Novel treatments in development for melanoma

Cancer Treatment and Research

Volumn 167, Issue , 2016, Pages 371-416

  Bernatchez, Chantale ^a   Cooper, Zachary A ^a   Wargo, Jennifer A ^a   Hwu, Patrick ^a   Lizée, Gregory ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

Immunotherapy; Personalized medicine; Targeted therapy

Indexed keywords

CANCER VACCINE; CHIMERIC ANTIGEN RECEPTOR; T LYMPHOCYTE RECEPTOR; TUMOR ANTIGEN; ANTINEOPLASTIC AGENT;

ADOPTIVE TRANSFER; ANTIGEN SPECIFICITY; CANCER IMMUNIZATION; CANCER IMMUNOTHERAPY; CANCER RESEARCH; CELL ENGINEERING; GENE MUTATION; HUMAN; LYMPHOCYTE FUNCTION; METASTATIC MELANOMA; MOLECULARLY TARGETED THERAPY; NONHUMAN; PERSONALIZED MEDICINE; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); T LYMPHOCYTE; TUMOR ASSOCIATED LEUKOCYTE; IMMUNOLOGY; MELANOMA; SECONDARY;

ADOPTIVE TRANSFER; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CANCER VACCINES; HUMANS; MELANOMA; MOLECULAR TARGETED THERAPY; PRECISION MEDICINE; T-LYMPHOCYTES;

EID: 84948807271     PISSN: 09273042     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-3-319-22539-5_16     Document Type: Chapter

References (231)

1. Stadler S, Weina K, Gebhardt C, Utikal J (2014) New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci 60(1):83–88. doi:10.1016/j.advms.2014.12.002
2. Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD (2014) Immune modulation in cancer with antibodies. Annu Rev Med 65:185–202. doi:10.1146/annurev-med-092012-112807
3. Ott PA, Hodi FS, Robert C (2013) CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res Official J Am Assoc Cancer Res 19(19):5300–5309. doi:10.1158/1078-0432. CCR-13-0143
4. Kwong LN, Davies MA (2014) Targeted therapy for melanoma: rational combinatorial approaches. Oncogene 33(1):1–9. doi:10.1038/onc.2013.34
5. Samatar AA, Poulikakos PI (2014) Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov 13(12):928–942. doi:10.1038/nrd4281
6. Kaufman HL (2015) Precision immunology: the promise of immunotherapy for the treatment of cancer. J Clin Oncol Official J Am Soc Clin Oncol. doi:10.1200/JCO.2014.59.6023
7. Aris M, Barrio MM (2015) Combining immunotherapy with oncogene-targeted therapy: a new road for melanoma treatment. Front Immunol 6:46. doi:10.3389/fimmu.2015.00046
8. Chen G, Davies MA (2014) Targeted therapy resistance mechanisms and therapeutic implications in melanoma. Hematol Oncol Clin North Am 28(3):523–536. doi:10.1016/j.hoc.2014.03.001
9. Menzies AM, Long GV (2014) Systemic treatment for BRAF-mutant melanoma: where do we go next? Lancet Oncol 15(9):e371–e381. doi:10.1016/S1470-2045(14)70072-5
10. Das Thakur M, Stuart DD (2014) Molecular pathways: response and resistance to BRAF and MEK inhibitors in BRAF(V600E) tumors. Clin Cancer Res Official J Am Assoc Cancer Res 20(5):1074–1080. doi:10.1158/1078-0432.CCR-13-0103
11. Knight DA, Ngiow SF, Li M, Parmenter T, Mok S, Cass A, Haynes NM, Kinross K, Yagita H, Koya RC, Graeber TG, Ribas A, McArthur GA, Smyth MJ (2013) Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Investig 123(3):1371– 1381. doi:10.1172/JCI66236
12. Croci DO, Zacarias Fluck MF, Rico MJ, Matar P, Rabinovich GA, Scharovsky OG (2007) Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol Immunother CII 56(11): 1687–1700. doi:10.1007/s00262-007-0343-y
13. Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, Zhang M, Cooper ZA, Frederick DT, Li Y, Joseph RW, Bernatchez C, Ekmekcioglu S, Grimm E, Radvanyi LG, Davis RE, Davies MA, Wargo JA, Hwu P, Lizee G (2012) Oncogenic BRAF (V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 18(19):5329–5340. doi:10.1158/1078-0432.CCR-12-1632
14. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51. doi:10.1016/j.cell.2010.03.014
15. Agwa E, Ma PC (2013) Overview of various techniques/platforms with critical evaluation of each. Curr Treat Options Oncol 14(4):623–633. doi:10.1007/s11864-013-0259-z
16. Ow TJ, Sandulache VC, Skinner HD, Myers JN (2013) Integration of cancer genomics with treatment selection: from the genome to predictive biomarkers. Cancer 119(22):3914–3928. doi:10.1002/cncr.28304
