, J. Larkin, Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017)CrossRefPubMedPubMedCentral J.D. Wolchok, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J.J. Grob, C.L. Cowey, C.D. Lao, J. Wagstaff, D. Schadendorf, P.F. Ferrucci, M. Smylie, R. Dummer, A. Hill, D. Hogg, J. Haanen, M.S. Carlino, O. Bechter, M. Maio, I. Marquez-Rodas, M. Guidoboni, G. McArthur, C. Lebbe, P.A. Ascierto, G.V. Long, J. Cebon, J. Sosman, M.A. Postow, M.K. Callahan, D. Walker, L. Rollin, R. Bhore, F.S. Hodi, J. Larkin, Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017)CrossRefPubMedPubMedCentral
123.
Zurück zum Zitat J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J.J. Grob, C.L. Cowey, C.D. Lao, D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski, P.F. Ferrucci, A. Hill, J. Wagstaff, M.S. Carlino, J.B. Haanen, M. Maio, I. Marquez-Rodas, G.A. McArthur, P.A. Ascierto, G.V. Long, M.K. Callahan, M.A. Postow, K. Grossmann, M. Sznol, B. Dreno, L. Bastholt, A. Yang, L.M. Rollin, C. Horak, F.S. Hodi, J.D. Wolchok, Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015)CrossRefPubMedPubMedCentral J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J.J. Grob, C.L. Cowey, C.D. Lao, D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski, P.F. Ferrucci, A. Hill, J. Wagstaff, M.S. Carlino, J.B. Haanen, M. Maio, I. Marquez-Rodas, G.A. McArthur, P.A. Ascierto, G.V. Long, M.K. Callahan, M.A. Postow, K. Grossmann, M. Sznol, B. Dreno, L. Bastholt, A. Yang, L.M. Rollin, C. Horak, F.S. Hodi, J.D. Wolchok, Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015)CrossRefPubMedPubMedCentral
124.
Zurück zum Zitat S.N. Gettinger, M.D. Hellmann, F.A. Shepherd, S.J. Antonia, J.R. Brahmer, L.Q.M. Chow, J.W. Goldman, R.A. Juergens, H. Borghaei, N. Ready, D.E. Gerber, F.E. Nathan, Y. Shen, C. Harbison, N.A. Rizvi, First-line monotherapy with nivolumab (NIVO; anti-programmed death-1 [PD-1]) in advanced non-small cell lung cancer (NSCLC): Safety, efficacy and correlation of outcomes with PD-1 ligand (PD-L1) expression. J. Clin. Oncol. 33, 8025–8025 (2015)CrossRef S.N. Gettinger, M.D. Hellmann, F.A. Shepherd, S.J. Antonia, J.R. Brahmer, L.Q.M. Chow, J.W. Goldman, R.A. Juergens, H. Borghaei, N. Ready, D.E. Gerber, F.E. Nathan, Y. Shen, C. Harbison, N.A. Rizvi, First-line monotherapy with nivolumab (NIVO; anti-programmed death-1 [PD-1]) in advanced non-small cell lung cancer (NSCLC): Safety, efficacy and correlation of outcomes with PD-1 ligand (PD-L1) expression. J. Clin. Oncol. 33, 8025–8025 (2015)CrossRef
125.
Zurück zum Zitat N.A. Rizvi, J. Mazieres, D. Planchard, T.E. Stinchcombe, G.K. Dy, S.J. Antonia, L. Horn, H. Lena, E. Minenza, B. Mennecier, G.A. Otterson, L.T. Campos, D.R. Gandara, B.P. Levy, S.G. Nair, G. Zalcman, J. Wolf, P.J. Souquet, E. Baldini, F. Cappuzzo, C. Chouaid, A. Dowlati, R. Sanborn, A. Lopez-Chavez, C. Grohe, R.M. Huber, C.T. Harbison, C. Baudelet, B.J. Lestini, S.S. Ramalingam, Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015)CrossRefPubMedPubMedCentral N.A. Rizvi, J. Mazieres, D. Planchard, T.E. Stinchcombe, G.K. Dy, S.J. Antonia, L. Horn, H. Lena, E. Minenza, B. Mennecier, G.A. Otterson, L.T. Campos, D.R. Gandara, B.P. Levy, S.G. Nair, G. Zalcman, J. Wolf, P.J. Souquet, E. Baldini, F. Cappuzzo, C. Chouaid, A. Dowlati, R. Sanborn, A. Lopez-Chavez, C. Grohe, R.M. Huber, C.T. Harbison, C. Baudelet, B.J. Lestini, S.S. Ramalingam, Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015)CrossRefPubMedPubMedCentral
126.
