Cellular Oncology

, Volume 42, Issue 5, pp 609–626 | Cite as

Recent advances in the clinical development of immune checkpoint blockade therapy

  • Atefeh Ghahremanloo
  • Arash Soltani
  • Seyed Mohamad Sadegh Modaresi
  • Seyed Isaac HashemyEmail author



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.


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.


Checkpoint inhibitors Cancer immunotherapy PD-1/PDL-1 mechanism Immune checkpoint blockade antibodies Immune resistance Combination immune therapy 


Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. 1.
    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)Google Scholar
  2. 2.
    D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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)CrossRefPubMedGoogle Scholar
  4. 4.
    R.A. Lake, B.W. Robinson, Immunotherapy and chemotherapy--a practical partnership. Nat. Rev. Cancer. 5, 397–405 (2005)CrossRefPubMedGoogle Scholar
  5. 5.
    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)CrossRefPubMedGoogle Scholar
  6. 6.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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)CrossRefPubMedGoogle Scholar
  8. 8.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    A. Salmaninejad, S.F. Valilou, A.G. Shabgah, S. Aslani, M. Alimardani, A. Pasdar, A. Sahebkar, PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy. J. Cell. Physiol. (2019).
  10. 10.
    P. Sharma, J.P. Allison, Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    A. Hoos, Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016)CrossRefPubMedGoogle Scholar
  12. 12.
    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)CrossRefPubMedGoogle Scholar
  13. 13.
    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)CrossRefPubMedGoogle Scholar
  14. 14.
    L.M. Francisco, P.T. Sage, A.H. Sharpe, The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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)CrossRefPubMedGoogle Scholar
  16. 16.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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)CrossRefPubMedGoogle Scholar
  18. 18.
    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)CrossRefPubMedGoogle Scholar
  19. 19.
    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)CrossRefPubMedGoogle Scholar
  20. 20.
    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)CrossRefPubMedGoogle Scholar
  21. 21.
    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)CrossRefPubMedGoogle Scholar
  22. 22.
    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)CrossRefPubMedGoogle Scholar
  23. 23.
    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)CrossRefPubMedGoogle Scholar
  24. 24.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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)CrossRefPubMedGoogle Scholar
  26. 26.
    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)CrossRefPubMedGoogle Scholar
  27. 27.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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)CrossRefPubMedGoogle Scholar
  29. 29.
    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)CrossRefPubMedGoogle Scholar
  30. 30.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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)CrossRefPubMedGoogle Scholar
  32. 32.
    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)CrossRefPubMedGoogle Scholar
  33. 33.
    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)CrossRefPubMedGoogle Scholar
  34. 34.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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)PubMedPubMedCentralGoogle Scholar
  36. 36.
    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)CrossRefPubMedGoogle Scholar
  37. 37.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    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)CrossRefPubMedGoogle Scholar
  39. 39.
    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)CrossRefPubMedGoogle Scholar
  40. 40.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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)CrossRefPubMedGoogle Scholar
  43. 43.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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)CrossRefPubMedGoogle Scholar
  45. 45.
    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)CrossRefPubMedGoogle Scholar
  46. 46.
    I.A. Mayer, C.L. Arteaga, The PI3K/AKT Pathway as a target for cancer treatment. Annu. Rev. Med. 67, 11–28 (2016)CrossRefPubMedGoogle Scholar
  47. 47.
    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)Google Scholar
  48. 48.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    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)PubMedGoogle Scholar
  51. 51.
    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)CrossRefPubMedGoogle Scholar
  52. 52.
    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)CrossRefPubMedGoogle Scholar
  53. 53.
    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)PubMedGoogle Scholar
  54. 54.
    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)CrossRefPubMedGoogle Scholar
  55. 55.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    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)CrossRefPubMedGoogle Scholar
  58. 58.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    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)CrossRefPubMedGoogle Scholar
  61. 61.
    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)CrossRefPubMedGoogle Scholar
  62. 62.
    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)CrossRefPubMedGoogle Scholar
  63. 63.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    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)PubMedPubMedCentralGoogle Scholar
  65. 65.
    M.E. Valsecchi, Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270 (2015)CrossRefPubMedGoogle Scholar
  66. 66.
    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)CrossRefGoogle Scholar
  67. 67.
    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)Google Scholar
  68. 68.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    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)CrossRefPubMedGoogle Scholar
  70. 70.
    P. Sharma, S. Hu-Lieskovan, J.A. Wargo, A. Ribas, Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    T.S. Nowicki, S. Hu-Lieskovan, A. Ribas, Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J. 24, 47–53 (2018)CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    J. Polivka Jr., F. Janku, Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 142, 164–175 (2014)CrossRefPubMedGoogle Scholar