17. Patel LR, Nykter M, Chen K, Zhang W (2013) Cancer genome sequencing: understanding malignancy as a disease of the genome, its conformation, and its evolution. Cancer Lett 340(2):152–160. doi:10.1016/j.canlet.2012.10.018
18. Bennett NC, Farah CS (2014) Next-generation sequencing in clinical oncology: next steps towards clinical validation. Cancers 6(4):2296–2312. doi:10.3390/cancers6042296
19. Yewdell JW, Bennink JR (1992) Cell biology of antigen processing and presentation to major histocompatibility complex class I molecule-restricted T lymphocytes. Adv Immunol 52:1–123
20. Joffre OP, Segura E, Savina A, Amigorena S (2012) Cross-presentation by dendritic cells. Nat Rev Immunol 12(8):557–569. doi:10.1038/nri3254
21. Peaper DR, Cresswell P (2008) Regulation of MHC class I assembly and peptide binding. Annu Rev Cell Dev Biol 24:343–368. doi:10.1146/annurev.cellbio.24.110707.175347
22. Lizee G, Basha G, Jefferies WA (2005) Tails of wonder: endocytic-sorting motifs key for exogenous antigen presentation. Trends Immunol 26(3):141–149. doi:10.1016/j.it.2005.01.005
23. Mlecnik B, Bindea G, Pages F, Galon J (2011) Tumor immunosurveillance in human cancers. Cancer Metastasis Rev 30(1):5–12. doi:10.1007/s10555-011-9270-7
24. Roberts SA, Gordenin DA (2014) Hypermutation in human cancer genomes: footprints and mechanisms. Nat Rev Cancer 14(12):786–800
25. Overwijk WW, Wang E, Marincola FM, Rammensee HG, Restifo NP (2013) Mining the mutanome: developing highly personalized Immunotherapies based on mutational analysis of tumors. J Immunother Cancer 1:11. doi:10.1186/2051-1426-1-11
26. Heemskerk B, Kvistborg P, Schumacher TN (2013) The cancer antigenome. EMBO J 32 (2):194–203. doi:10.1038/emboj.2012.333
27. Burrell RA, Swanton C (2014) The evolution of the unstable cancer genome. Curr Opin Genet Dev 24:61–67. doi:10.1016/j.gde.2013.11.011
28. Lundegaard C, Lund O, Buus S, Nielsen M (2010) Major histocompatibility complex class I binding predictions as a tool in epitope discovery. Immunology 130(3):309–318. doi:10.1111/j.1365-2567.2010.03300.x
29. Liao WW, Arthur JW (2011) Predicting peptide binding affinities to MHC molecules using a modified semi-empirical scoring function. PLoS ONE 6(9):e25055. doi:10.1371/journal.pone.0025055
30. Fritsch EF, Rajasagi M, Ott PA, Brusic V, Hacohen N, Wu CJ (2014) HLA-binding properties of tumor neoepitopes in humans. Cancer Immunol Res 2(6):522–529. doi:10.1158/2326-6066.CIR-13-0227
31. Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, Lin JC, Teer JK, Cliften P, Tycksen E, Samuels Y, Rosenberg SA (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 19 (6):747–752. doi:10.1038/nm.3161
32. Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, Behjati S, Velds A, Hilkmann H, Atmioui DE, Visser M, Stratton MR, Haanen JB, Spits H, van der Burg SH, Schumacher TN (2015) High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat Med 21(1):81–85. doi:10.1038/nm.3773
33. Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482(7385):400–404. doi:10.1038/nature10755
34. Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, Bumbaca S, Franci C, Cheung TK, Fritsche J, Weinschenk T, Modrusan Z, Mellman I, Lill JR, Delamarre L (2014) Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515(7528):572–576. doi:10.1038/nature14001
35. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199. doi:10.1056/NEJMoa1406498
36. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457):214–218. doi:10.1038/nature12213
37. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954. doi:10.1038/nature00766
38. Sharkey MS, Lizee G, Gonzales MI, Patel S, Topalian SL (2004) CD4(+) T-cell recognition of mutated B-RAF in melanoma patients harboring the V599E mutation. Cancer Res 64 (5):1595–1599
39. Miglio U, Oldani A, Mezzapelle R, Veggiani C, Paganotti A, Garavoglia M, Boldorini R (2014) KRAS mutational analysis in ductal adenocarcinoma of the pancreas and its clinical significance. Pathol Res Pract 210(5):307–311. doi:10.1016/j.prp.2014.01.011