Zurück zum Zitat H. Borghaei, L. Paz-Ares, L. Horn, D.R. Spigel, M. Steins, N.E. Ready, L.Q. Chow, E.E. Vokes, E. Felip, E. Holgado, F. Barlesi, M. Kohlhaufl, O. Arrieta, M.A. Burgio, J. Fayette, H. Lena, E. Poddubskaya, D.E. Gerber, S.N. Gettinger, C.M. Rudin, N. Rizvi, L. Crino, G.R. Blumenschein Jr., S.J. Antonia, C. Dorange, C.T. Harbison, F. Graf Finckenstein, J.R. Brahmer, Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015)CrossRefPubMedPubMedCentral H. Borghaei, L. Paz-Ares, L. Horn, D.R. Spigel, M. Steins, N.E. Ready, L.Q. Chow, E.E. Vokes, E. Felip, E. Holgado, F. Barlesi, M. Kohlhaufl, O. Arrieta, M.A. Burgio, J. Fayette, H. Lena, E. Poddubskaya, D.E. Gerber, S.N. Gettinger, C.M. Rudin, N. Rizvi, L. Crino, G.R. Blumenschein Jr., S.J. Antonia, C. Dorange, C.T. Harbison, F. Graf Finckenstein, J.R. Brahmer, Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015)CrossRefPubMedPubMedCentral
127.
Zurück zum Zitat S.J. Antonia, S.N. Gettinger, L.Q.M. Chow, R.A. Juergens, H. Borghaei, Y. Shen, C. Harbison, A.C. Chen, N. Ready, N.A. Rizvi, Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results. J. Clin. Oncol. 32, 8023–8023 (2014)CrossRef S.J. Antonia, S.N. Gettinger, L.Q.M. Chow, R.A. Juergens, H. Borghaei, Y. Shen, C. Harbison, A.C. Chen, N. Ready, N.A. Rizvi, Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results. J. Clin. Oncol. 32, 8023–8023 (2014)CrossRef
128.
Zurück zum Zitat R.J. Motzer, B. Escudier, D.F. McDermott, S. George, H.J. Hammers, S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, D. Castellano, T.K. Choueiri, H. Gurney, F. Donskov, P. Bono, J. Wagstaff, T.C. Gauler, T. Ueda, Y. Tomita, F.A. Schutz, C. Kollmannsberger, J. Larkin, A. Ravaud, J.S. Simon, L.A. Xu, I.M. Waxman, P. Sharma, Nivolumab versus Everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015)CrossRefPubMedPubMedCentral R.J. Motzer, B. Escudier, D.F. McDermott, S. George, H.J. Hammers, S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, D. Castellano, T.K. Choueiri, H. Gurney, F. Donskov, P. Bono, J. Wagstaff, T.C. Gauler, T. Ueda, Y. Tomita, F.A. Schutz, C. Kollmannsberger, J. Larkin, A. Ravaud, J.S. Simon, L.A. Xu, I.M. Waxman, P. Sharma, Nivolumab versus Everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015)CrossRefPubMedPubMedCentral
129.
Zurück zum Zitat J. Hamanishi, M. Mandai, T. Ikeda, M. Minami, A. Kawaguchi, N. Matsumura, K. Abiko, T. Baba, K. Yamaguchi, A. Ueda, Y. Hosoe, S. Morita, A. Shimizu, T. Honjo, I. Konishi, Durable tumor remission in patients with platinum-resistant ovarian cancer receiving nivolumab. J. Clin. Oncol. 33, 5570–5570 (2015)CrossRef J. Hamanishi, M. Mandai, T. Ikeda, M. Minami, A. Kawaguchi, N. Matsumura, K. Abiko, T. Baba, K. Yamaguchi, A. Ueda, Y. Hosoe, S. Morita, A. Shimizu, T. Honjo, I. Konishi, Durable tumor remission in patients with platinum-resistant ovarian cancer receiving nivolumab. J. Clin. Oncol. 33, 5570–5570 (2015)CrossRef
130.
