Skip to main content

Advertisement

SpringerLink
Log in

Recent advances in the clinical development of immune checkpoint blockade therapy

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  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)

  2. D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  4. R.A. Lake, B.W. Robinson, Immunotherapy and chemotherapy--a practical partnership. Nat. Rev. Cancer. 5, 397–405 (2005)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). https://doi.org/10.1002/jcp.28358

  10. P. Sharma, J.P. Allison, Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. A. Hoos, Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  14. L.M. Francisco, P.T. Sage, A.H. Sharpe, The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  46. I.A. Mayer, C.L. Arteaga, The PI3K/AKT Pathway as a target for cancer treatment. Annu. Rev. Med. 67, 11–28 (2016)

    Article  CAS  PubMed  Google Scholar 

  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)

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    CAS  PubMed  PubMed Central  Google Scholar 

  65. M.E. Valsecchi, Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270 (2015)

    Article  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  70. P. Sharma, S. Hu-Lieskovan, J.A. Wargo, A. Ribas, Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. J. Polivka Jr., F. Janku, Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 142, 164–175 (2014)

    Article  CAS  PubMed  Google Scholar 

  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). https://doi.org/10.1002/jcb.28401

  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)

    Article  CAS  PubMed  Google Scholar 

  75. S. Spranger, R. Bao, T.F. Gajewski, Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. L.C. Platanias, Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005)

    Article  CAS  PubMed  Google Scholar 

  85. A. Ribas, Adaptive Immune resistance: How cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  PubMed  PubMed Central  Google Scholar 

  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)

    CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. S. Sakaguchi, T. Yamaguchi, T. Nomura, M. Ono, Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  PubMed  PubMed Central  Google Scholar 

  100. J.J. Lebrun, The dual role of TGFbeta in human cancer: From tumor suppression to cancer metastasis. ISRN Mol. Biol. 2012, 381428 (2012)

    PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  PubMed  PubMed Central  Google Scholar 

  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. 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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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. 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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Atefeh Ghahremanloo & Arash Soltani

  2. Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Atefeh Ghahremanloo & Arash Soltani

  3. College of Pharmacy, University of Rhode Island, Kingston, RI, USA

    Seyed Mohamad Sadegh Modaresi

  4. Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Isaac Hashemy

Authors
  1. Atefeh Ghahremanloo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arash Soltani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seyed Mohamad Sadegh Modaresi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seyed Isaac Hashemy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seyed Isaac Hashemy.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghahremanloo, A., Soltani, A., Modaresi, S.M.S. et al. Recent advances in the clinical development of immune checkpoint blockade therapy. Cell Oncol. 42, 609–626 (2019). https://doi.org/10.1007/s13402-019-00456-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-019-00456-w

Keywords

Search

Navigation