40. Warren RL, Holt RA (2010) A census of predicted mutational epitopes suitable for immunologic cancer control. Hum Immunol 71(3):245–254. doi:10.1016/j.humimm.2009.12.007
41. Phan GQ, Rosenberg SA (2013) Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy. Cancer Control J Moffitt Cancer Cent 20(4):289–297
42. Kawakami Y, Robbins PF, Rosenberg SA (1996) Human melanoma antigens recognized by T lymphocytes. Keio J Med 45(2):100–108
43. Chen YT, Old LJ (1999) Cancer-testis antigens: targets for cancer immunotherapy. Cancer J Sci Am 5(1):16–17
44. Meek DW, Marcar L (2012) MAGE-A antigens as targets in tumour therapy. Cancer Lett 324(2):126–132. doi:10.1016/j.canlet.2012.05.011
45. Rycaj K, Plummer JB, Yin B, Li M, Garza J, Radvanyi L, Ramondetta LM, Lin K, Johanning GL, Tang DG, Wang-Johanning F (2015) Cytotoxicity of human endogenous retrovirus K-specific T cells toward autologous ovarian cancer cells. Clin Cancer Res Official J Am Assoc Cancer Res 21(2):471–483. doi:10.1158/1078-0432.CCR-14-0388
46. Gordan JD, Vonderheide RH (2002) Universal tumor antigens as targets for immunotherapy. Cytotherapy 4(4):317–327. doi:10.1080/146532402760271091
47. Asai T, Storkus WJ, Mueller-Berghaus J, Knapp W, DeLeo AB, Chikamatsu K, Whiteside TL (2002) In vitro generated cytolytic T lymphocytes reactive against head and neck cancer recognize multiple epitopes presented by HLA-A2, including peptides derived from the p53 and MDM-2 proteins. Cancer Immun 2:3
48. Hunt DF, Henderson RA, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, Cox AL, Appella E, Engelhard VH (1992) Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 255(5049):1261–1263
49. Singh-Jasuja H, Emmerich NP, Rammensee HG (2004) The Tubingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy. Cancer Immunol Immunother CII 53(3):187–195. doi:10.1007/s00262-003-0480-x
50. Rammensee HG, Falk K, Rotzschke O (1993) Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 11:213–244. doi:10.1146/annurev.iy.11.040193.001241
51. Bassani-Sternberg M, Barnea E, Beer I, Avivi I, Katz T, Admon A (2010) Soluble plasma HLA peptidome as a potential source for cancer biomarkers. Proc Natl Acad Sci USA 107 (44):18769–18776. doi:10.1073/pnas.1008501107
52. Rammensee HG, Singh-Jasuja H (2013) HLA ligandome tumor antigen discovery for personalized vaccine approach. Expert Rev Vaccines 12(10):1211–1217. doi:10.1586/14760584.2013.836911
53. Khong HT, Restifo NP (2002) Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 3(11):999–1005. doi:10.1038/ni1102-999
54. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570. doi:10.1126/science.1203486
55. Kawakami Y, Rosenberg SA (1997) Immunobiology of human melanoma antigens MART-1 and gp100 and their use for immuno-gene therapy. Int Rev Immunol 14(2–3):173–192
56. Li Y, Yee C (2008) IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111(1):229–235. doi:10.1182/blood-2007-05-089375
57. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, Hilf N, Schoor O, Fritsche J, Mahr A, Maurer D, Vass V, Trautwein C, Lewandrowski P, Flohr C, Pohla H, Stanczak JJ, Bronte V, Mandruzzato S, Biedermann T, Pawelec G, Derhovanessian E, Yamagishi H, Miki T, Hongo F, Takaha N, Hirakawa K, Tanaka H, Stevanovic S, Frisch J, Mayer-Mokler A, Kirner A, Rammensee HG, Reinhardt C, Singh-Jasuja H (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18(8):1254–1261. doi:10.1038/nm.2883
58. Mittendorf EA, Clifton GT, Holmes JP, Schneble E, van Echo D, Ponniah S, Peoples GE (2014) Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann Oncol Official J Eur Soc Med Oncol/ESMO 25(9):1735–1742. doi:10.1093/annonc/mdu211
59. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796):126–129. doi:10.1126/science.1129003
60. Gnjatic S, Jager E, Chen W, Altorki NK, Matsuo M, Lee SY, Chen Q, Nagata Y, Atanackovic D, Chen YT, Ritter G, Cebon J, Knuth A, Old LJ (2002) CD8(+) T cell responses against a dominant cryptic HLA-A2 epitope after NY-ESO-1 peptide immunization of cancer patients. Proc Natl Acad Sci USA 99(18):11813–11818. doi:10.1073/pnas.142417699