Zurück zum Zitat J. Hamanishi, M. Mandai, T. Ikeda, M. Minami, A. Kawaguchi, N. Matsumura, K. Abiko, T. Baba, K. Yamaguchi, A. Ueda, M. Kanai, Y. Mori, S. Matsumoto, T. Murayama, S. Chikuma, S. Morita, M. Yokode, A. Shimizu, T. Honjo, I. Konishi, Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 32, 5511–5511 (2014)CrossRef J. Hamanishi, M. Mandai, T. Ikeda, M. Minami, A. Kawaguchi, N. Matsumura, K. Abiko, T. Baba, K. Yamaguchi, A. Ueda, M. Kanai, Y. Mori, S. Matsumoto, T. Murayama, S. Chikuma, S. Morita, M. Yokode, A. Shimizu, T. Honjo, I. Konishi, Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 32, 5511–5511 (2014)CrossRef
131.
Zurück zum Zitat L. Festino, G. Botti, P. Lorigan, G.V. Masucci, J.D. Hipp, C.E. Horak, I. Melero, P.A. Ascierto, Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 expression a biomarker for patient selection? Drugs 76, 925–945 (2016)CrossRefPubMed L. Festino, G. Botti, P. Lorigan, G.V. Masucci, J.D. Hipp, C.E. Horak, I. Melero, P.A. Ascierto, Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 expression a biomarker for patient selection? Drugs 76, 925–945 (2016)CrossRefPubMed
132.
Zurück zum Zitat R.S. Herbst, M.S. Gordon, G.D. Fine, J.A. Sosman, J.-C. Soria, O. Hamid, J.D. Powderly, H.A. Burris, A. Mokatrin, M. Kowanetz, M. Leabman, M. Anderson, D.S. Chen, F.S. Hodi, A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J. Clin. Oncol. 31, 3000–3000 (2013) R.S. Herbst, M.S. Gordon, G.D. Fine, J.A. Sosman, J.-C. Soria, O. Hamid, J.D. Powderly, H.A. Burris, A. Mokatrin, M. Kowanetz, M. Leabman, M. Anderson, D.S. Chen, F.S. Hodi, A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J. Clin. Oncol. 31, 3000–3000 (2013)
133.
Zurück zum Zitat H. Mizugaki, N. Yamamoto, H. Murakami, H. Kenmotsu, Y. Fujiwara, Y. Ishida, T. Kawakami, T. Takahashi, Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors. Invest. New Drugs 34, 596–603 (2016)CrossRefPubMedPubMedCentral H. Mizugaki, N. Yamamoto, H. Murakami, H. Kenmotsu, Y. Fujiwara, Y. Ishida, T. Kawakami, T. Takahashi, Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors. Invest. New Drugs 34, 596–603 (2016)CrossRefPubMedPubMedCentral
134.
Zurück zum Zitat L. Horn, D.R. Spigel, S.N. Gettinger, S.J. Antonia, M.S. Gordon, R.S. Herbst, L.V. Sequist, C. Chappey, M. Kowanetz, A. Sandler, J.C. Soria, Clinical activity, safety and predictive biomarkers of the engineered antibody MPDL3280A (anti-PDL1) in non-small cell lung cancer (NSCLC): update from a phase Ia study. J. Clin. Oncol. 33, 8029–8029 (2015)CrossRef L. Horn, D.R. Spigel, S.N. Gettinger, S.J. Antonia, M.S. Gordon, R.S. Herbst, L.V. Sequist, C. Chappey, M. Kowanetz, A. Sandler, J.C. Soria, Clinical activity, safety and predictive biomarkers of the engineered antibody MPDL3280A (anti-PDL1) in non-small cell lung cancer (NSCLC): update from a phase Ia study. J. Clin. Oncol. 33, 8029–8029 (2015)CrossRef
135.
