Monoclonal Antibodies for the Treatment of Melanoma: Present and Future Strategies

  • Madhuri Bhandaru
  • Anand Rotte
Part of the Methods in Molecular Biology book series (MIMB, volume 1904)


Metastatic melanoma is a dreadful type of skin cancer arising due to uncontrolled proliferation of melanocytes. It has very poor prognosis, low 5-year survival rates and until recently there were only handful of treatment options for metastatic melanoma patients. The drugs that were approved for the treatment had low response rates and were associated with severe adverse events. With the introduction of monoclonal antibodies against inhibitory immune checkpoints the treatment landscape for metastatic melanoma has changed dramatically. Ipilimumab, the first monoclonal antibody to be approved for the treatment of metastatic melanoma, showed significant improvements in durable response rates in patients and paved the way for next class of monoclonal antibodies. Nivolumab and pembrolizumab, the anti-PD-1 antibodies that were approved 3-years after the approval of ipilimumab, had decent response rates, low relapse rates and showed manageable safety profile. Antibodies against ligands for PD-1 receptors were then developed to overcome the adverse effects of anti-PD-1 antibodies and combination of monoclonal antibodies (ipilimumab plus nivolumab) was tested to increase the response rates. Additional target receptors that regulate T cell activity were identified on T cells and monoclonal antibodies against potential targets such as TIGIT, TIM-3, and LAG-3 were developed. This chapter discusses the details of monoclonal antibodies used for the treatment of melanoma along with the ones that could be introduced in the near future with emphasis on mechanisms by which antibodies stimulate anti-tumor immune response and the specifics of target molecules of the antibodies.

Key words

Co-stimulation Checkpoints T cells CTLA-4 PD-1 TIGIT TIM-3 LAG-3 ADCC 


  1. 1.
    Miller AJ, Mihm MC Jr (2006) Melanoma. N Engl J Med 355(1):51–65. Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30. Scholar
  3. 3.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30. Scholar
  4. 4.
    Rotte A, Bhandaru M (2016) Melanoma – introduction, history and epidemiology (Immunotherapy of melanoma). Springer, ChamGoogle Scholar
  5. 5.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. Scholar
  6. 6.
    Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M et al (eds) (2014) Cancer incidence in five continents Vol. X (Vol. X, IARC Scientific Publication no. 164). IARC Publications, LyonGoogle Scholar
  7. 7.
    Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206. Scholar
  8. 8.
    Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI et al (2017) Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67(6):472–492. Scholar
  9. 9.
    Rotte A, Bhandaru M, Zhou Y, McElwee KJ (2015) Immunotherapy of melanoma: present options and future promises. Cancer Metastasis Rev 34(1):115–128. Scholar
  10. 10.
    Rotte A, Bhandaru M (2016) Melanoma – treatment (immunotherapy of melanoma). Springer, ChamCrossRefGoogle Scholar
  11. 11.
    Rotte A, Bhandaru M (2016) Ipilimumab (immunotherapy of melanoma). Springer, ChamCrossRefGoogle Scholar
  12. 12.
    Rotte A, Bhandaru M (2016) Nivolumab (immunotherapy of melanoma). Springer, ChamCrossRefGoogle Scholar
  13. 13.
    Rotte A, Bhandaru M (2016) Pembrolizumab (immunotherapy of melanoma). Springer, ChamCrossRefGoogle Scholar
  14. 14.
    Rotte A, Jin JY, Lemaire V (2018) Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol 29(1):71–83. Scholar
  15. 15.
    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK et al (2017) Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science.
  16. 16.
    FDA (2017) FDA approves first cancer treatment for any solid tumor with a specific genetic feature. Scholar
  17. 17.
    FDA (2017) FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer. Scholar
  18. 18.
    Teillaud J-L (2001) Antibody-dependent cellular cytotoxicity (ADCC). In: eLS. John Wiley & Sons, LtdGoogle Scholar
  19. 19.
    Furness AJ, Vargas FA, Peggs KS, Quezada SA (2014) Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies. Trends Immunol 35(7):290–298. Scholar
  20. 20.
    Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S et al (2009) Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 113(16):3716–3725. Scholar
  21. 21.