61. Lundegaard C, Lund O, Nielsen M (2008) Accurate approximation method for prediction of class I MHC affinities for peptides of length 8, 10 and 11 using prediction tools trained on 9mers. Bioinformatics 24(11):1397–1398. doi:10.1093/bioinformatics/btn128
62. Yi Z, Luo M, Carroll CA, Weintraub ST, Mandarino LJ (2005) Identification of phosphorylation sites in insulin receptor substrate-1 by hypothesis-driven high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. Anal Chem 77(17):5693–5699. doi:10.1021/ac050760y
63. Kalkum M, Lyon GJ, Chait BT (2003) Detection of secreted peptides by using hypothesis-driven multistage mass spectrometry. Proc Natl Acad Sci USA 100(5):2795– 2800. doi:10.1073/pnas.0436605100
64. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10(9):909–915. doi:10.1038/nm1100
65. Robin C, Beckerich F, Cordonnier C (2015) Immunization in cancer patients: where we stand. Pharmacol Res Official J Ital Pharmacol Soc 92C:23–30. doi:10.1016/j.phrs.2014.10.002
66. Lindsey KR, Gritz L, Sherry R, Abati A, Fetsch PA, Goldfeder LC, Gonzales MI, Zinnack KA, Rogers-Freezer L, Haworth L, Mavroukakis SA, White DE, Steinberg SM, Restifo NP, Panicali DL, Rosenberg SA, Topalian SL (2006) Evaluation of prime/boost regimens using recombinant poxvirus/tyrosinase vaccines for the treatment of patients with metastatic melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 12(8):2526–2537. doi:10.1158/1078-0432.CCR-05-2061
67. Irvine KR, Chamberlain RS, Shulman EP, Surman DR, Rosenberg SA, Restifo NP (1997) Enhancing efficacy of recombinant anticancer vaccines with prime/boost regimens that use two different vectors. J Natl Cancer Inst 89(21):1595–1601
68. Kaufman HL, Kim DW, Kim-Schulze S, DeRaffele G, Jagoda MC, Broucek JR, Zloza A (2014) Results of a randomized phase I gene therapy clinical trial of nononcolytic fowlpox viruses encoding T cell costimulatory molecules. Hum Gene Ther 25(5):452–460. doi:10.1089/hum.2013.217
69. Pulido J, Kottke T, Thompson J, Galivo F, Wongthida P, Diaz RM, Rommelfanger D, Ilett E, Pease L, Pandha H, Harrington K, Selby P, Melcher A, Vile R (2012) Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat Biotechnol 30(4):337–343. doi:10.1038/nbt.2157
70. Adair RA, Roulstone V, Scott KJ, Morgan R, Nuovo GJ, Fuller M, Beirne D, West EJ, Jennings VA, Rose A, Kyula J, Fraser S, Dave R, Anthoney DA, Merrick A, Prestwich R, Aldouri A, Donnelly O, Pandha H, Coffey M, Selby P, Vile R, Toogood G, Harrington K, Melcher AA (2012) Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. Science Transl Med 4(138):138ra177
71. Durantez M, Lopez-Vazquez AB, de Cerio AL, Huarte E, Casares N, Prieto J, Borras-Cuesta F, Lasarte JJ, Sarobe P (2009) Induction of multiepitopic and long-lasting immune responses against tumour antigens by immunization with peptides, DNA and recombinant adenoviruses expressing minigenes. Scand J Immunol 69(2):80–89. doi:10.1111/j.1365-3083.2008.02202.x
72. Lizee G, Overwijk WW, Radvanyi L, Gao J, Sharma P, Hwu P (2013) Harnessing the power of the immune system to target cancer. Annu Rev Med 64:71–90. doi:10.1146/annurev-med-112311-083918
73. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392(6673):245–252. doi:10.1038/32588
74. Benteyn D, Heirman C, Bonehill A, Thielemans K, Breckpot K (2015) mRNA-based dendritic cell vaccines. Expert Rev Vaccines 14(2):161–176. doi:10.1586/14760584.2014.957684
75. Powell DJ Jr, Rosenberg SA (2004) Phenotypic and functional maturation of tumor antigen-reactive CD8+ T lymphocytes in patients undergoing multiple course peptide vaccination. J Immunother 27(1):36–47
76. Bettinotti MP, Panelli MC, Ruppe E, Mocellin S, Phan GQ, White DE, Marincola FM (2003) Clinical and immunological evaluation of patients with metastatic melanoma undergoing immunization with the HLA-Cw* 0702-associated epitope MAGE-A12:170-178. Int J Cancer J Int du Cancer 105(2):210–216. doi:10.1002/ijc.11045