Zurück zum Zitat S. Peters, S. Gettinger, M.L. Johnson, P.A. Janne, M.C. Garassino, D. Christoph, C.K. Toh, N.A. Rizvi, J.E. Chaft, E.C. Costa, J.D. Patel, L.Q.M. Chow, M. Koczywas, C. Ho, M. Fruh, M. van den Heuvel, J. Rothenstein, M. Reck, L. Paz-Ares, F.A. Shepherd, T. Kurata, Z. Li, J. Qiu, M. Kowanetz, S. Mocci, G. Shankar, A. Sandler, E. Felip, Phase II trial of Atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J. Clin. Oncol. 35, 2781–2789 (2017)CrossRefPubMedPubMedCentral S. Peters, S. Gettinger, M.L. Johnson, P.A. Janne, M.C. Garassino, D. Christoph, C.K. Toh, N.A. Rizvi, J.E. Chaft, E.C. Costa, J.D. Patel, L.Q.M. Chow, M. Koczywas, C. Ho, M. Fruh, M. van den Heuvel, J. Rothenstein, M. Reck, L. Paz-Ares, F.A. Shepherd, T. Kurata, Z. Li, J. Qiu, M. Kowanetz, S. Mocci, G. Shankar, A. Sandler, E. Felip, Phase II trial of Atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J. Clin. Oncol. 35, 2781–2789 (2017)CrossRefPubMedPubMedCentral
136.
Zurück zum Zitat J.E. Rosenberg, J. Hoffman-Censits, T. Powles, M.S. van der Heijden, A.V. Balar, A. Necchi, N. Dawson, P.H. O'Donnell, A. Balmanoukian, Y. Loriot, S. Srinivas, M.M. Retz, P. Grivas, R.W. Joseph, M.D. Galsky, M.T. Fleming, D.P. Petrylak, J.L. Perez-Gracia, H.A. Burris, D. Castellano, C. Canil, J. Bellmunt, D. Bajorin, D. Nickles, R. Bourgon, G.M. Frampton, N. Cui, S. Mariathasan, O. Abidoye, G.D. Fine, R. Dreicer, Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016)CrossRefPubMedPubMedCentral J.E. Rosenberg, J. Hoffman-Censits, T. Powles, M.S. van der Heijden, A.V. Balar, A. Necchi, N. Dawson, P.H. O'Donnell, A. Balmanoukian, Y. Loriot, S. Srinivas, M.M. Retz, P. Grivas, R.W. Joseph, M.D. Galsky, M.T. Fleming, D.P. Petrylak, J.L. Perez-Gracia, H.A. Burris, D. Castellano, C. Canil, J. Bellmunt, D. Bajorin, D. Nickles, R. Bourgon, G.M. Frampton, N. Cui, S. Mariathasan, O. Abidoye, G.D. Fine, R. Dreicer, Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016)CrossRefPubMedPubMedCentral
137.
Zurück zum Zitat A.V. Balar, M.D. Galsky, J.E. Rosenberg, T. Powles, D.P. Petrylak, J. Bellmunt, Y. Loriot, A. Necchi, J. Hoffman-Censits, J.L. Perez-Gracia, N.A. Dawson, M.S. van der Heijden, R. Dreicer, S. Srinivas, M.M. Retz, R.W. Joseph, A. Drakaki, U.N. Vaishampayan, S.S. Sridhar, D.I. Quinn, I. Duran, D.R. Shaffer, B.J. Eigl, P.D. Grivas, E.Y. Yu, S. Li, E.E. Kadel 3rd, Z. Boyd, R. Bourgon, P.S. Hegde, S. Mariathasan, A. Thastrom, O.O. Abidoye, G.D. Fine, D.F. Bajorin, Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017)CrossRefPubMed A.V. Balar, M.D. Galsky, J.E. Rosenberg, T. Powles, D.P. Petrylak, J. Bellmunt, Y. Loriot, A. Necchi, J. Hoffman-Censits, J.L. Perez-Gracia, N.A. Dawson, M.S. van der Heijden, R. Dreicer, S. Srinivas, M.M. Retz, R.W. Joseph, A. Drakaki, U.N. Vaishampayan, S.S. Sridhar, D.I. Quinn, I. Duran, D.R. Shaffer, B.J. Eigl, P.D. Grivas, E.Y. Yu, S. Li, E.E. Kadel 3rd, Z. Boyd, R. Bourgon, P.S. Hegde, S. Mariathasan, A. Thastrom, O.O. Abidoye, G.D. Fine, D.F. Bajorin, Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017)CrossRefPubMed
138.