  73. 73.
    H. Javid, A. Soltani, F. Mohammadi, S.I. Hashemy, Emerging roles of microRNAs in regulating the mTOR signaling pathway during tumorigenesis. J. Cell. Biochem. (2019).
  74. 74.
    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)CrossRefGoogle Scholar
  75. 75.
    S. Spranger, R. Bao, T.F. Gajewski, Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    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)CrossRefGoogle Scholar
  78. 78.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    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)CrossRefPubMedGoogle Scholar
  80. 80.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    L.C. Platanias, Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005)CrossRefPubMedGoogle Scholar
  85. 85.
    A. Ribas, Adaptive Immune resistance: How cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    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)CrossRefPubMedGoogle Scholar
  87. 87.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    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)PubMedGoogle Scholar
  89. 89.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    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)CrossRefPubMedGoogle Scholar
  92. 92.
    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)CrossRefPubMedGoogle Scholar
  93. 93.
    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)CrossRefGoogle Scholar
  94. 94.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    S. Sakaguchi, T. Yamaguchi, T. Nomura, M. Ono, Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008)CrossRefPubMedGoogle Scholar
  96. 96.
    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)CrossRefPubMedGoogle Scholar
  97. 97.
    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)CrossRefPubMedGoogle Scholar
  98. 98.
    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)CrossRefGoogle Scholar
  99. 99.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    J.J. Lebrun, The dual role of TGFbeta in human cancer: From tumor suppression to cancer metastasis. ISRN Mol. Biol. 2012, 381428 (2012)PubMedPubMedCentralGoogle Scholar
  101. 101.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    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)CrossRefPubMedGoogle Scholar
  103. 103.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    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)CrossRefPubMedGoogle Scholar
  105. 105.
    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)CrossRefPubMedGoogle Scholar
  106. 106.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    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)Google Scholar
  109. 109.
    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)CrossRefPubMedGoogle Scholar
  110. 110.
    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)CrossRefPubMedGoogle Scholar
  111. 111.
    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)CrossRefPubMedGoogle Scholar
  112. 112.
    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)CrossRefGoogle Scholar
  113. 113.
    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)CrossRefGoogle Scholar
  114. 114.
    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)CrossRefPubMedGoogle Scholar
  115. 115.
    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)CrossRefGoogle Scholar
  116. 116.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    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)CrossRefGoogle Scholar
  118. 118.
    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)CrossRefPubMedGoogle Scholar
  119. 119.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    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)CrossRefGoogle Scholar
  121. 121.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    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)CrossRefGoogle Scholar
  125. 125.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    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)CrossRefGoogle Scholar
  128. 128.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    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)CrossRefGoogle Scholar
  130. 130.
    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)CrossRefGoogle Scholar
  131. 131.
    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)CrossRefPubMedGoogle Scholar
  132. 132.
    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)Google Scholar
  133. 133.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    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)CrossRefGoogle Scholar
  135. 135.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    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)CrossRefPubMedGoogle Scholar
  138. 138.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    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)Google Scholar
  140. 140.
    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)CrossRefPubMedGoogle Scholar
  141. 141.
    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)CrossRefGoogle Scholar
  142. 142.
    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)CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    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)Google Scholar
  144. 144.
    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)CrossRefGoogle Scholar
  145. 145.
    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)CrossRefGoogle Scholar
  146. 146.
    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)CrossRefGoogle Scholar
  147. 147.
    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)CrossRefGoogle Scholar
  148. 148.
    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)CrossRefGoogle Scholar
  149. 149.
    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)CrossRefGoogle Scholar
  150. 150.
    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)CrossRefPubMedGoogle Scholar
  151. 151.
    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)CrossRefGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2019

Authors and Affiliations

  1. 1.Department of Clinical Biochemistry, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  2. 2.Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  3. 3.College of PharmacyUniversity of Rhode IslandKingstonUSA
  4. 4.Surgical Oncology Research CenterMashhad University of Medical SciencesMashhadIran

Personalised recommendations