77. Hailemichael Y, Overwijk WW (2013) Peptide-based anticancer vaccines: the making and unmaking of a T-cell graveyard. Oncoimmunology 2(7):e24743. doi:10.4161/onci.24743
78. Hailemichael Y, Dai Z, Jaffarzad N, Ye Y, Medina MA, Huang XF, Dorta-Estremera SM, Greeley NR, Nitti G, Peng W, Liu C, Lou Y, Wang Z, Ma W, Rabinovich B, Sowell RT, Schluns KS, Davis RE, Hwu P, Overwijk WW (2013) Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell sequestration, dysfunction and deletion. Nat Med 19 (4):465–472. doi:10.1038/nm.3105
79. Salerno EP, Shea SM, Olson WC, Petroni GR, Smolkin ME, McSkimming C, Chianese-Bullock KA, Slingluff CL Jr (2013) Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund’s adjuvant, with or without peptide. Cancer Immunol Immunother CII 62(7):1149–1159. doi:10.1007/s00262-013-1435-5
80. Bijker MS, van den Eeden SJ, Franken KL, Melief CJ, Offringa R, van der Burg SH (2007) CD8+ CTL priming by exact peptide epitopes in incomplete Freund’s adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J Immunol 179(8):5033–5040
81. van Poelgeest MI, Welters MJ, van Esch EM, Stynenbosch LF, Kerpershoek G, van Persijn van Meerten EL, van den Hende M, Lowik MJ, Berends-van derMeer DM, Fathers LM, Valentijn AR, Oostendorp J, Fleuren GJ, Melief CJ, Kenter GG, van der Burg SH (2013) HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial. J Transl Med 11:88. doi:10.1186/1479-5876-11-88
82. Steinman RM, Witmer-Pack M, Inaba K (1993) Dendritic cells: antigen presentation, accessory function and clinical relevance. Adv Exp Med Biol 329:1–9
83. Smith CM, Wilson NS, Waithman J, Villadangos JA, Carbone FR, Heath WR, Belz GT (2004) Cognate CD4(+) T cell licensing of dendritic cells in CD8(+) T cell immunity. Nat Immunol 5(11):1143–1148. doi:10.1038/ni1129
84. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5(10):987–995. doi:10.1038/ni1112
85. O’Sullivan B, Thomas R (2003) CD40 and dendritic cell function. Crit Rev Immunol 23(1–2): 83–107
86. Bullock TN, Yagita H (2005) Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. J Immunol 174(2):710–717
87. Van Deusen KE, Rajapakse R, Bullock TN (2010) CD70 expression by dendritic cells plays a critical role in the immunogenicity of CD40-independent, CD4+ T cell-dependent, licensed CD8+ T cell responses. J Leukoc Biol 87(3):477–485. doi:10.1189/jlb.0809535
88. Fehres CM, Bruijns SC, van Beelen AJ, Kalay H, Ambrosini M, Hooijberg E, Unger WW, de Gruijl TD, van Kooyk Y (2014) Topical rather than intradermal application of the TLR7 ligand imiquimod leads to human dermal dendritic cell maturation and CD8+ T-cell cross-priming. Eur J Immunol 44(8):2415–2424. doi:10.1002/eji.201344094
89. Rosalia RA, Cruz LJ, van Duikeren S, Tromp AT, Silva AL, Jiskoot W, de Gruijl T, Lowik C, Oostendorp J, van der Burg SH, Ossendorp F (2015) CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent anti-tumor responses. Biomaterials 40:88–97. doi:10.1016/j.biomaterials.2014.10.053
90. Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449 (7161):419–426. doi:10.1038/nature06175
91. Lou Y, Wang G, Lizee G, Kim GJ, Finkelstein SE, Feng C, Restifo NP, Hwu P (2004) Dendritic cells strongly boost the antitumor activity of adoptively transferred T cells in vivo. Cancer Res 64(18):6783–6790. doi:10.1158/0008-5472.CAN-04-1621
92. Yewdell JW, Norbury CC, Bennink JR (1999) Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: implications for generating CD8+ T cell responses to infectious agents, tumors, transplants, and vaccines. Adv Immunol 73:1–77
93. Keenan BP, Jaffee EM (2012) Whole cell vaccines–past progress and future strategies. Semin Oncol 39(3):276–286. doi:10.1053/j.seminoncol.2012.02.007
94. Yamada A, Sasada T, Noguchi M, Itoh K (2013) Next-generation peptide vaccines for advanced cancer. Cancer Sci 104(1):15–21. doi:10.1111/cas.12050
95. Melief CJ (2008) Cancer immunotherapy by dendritic cells. Immunity 29(3):372–383. doi:10.1016/j.immuni.2008.08.004