Zurück zum Zitat D.P. Petrylak, T. Powles, J. Bellmunt, F. Braiteh, Y. Loriot, R. Morales-Barrera, H.A. Burris, J.W. Kim, B. Ding, C. Kaiser, M. Fasso, C. O'Hear, N.J. Vogelzang, Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer: Long-term outcomes from a Phase 1 study. JAMA Oncol. 4, 537–544 (2018)CrossRefPubMedPubMedCentral D.P. Petrylak, T. Powles, J. Bellmunt, F. Braiteh, Y. Loriot, R. Morales-Barrera, H.A. Burris, J.W. Kim, B. Ding, C. Kaiser, M. Fasso, C. O'Hear, N.J. Vogelzang, Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer: Long-term outcomes from a Phase 1 study. JAMA Oncol. 4, 537–544 (2018)CrossRefPubMedPubMedCentral
139.
Zurück zum Zitat O. Hamid, J.A. Sosman, D.P. Lawrence, R.J. Sullivan, N. Ibrahim, H.M. Kluger, P.D. Boasberg, K. Flaherty, P. Hwu, M. Ballinger, A. Mokatrin, M. Kowanetz, D.S. Chen, F.S. Hodi, Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J. Clin. Oncol. 31, 9010–9010 (2013) O. Hamid, J.A. Sosman, D.P. Lawrence, R.J. Sullivan, N. Ibrahim, H.M. Kluger, P.D. Boasberg, K. Flaherty, P. Hwu, M. Ballinger, A. Mokatrin, M. Kowanetz, D.S. Chen, F.S. Hodi, Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J. Clin. Oncol. 31, 9010–9010 (2013)
140.
Zurück zum Zitat D.F. McDermott, J.A. Sosman, M. Sznol, C. Massard, M.S. Gordon, O. Hamid, J.D. Powderly, J.R. Infante, M. Fassò, Y.V. Wang, Atezolizumab, an anti–programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J. Clin. Oncol. 34, 833–842 (2016)CrossRefPubMed D.F. McDermott, J.A. Sosman, M. Sznol, C. Massard, M.S. Gordon, O. Hamid, J.D. Powderly, J.R. Infante, M. Fassò, Y.V. Wang, Atezolizumab, an anti–programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J. Clin. Oncol. 34, 833–842 (2016)CrossRefPubMed
141.
Zurück zum Zitat L. Fehrenbacher, A. Spira, M. Ballinger, M. Kowanetz, J. Vansteenkiste, J. Mazieres, K. Park, D. Smith, A. Artal-Cortes, C. Lewanski, Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. The Lancet. 387, 1837–1846 (2016)CrossRef L. Fehrenbacher, A. Spira, M. Ballinger, M. Kowanetz, J. Vansteenkiste, J. Mazieres, K. Park, D. Smith, A. Artal-Cortes, C. Lewanski, Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. The Lancet. 387, 1837–1846 (2016)CrossRef
142.
Zurück zum Zitat M.A. Socinski, R.M. Jotte, F. Cappuzzo, F. Orlandi, D. Stroyakovskiy, N. Nogami, D. Rodriguez-Abreu, D. Moro-Sibilot, C.A. Thomas, F. Barlesi, G. Finley, C. Kelsch, A. Lee, S. Coleman, Y. Deng, Y. Shen, M. Kowanetz, A. Lopez-Chavez, A. Sandler, M. Reck, Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018)CrossRefPubMed M.A. Socinski, R.M. Jotte, F. Cappuzzo, F. Orlandi, D. Stroyakovskiy, N. Nogami, D. Rodriguez-Abreu, D. Moro-Sibilot, C.A. Thomas, F. Barlesi, G. Finley, C. Kelsch, A. Lee, S. Coleman, Y. Deng, Y. Shen, M. Kowanetz, A. Lopez-Chavez, A. Sandler, M. Reck, Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018)CrossRefPubMed
143.