    DiLillo DJ, Ravetch JV (2015) Fc-receptor interactions regulate both cytotoxic and immunomodulatory therapeutic antibody effector functions. Cancer Immunol Res 3(7):704–713. Scholar
  22. 22.
    Nimmerjahn F, Gordan S, Lux A (2015) FcgammaR dependent mechanisms of cytotoxic, agonistic, and neutralizing antibody activities. Trends Immunol 36(6):325–336. Scholar
  23. 23.
    Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM (2015) NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front Immunol 6:368. Scholar
  24. 24.
    Seidel UJ, Schlegel P, Lang P (2013) Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Front Immunol 4:76. Scholar
  25. 25.
    Rotte A, Bhandaru M (2016) Dendritic cells (immunotherapy of melanoma). Springer, ChamGoogle Scholar
  26. 26.
    Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619. Scholar
  27. 27.
    Fife BT, Bluestone JA (2008) Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 224:166–182. Scholar
  28. 28.
    Ley K (2014) The second touch hypothesis: T cell activation, homing and polarization. F1000Res 3:37. Scholar
  29. 29.
    Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG et al (1987) A new member of the immunoglobulin superfamily—CTLA-4. Nature 328(6127):267–270. Scholar
  30. 30.
    Dariavach P, Mattei MG, Golstein P, Lefranc MP (1988) Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol 18(12):1901–1905. Scholar
  31. 31.
    Metzler WJ, Bajorath J, Fenderson W, Shaw SY, Constantine KL, Naemura J et al (1997) Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28. Nat Struct Biol 4(7):527–531CrossRefGoogle Scholar
  32. 32.
    Perkins D, Wang Z, Donovan C, He H, Mark D, Guan G et al (1996) Regulation of CTLA-4 expression during T cell activation. J Immunol 156(11):4154–4159PubMedGoogle Scholar
  33. 33.
    Alegre ML, Noel PJ, Eisfelder BJ, Chuang E, Clark MR, Reiner SL et al (1996) Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol 157(11):4762–4770PubMedGoogle Scholar
  34. 34.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. Scholar
  35. 35.
    Stamper CC, Zhang Y, Tobin JF, Erbe DV, Ikemizu S, Davis SJ et al (2001) Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 410(6828):608–611. Scholar
  36. 36.
    Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. Scholar
  37. 37.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547CrossRefGoogle Scholar
  38. 38.
    Chambers CA, Sullivan TJ, Allison JP (1997) Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7(6):885–895CrossRefGoogle Scholar
  39. 39.
    Intlekofer AM, Thompson CB (2013) At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol 94(1):25–39. Scholar
  40. 40.
    Carreno BM, Bennett F, Chau TA, Ling V, Luxenberg D, Jussif J et al (2000) CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol 165(3):1352–1356CrossRefGoogle Scholar
  41. 41.
    Chikuma S, Abbas AK, Bluestone JA (2005) B7-independent inhibition of T cells by CTLA-4. J Immunol 175(1):177–181CrossRefGoogle Scholar
  42. 42.
    Schneider H, Valk E, Leung R, Rudd CE (2008) CTLA-4 activation of phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. PLoS One 3(12):e3842. Scholar
  43. 43.
    Fraser JH, Rincon M, McCoy KD, Le Gros G (1999) CTLA4 ligation attenuates AP-1, NFAT and NF-kappaB activity in activated T cells. Eur J Immunol 29(3):838–844CrossRefGoogle Scholar
  44. 44.
    Olsson C, Riesbeck K, Dohlsten M, Michaelsson E (1999) CTLA-4 ligation suppresses CD28-induced NF-kappaB and AP-1 activity in mouse T cell blasts. J Biol Chem 274(20):14400–14405CrossRefGoogle Scholar
  45. 45.
    Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736CrossRefGoogle Scholar
  46. 46.
    CHMP (2011) Assessment report for Yervoy (Ipilimumab): procedure no.: EMEA/H/C/002213 (2011). In: C.f.M.P.f.H.U. (CHMP) (Ed.). EMA, LondonGoogle Scholar
  47. 47.
    Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11(11):3887–3895CrossRefGoogle Scholar
  48. 48.
    Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (1994) Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 23(3):704–706. Scholar
  49. 49.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. Scholar
  50. 50.
    Francisco LM, Sage PT, Sharpe AH (2010) The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 236(1):219–242. Scholar
  51. 51.
    Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I et al (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268. Scholar
  52. 52.
    Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan SH et al (2013) Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem 288(17):11771–11785. Scholar
  53. 53.
    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK et al (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029. Scholar
  54. 54.
    Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151CrossRefGoogle Scholar
  55. 55.
    Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A et al (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291(5502):319–322. Scholar
  56. 56.
    Pauken KE, Wherry EJ (2015) Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36(4):265–276. Scholar
  57. 57.
    Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV et al (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25(21):9543–9553. Scholar
  58. 58.
    Malek TR, Castro I (2010) Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33(2):153–165. Scholar
  59. 59.
    Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D et al (2003) Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J Immunol 170(2):711–718CrossRefGoogle Scholar
  60. 60.
    Bhandaru M, Rotte A (2017) Blockade of programmed cell death protein-1 pathway for the treatment of melanoma [short communication]. J Dermatol Res Ther 1(3):1–11. Scholar
  61. 61.
    Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D et al (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2(9):846–856. Scholar
  62. 62.
    Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14(8):561–584. Scholar
  63. 63.
    Tan S, Zhang H, Chai Y, Song H, Tong Z, Wang Q et al (2017) An unexpected N-terminal loop in PD-1 dominates binding by nivolumab. Nat Commun 8:14369. Scholar
  64. 64.
    Tan S, Liu K, Chai Y, Zhang CW, Gao S, Gao GF et al (2018) Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab. Protein Cell 9(1):135–139. Scholar
  65. 65.
    Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B et al (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10(1):48–57. Scholar
  66. 66.
    Boles KS, Vermi W, Facchetti F, Fuchs A, Wilson TJ, Diacovo TG et al (2009) A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur J Immunol 39(3):695–703. Scholar
  67. 67.
    Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A et al (2009) The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A 106(42):17858–17863. Scholar
  68. 68.
    Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y et al (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 26(6):923–937. Scholar
  69. 69.
    Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW et al (2015) TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 125(11):4053–4062. Scholar
  70. 70.
    Chew GM, Fujita T, Webb GM, Burwitz BJ, Wu HL, Reed JS et al (2016) TIGIT marks exhausted T cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV infection. PLoS Pathog 12(1):e1005349. Scholar
  71. 71.
    Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44(5):989–1004. Scholar
  72. 72.
    Manieri NA, Chiang EY, Grogan JL (2017) TIGIT: a key inhibitor of the cancer immunity cycle. Trends Immunol 38(1):20–28. Scholar
  73. 73.
    Liu S, Zhang H, Li M, Hu D, Li C, Ge B et al (2013) Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ 20(3):456–464. Scholar
  74. 74.
    Li M, Xia P, Du Y, Liu S, Huang G, Chen J et al (2014) T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-gamma production of natural killer cells via beta-arrestin 2-mediated negative signaling. J Biol Chem 289(25):17647–17657. Scholar
  75. 75.
    Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M et al (2015) Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42(2):344–355. Scholar
  76. 76.
    Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD et al (2011) Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 186(3):1338–1342. Scholar
  77. 77.
    Sakisaka T, Takai Y (2004) Biology and pathology of nectins and nectin-like molecules. Curr Opin Cell Biol 16(5):513–521. Scholar
  78. 78.
    Fuchs A, Colonna M (2006) The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance. Semin Cancer Biol 16(5):359–366. Scholar
  79. 79.
    Masson D, Jarry A, Baury B, Blanchardie P, Laboisse C, Lustenberger P et al (2001) Overexpression of the CD155 gene in human colorectal carcinoma. Gut 49(2):236–240CrossRefGoogle Scholar
  80. 80.
    Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415(6871):536–541. Scholar
  81. 81.
    Gorman JV, Colgan JD (2014) Regulation of T cell responses by the receptor molecule Tim-3. Immunol Res 59(1–3):56–65. Scholar
  82. 82.
    Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ et al (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6(12):1245–1252. Scholar
  83. 83.
    Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A et al (2015) CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517(7534):386–390. Scholar
  84. 84.
    Anderson AC (2014) Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res 2(5):393–398. Scholar
  85. 85.
    Sehrawat S, Suryawanshi A, Hirashima M, Rouse BT (2009) Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: shifting the balance toward regulators. J Immunol 182(5):3191–3201. Scholar
  86. 86.
    Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH et al (2010) Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J Immunol 185(3):1383–1392. Scholar
  87. 87.
    Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX et al (2003) Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 4(11):1102–1110. Scholar
  88. 88.
    Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA et al (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4(11):1093–1101. Scholar
  89. 89.
    Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A et al (2012) Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med 18(9):1394–1400. Scholar
  90. 90.
    Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R (2009) T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol Rev 228(1):9–22. Scholar
  91. 91.
    Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E et al (1990) LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 171(5):1393–1405CrossRefGoogle Scholar
  92. 92.
    Miyazaki T, Dierich A, Benoist C, Mathis D (1996) LAG-3 is not responsible for selecting T helper cells in CD4-deficient mice. Int Immunol 8(5):725–729CrossRefGoogle Scholar
  93. 93.
    Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA (2004) Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol 172(9):5450–5455CrossRefGoogle Scholar
  94. 94.
    He Y, Rivard CJ, Rozeboom L, Yu H, Ellison K, Kowalewski A et al (2016) Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer Sci 107(9):1193–1197. Scholar
  95. 95.
    Workman CJ, Dugger KJ, Vignali DA (2002) Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol 169(10):5392–5395CrossRefGoogle Scholar
  96. 96.
    Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z et al (2014) LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res 74(13):3418–3428. Scholar
  97. 97.
    Richter K, Agnellini P, Oxenius A (2010) On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int Immunol 22(1):13–23. Scholar
  98. 98.
    Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15(8):486–499. Scholar
  99. 99.
    Bettini M, Szymczak-Workman AL, Forbes K, Castellaw AH, Selby M, Pan X et al (2011) Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3. J Immunol 187(7):3493–3498. Scholar
  100. 100.
    Jha V, Workman CJ, McGaha TL, Li L, Vas J, Vignali DA et al (2014) Lymphocyte activation gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. PLoS One 9(8):e104484. Scholar
  101. 101.
    Hannier S, Tournier M, Bismuth G, Triebel F (1998) CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J Immunol 161(8):4058–4065PubMedGoogle Scholar
  102. 102.
    Thommen DS, Schreiner J, Muller P, Herzig P, Roller A, Belousov A et al (2015) Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res 3(12):1344–1355. Scholar
  103. 103.
    Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T et al (2010) Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 107(17):7875–7880. Scholar
  104. 104.
    Chen J, Chen Z (2014) The effect of immune microenvironment on the progression and prognosis of colorectal cancer. Med Oncol 31(8):82. Scholar
  105. 105.
    Lee HT, Lee JY, Lim H, Lee SH, Moon YJ, Pyo HJ et al (2017) Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep 7(1):5532. Scholar
  106. 106.
    Madorsky Rowdo FP, Baron A, Urrutia M, Mordoh J (2015) Immunotherapy in cancer: a combat between tumors and the immune system; you win some, you lose some. Front Immunol 6:127. Scholar
  107. 107.
    Scapin G, Yang X, Prosise WW, McCoy M, Reichert P, Johnston JM et al (2015) Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. Nat Struct Mol Biol 22(12):953–958. Scholar
  108. 108.
    Nimmerjahn F, Ravetch JV (2005) Divergent immunoglobulin G subclass activity through selective Fc receptor binding. Science 310(5753):1510–1512. Scholar
  109. 109.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. Scholar
  110. 110.
    Hamid O, Carvajal RD (2013) Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin Biol Ther 13(6):847–861. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Madhuri Bhandaru
    • 1
  • Anand Rotte
    • 2
    • 3
  1. 1.Department of Dermatology and Skin ScienceUniversity of British ColumbiaVancouverCanada
  2. 2.Department of Clinical PharmacologyGenentech Research and Early DevelopmentSouth San FranciscoUSA
  3. 3.Department of Clinical and Regulatory AffairsNevro Corp.Redwood CityUSA

Personalised recommendations