96. Thurner B, Haendle I, Roder C, Dieckmann D, Keikavoussi P, Jonuleit H, Bender A, Maczek C, Schreiner D, von den Driesch P, Brocker EB, Steinman RM, Enk A, Kampgen E, Schuler G (1999) Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190(11):1669–1678
97. Nestle FO, Farkas A, Conrad C (2005) Dendritic-cell-based therapeutic vaccination against cancer. Curr Opin Immunol 17(2):163–169. doi:10.1016/j.coi.2005.02.003
98. Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12(4):269–281. doi:10.1038/nri3191
99. Chandran SS, Paria BC, Srivastava AK, Rothermel LD, Stephens DJ, Dudley ME, Somerville RP, Wunderlich JR, Sherry RM, Yang JC, Rosenberg SA, Kammula US (2014) Persistence of CTL clones targeting melanocyte differentiation antigens was insufficient to mediate significant melanoma regression in humans. Clin Cancer Res Official J Am Assoc Cancer Res. doi:10.1158/1078-0432.CCR-14-2208
100. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, Schwartzentruber DJ, Hwu P, Marincola FM, Sherry R, Leitman SF, Rosenberg SA (2001) Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 24(4):363–373
101. Dudley ME, Wunderlich JR, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry RM, Marincola FM, Leitman SF, Seipp CA, Rogers-Freezer L, Morton KE, Nahvi A, Mavroukakis SA, White DE, Rosenberg SA (2002) A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother 25(3):243–251
102. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99(25):16168–16173. doi:10.1073/pnas.242600099
103. Khammari A, Labarriere N, Vignard V, Nguyen JM, Pandolfino MC, Knol AC, Quereux G, Saiagh S, Brocard A, Jotereau F, Dreno B (2009) Treatment of metastatic melanoma with autologous Melan-A/MART-1-specific cytotoxic T lymphocyte clones. J Invest Dermatol 129(12):2835–2842. doi:10.1038/jid.2009.144
104. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358(25):2698–2703. doi:10.1056/NEJMoa0800251
105. Pollack SM, Jones RL, Farrar EA, Lai IP, Lee SM, Cao J, Pillarisetty VG, Hoch BL, Gullett A, Bleakley M, Conrad EU 3rd, Eary JF, Shibuya KC, Warren EH, Carstens JN, Heimfeld S, Riddell SR, Yee C (2014) Tetramer guided, cell sorter assisted production of clinical grade autologous NY-ESO-1 specific CD8(+) T cells. J Immunother Cancer 2(1):36. doi:10.1186/s40425-014-0036-y
106. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515(7528):577–581. doi:10.1038/nature13988
107. Robbins PF, El-Gamil M, Li YF, Kawakami Y, Loftus D, Appella E, Rosenberg SA (1996) A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med 183(3):1185–1192
108. Pieper R, Christian RE, Gonzales MI, Nishimura MI, Gupta G, Settlage RE, Shabanowitz J, Rosenberg SA, Hunt DF, Topalian SL (1999) Biochemical identification of a mutated human melanoma antigen recognized by CD4(+) T cells. J Exp Med 189(5):757–766
109. Huang J, El-Gamil M, Dudley ME, Li YF, Rosenberg SA, Robbins PF (2004) T cells associated with tumor regression recognize frameshifted products of the CDKN2A tumor suppressor gene locus and a mutated HLA class I gene product. J Immunol 172(10):6057–6064
110. Lu YC, Yao X, Li YF, El-Gamil M, Dudley ME, Yang JC, Almeida JR, Douek DC, Samuels Y, Rosenberg SA, Robbins PF (2013) Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J Immunol 190(12):6034–6042. doi:10.4049/jimmunol.1202830
111. Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233(4770):1318–1321
112. Topalian SL, Muul LM, Solomon D, Rosenberg SA (1987) Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials. J Immunol Methods 102(1):127–141
113. Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Yang JC, Topalian SL et al (1990) Gene transfer into humans–immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 323(9):570–578. doi:10.1056/NEJM199008303230904
114. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA et al (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319(25):1676–1680. doi:10.1056/NEJM198812223192527
115. Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, Levy D, Kubi A, Hovav E, Chermoshniuk N, Shalmon B, Hardan I, Catane R, Markel G, Apter S, Ben-Nun A, Kuchuk I, Shimoni A, Nagler A, Schachter J (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res Official J Am Assoc Cancer Res 16(9): 2646–2655. doi:10.1158/1078-0432.CCR-10-0041
116. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850–854. doi:10.1126/science.1076514
117. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol Official J Am Soc Clin Oncol 23(10):2346–2357. doi:10.1200/JCO.2005.00.240
118. Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, Wu R, Lizee G, Mahoney S, Alvarado G, Glass M, Johnson VE, McMannis JD, Shpall E, Prieto V, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Patel S, Ross MI, Lee JE, Gershenwald JE, Lucci A, Royal R, Cormier JN, Davies MA, Mansaray R, Fulbright OJ, Toth C, Ramachandran R, Wardell S, Gonzalez A, Hwu P (2012) Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res Official J Am Assoc Cancer Res 18(24):6758–6770. doi:10.1158/1078-0432.CCR-12-1177
119. Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, Kudchadkar R, Zager J, Gibney G, Sondak VK, Weber J, Mule JJ, Sarnaik AA (2012) Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother 35(8):615–620. doi:10.1097/CJI.0b013e31826e8f5f
120. Ellebaek E, Iversen TZ, Junker N, Donia M, Engell-Noerregaard L, Met O, Holmich LR, Andersen RS, Hadrup SR, Andersen MH, thor Straten P, Svane IM (2012) Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J Transl Med 10:169. doi:10.1186/1479-5876-10-169
121. Ullenhag GJ, Sadeghi AM, Carlsson B, Ahlstrom H, Mosavi F, Wagenius G, Totterman TH (2012) Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy. Cancer Immunol Immunother CII 61(5):725–732. doi:10.1007/s00262-011-1182-4
122. Sherwood AM, Emerson RO, Scherer D, Habermann N, Buck K, Staffa J, Desmarais C, Halama N, Jaeger D, Schirmacher P, Herpel E, Kloor M, Ulrich A, Schneider M, Ulrich CM, Robins H (2013) Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer Immunol Immunother CII 62(9):1453–1461. doi:10.1007/s00262-013-1446-2
123. Kvistborg P, Shu CJ, Heemskerk B, Fankhauser M, Thrue CA, Toebes M, van Rooij N, Linnemann C, van Buuren MM, Urbanus JH, Beltman JB, Thor Straten P, Li YF, Robbins PF, Besser MJ, Schachter J, Kenter GG, Dudley ME, Rosenberg SA, Haanen JB, Hadrup SR, Schumacher TN (2012) TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients. Oncoimmunology 1(4):409–418
124. Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M, Gross C, Davis L, Dudley ME, Yang JC, Samuels Y, Rosenberg SA, Robbins PF (2014) Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res Official J Am Assoc Cancer Res 20(13):3401–3410. doi:10.1158/1078-0432.CCR-14-0433
125. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA (2014) Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344(6184):641–645. doi:10.1126/science.1251102
126. Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel DB, Levy D, Kubi A, Shoshani N, Zikich D, Ohayon Y, Ohayon D, Shalmon B, Markel G, Yerushalmi R, Apter S, Ben-Nun A, Ben-Ami E, Shimoni A, Nagler A, Schachter J (2013) Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res Official J Am Assoc Cancer Res 19(17):4792–4800. doi:10.1158/1078-0432.CCR-13-0380
127. Dudley ME, Gross CA, Langhan MM, Garcia MR, Sherry RM, Yang JC, Phan GQ, Kammula US, Hughes MS, Citrin DE, Restifo NP, Wunderlich JR, Prieto PA, Hong JJ, Langan RC, Zlott DA, Morton KE, White DE, Laurencot CM, Rosenberg SA (2010) CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clinical Cancer Res Official J Am Assoc Cancer Res 16(24):6122–6131. doi:10.1158/1078-0432.CCR-10-1297
128. Dudley ME, Gross CA, Somerville RP, Hong Y, Schaub NP, Rosati SF, White DE, Nathan D, Restifo NP, Steinberg SM, Wunderlich JR, Kammula US, Sherry RM, Yang JC, Phan GQ, Hughes MS, Laurencot CM, Rosenberg SA (2013) Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol Official J Am Soc Clin Oncol 31(17):2152–2159. doi:10.1200/JCO.2012.46.6441