Zurück zum Zitat S.S. Tykodi, J.R. Brahmer, W.J. Hwu, L.Q. Chow, S.L. Topalian, P. Hwu, K. Odunsi, L.H. Camacho, J.S. Kauh, H.C. Pitot, O. Hamid, D.M. Pardoll, S. Agrawal, S. Parker, S. Goldberg, A.K. Gupta, J. Wigginton, PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with solid tumors. J. Clin. Oncol. 30, 2510–2510 (2012) S.S. Tykodi, J.R. Brahmer, W.J. Hwu, L.Q. Chow, S.L. Topalian, P. Hwu, K. Odunsi, L.H. Camacho, J.S. Kauh, H.C. Pitot, O. Hamid, D.M. Pardoll, S. Agrawal, S. Parker, S. Goldberg, A.K. Gupta, J. Wigginton, PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with solid tumors. J. Clin. Oncol. 30, 2510–2510 (2012)
144.
Zurück zum Zitat C.R. Heery, G.H.O. Coyne, R.A. Madan, J. Schlom, A. von Heydebreck, J.M. Cuillerot, H. Sabzevari, J.L. Gulley, Phase I open-label, multiple ascending dose trial of MSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies. J. Clin. Oncol. 32, 3064–3064 (2014)CrossRef C.R. Heery, G.H.O. Coyne, R.A. Madan, J. Schlom, A. von Heydebreck, J.M. Cuillerot, H. Sabzevari, J.L. Gulley, Phase I open-label, multiple ascending dose trial of MSB0010718C, an anti-PD-L1 monoclonal antibody, in advanced solid malignancies. J. Clin. Oncol. 32, 3064–3064 (2014)CrossRef
145.
Zurück zum Zitat M.L. Disis, M.R. Patel, S. Pant, E.P. Hamilton, A.C. Lockhart, K. Kelly, J.T. Beck, M.S. Gordon, G.J. Weiss, M.H. Taylor, J. Chaves, A.C. Mita, K.M. Chin, A.V. Heydebreck, J.-M. Cuillerot, J.L. Gulley, Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. J. Clin. Oncol. 34, 5533–5533 (2016)CrossRef M.L. Disis, M.R. Patel, S. Pant, E.P. Hamilton, A.C. Lockhart, K. Kelly, J.T. Beck, M.S. Gordon, G.J. Weiss, M.H. Taylor, J. Chaves, A.C. Mita, K.M. Chin, A.V. Heydebreck, J.-M. Cuillerot, J.L. Gulley, Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. J. Clin. Oncol. 34, 5533–5533 (2016)CrossRef
146.
Zurück zum Zitat A.B. Apolo, J.A. Ellerton, J.R. Infante, M. Agrawal, M.S. Gordon, R. Aljumaily, C.D. Britten, L.Y. Dirix, K.W. Lee, M.H. Taylor, P. Schoffski, D. Wang, A. Ravaud, A. Gelb, J. Xiong, G. Rosen, M.R. Patel, Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): Pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study. J. Clin. Oncol. 35, 4528–4528 (2017)CrossRef A.B. Apolo, J.A. Ellerton, J.R. Infante, M. Agrawal, M.S. Gordon, R. Aljumaily, C.D. Britten, L.Y. Dirix, K.W. Lee, M.H. Taylor, P. Schoffski, D. Wang, A. Ravaud, A. Gelb, J. Xiong, G. Rosen, M.R. Patel, Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): Pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study. J. Clin. Oncol. 35, 4528–4528 (2017)CrossRef
147.
Zurück zum Zitat J.L. Gulley, D. Spigel, K. Kelly, J.C. Chandler, A. Rajan, R. Hassan, D.J.L. Wong, J. Leach, W.J. Edenfield, D. Wang, N. Vrindavanam, G.J. Weiss, J.S. Gurtler, H.J. Grote, A. von Heydebreck, K.M. Chin, N. Iannotti, Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. J. Clin. Oncol. 33, 8034–8034 (2015)CrossRef J.L. Gulley, D. Spigel, K. Kelly, J.C. Chandler, A. Rajan, R. Hassan, D.J.L. Wong, J. Leach, W.J. Edenfield, D. Wang, N. Vrindavanam, G.J. Weiss, J.S. Gurtler, H.J. Grote, A. von Heydebreck, K.M. Chin, N. Iannotti, Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. J. Clin. Oncol. 33, 8034–8034 (2015)CrossRef
148.
Zurück zum Zitat J. Lutzky, S.J. Antonia, A. Blake-Haskins, X. Li, P.B. Robbins, A.M. Shalabi, J. Vasselli, R.A. Ibrahim, S. Khleif, N.H. Segal, A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. J. Clin. Oncol. 32, 3001–3001 (2014)CrossRef J. Lutzky, S.J. Antonia, A. Blake-Haskins, X. Li, P.B. Robbins, A.M. Shalabi, J. Vasselli, R.A. Ibrahim, S. Khleif, N.H. Segal, A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. J. Clin. Oncol. 32, 3001–3001 (2014)CrossRef
149.
Zurück zum Zitat N.A. Rizvi, J.R. Brahmer, S.H.I. Ou, N.H. Segal, S. Khleif, W.J. Hwu, M. Gutierrez, P. Schoffski, O. Hamid, J. Weiss, J. Lutzky, M. Maio, J.J. Nemunaitis, D. Jaeger, A.S. Balmanoukian, M. Rebelatto, K. Steele, X. Li, J.A. Blake-Haskins, S.J. Antonia, Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). J. Clin. Oncol. 33, 8032–8032 (2015)CrossRef N.A. Rizvi, J.R. Brahmer, S.H.I. Ou, N.H. Segal, S. Khleif, W.J. Hwu, M. Gutierrez, P. Schoffski, O. Hamid, J. Weiss, J. Lutzky, M. Maio, J.J. Nemunaitis, D. Jaeger, A.S. Balmanoukian, M. Rebelatto, K. Steele, X. Li, J.A. Blake-Haskins, S.J. Antonia, Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). J. Clin. Oncol. 33, 8032–8032 (2015)CrossRef
150.
Zurück zum Zitat S.J. Antonia, A. Villegas, D. Daniel, D. Vicente, S. Murakami, R. Hui, T. Yokoi, A. Chiappori, K.H. Lee, M. de Wit, B.C. Cho, M. Bourhaba, X. Quantin, T. Tokito, T. Mekhail, D. Planchard, Y.C. Kim, C.S. Karapetis, S. Hiret, G. Ostoros, K. Kubota, J.E. Gray, L. Paz-Ares, J. de Castro Carpeno, C. Wadsworth, G. Melillo, H. Jiang, Y. Huang, P.A. Dennis, M. Ozguroglu, Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017)CrossRefPubMed S.J. Antonia, A. Villegas, D. Daniel, D. Vicente, S. Murakami, R. Hui, T. Yokoi, A. Chiappori, K.H. Lee, M. de Wit, B.C. Cho, M. Bourhaba, X. Quantin, T. Tokito, T. Mekhail, D. Planchard, Y.C. Kim, C.S. Karapetis, S. Hiret, G. Ostoros, K. Kubota, J.E. Gray, L. Paz-Ares, J. de Castro Carpeno, C. Wadsworth, G. Melillo, H. Jiang, Y. Huang, P.A. Dennis, M. Ozguroglu, Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017)CrossRefPubMed
151.
Zurück zum Zitat N.M. Hahn, T. Powles, C. Massard, H.T. Arkenau, T.W. Friedlander, C.J. Holmes, J.L. Lee, M. Ong, S.S. Sridhar, N.J. Vogelzang, M.N. Fishman, J. Zhang, S. Srinivas, J. Parikh, J. Antal, X. Jin, Y. Ben, A.K. Gupta, P.H. O'Donnell, Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC). J. Clin. Oncol. 35, 4525–4525 (2017)CrossRef N.M. Hahn, T. Powles, C. Massard, H.T. Arkenau, T.W. Friedlander, C.J. Holmes, J.L. Lee, M. Ong, S.S. Sridhar, N.J. Vogelzang, M.N. Fishman, J. Zhang, S. Srinivas, J. Parikh, J. Antal, X. Jin, Y. Ben, A.K. Gupta, P.H. O'Donnell, Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC). J. Clin. Oncol. 35, 4525–4525 (2017)CrossRef
Metadaten
Titel
Recent advances in the clinical development of immune checkpoint blockade therapy
verfasst von
Atefeh Ghahremanloo
Arash Soltani
Seyed Mohamad Sadegh Modaresi
Seyed Isaac Hashemy
Publikationsdatum
14.06.2019
Verlag
Springer Netherlands
Erschienen in
Cellular Oncology / Ausgabe 5/2019
Print ISSN: 2211-3428
Elektronische ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-019-00456-w

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