129. Church SE, Jensen SM, Antony PA, Restifo NP, Fox BA (2014) Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells. Eur J Immunol 44(1):69– 79. doi:10.1002/eji.201343718
130. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP (2011) A human memory T cell subset with stem cell-like properties. Nat Med 17(10):1290–1297. doi:10.1038/nm.2446
131. Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, Bondanza A, Bordignon C, Peccatori J, Ciceri F, Lupo-Stanghellini MT, Mavilio F, Mondino A, Bicciato S, Recchia A, Bonini C (2013) IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 121(4):573–584. doi:10.1182/blood-2012-05-431718
132. Crompton JG, Sukumar M, Roychoudhuri R, Clever D, Gros A, Eil RL, Tran E, Hanada K, Yu Z, Palmer DC, Kerkar SP, Michalek RD, Upham T, Leonardi A, Acquavella N, Wang E, Marincola FM, Gattinoni L, Muranski P, Sundrud MS, Klebanoff CA, Rosenberg SA, Fearon DT, Restifo NP (2015) Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res 75(2):296–305. doi:10.1158/0008-5472.CAN-14-2277
133. Forget MA, Huon Y, Reuben A, Grange C, Liberman M, Martin J, Mes-Masson AM, Arbour N, Lapointe R (2012) Stimulation of Wnt/ss-catenin pathway in human CD8+ T lymphocytes from blood and lung tumors leads to a shared young/memory phenotype. PLoS ONE 7(7):e41074. doi:10.1371/journal.pone.0041074
134. Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Garvin LM, Paulos CM, Muranski P, Restifo NP (2009) Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15(7):808– 813. doi:10.1038/nm.1982
135. Cara L Haymaker, Richard C Wu, Ritthipichai K, Bernatchez C, Forget MA, Chen JQ, Liu H, Wang E, Marincola F, Hwu P, Radvanyi LG (2015) BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties. OncoImmunology, Vol. 4(8), doi:10.1080/2162402X.2015.1014246
136. Chacon J, Sarnaik A, Chen J, Creasy C, Kale C, Robinson J, Weber J, Hwu P, Pilon-Thomas S, Radvanyi LG (2014) Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. Clinical Cancer Res Official J Am Assoc Cancer Res. doi:10.1158/1078-0432.CCR-14-1934
137. Donia M, Larsen SM, Met O, Svane IM (2014) Simplified protocol for clinical-grade tumor-infiltrating lymphocyte manufacturing with use of the Wave bioreactor. Cytotherapy 16(8):1117–1120. doi:10.1016/j.jcyt.2014.02.004
138. Jin J, Sabatino M, Somerville R, Wilson JR, Dudley ME, Stroncek DF, Rosenberg SA (2012) Simplified method of the growth of human tumor infiltrating lymphocytes in gas-permeable flasks to numbers needed for patient treatment. J Immunother 35(3):283–292. doi:10.1097/CJI.0b013e31824e801f
139. Somerville RP, Devillier L, Parkhurst MR, Rosenberg SA, Dudley ME (2012) Clinical scale rapid expansion of lymphocytes for adoptive cell transfer therapy in the WAVE(R) bioreactor. J Transl Med 10:69. doi:10.1186/1479-5876-10-69
140. Friedman KM, Devillier LE, Feldman SA, Rosenberg SA, Dudley ME (2011) Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement. J Immunother 34(9):651–661. doi:10.1097/CJI.0b013e31823284c3
141. Turcotte S, Gros A, Hogan K, Tran E, Hinrichs CS, Wunderlich JR, Dudley ME, Rosenberg SA (2013) Phenotype and function of T cells infiltrating visceral metastases from gastrointestinal cancers and melanoma: implications for adoptive cell transfer therapy. J Immunol 191(5):2217–2225. doi:10.4049/jimmunol.1300538
142. Ye Q, Loisiou M, Levine BL, Suhoski MM, Riley JL, June CH, Coukos G, Powell DJ Jr (2011) Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes. J Transl Med 9:131. doi:10.1186/1479-5876-9-131
143. Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K (1995) Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res Official J Am Assoc Cancer Res 1(5):501–507
144. deLeeuw RJ, Kroeger DR, Kost SE, Chang PP, Webb JR, Nelson BH (2015) CD25 identifies a subset of CD4+ FoxP3- TIL that are exhausted yet prognostically favorable in human ovarian cancer. Cancer Immunol Res 3(3):245–253. doi:10.1158/2326-6066.CIR-14-0146
145. Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, Royal RE, Sherry RM, Wunderlich JR, Lee CC, Restifo NP, Schwarz SL, Cogdill AP, Bishop RJ, Kim H, Brewer CC, Rudy SF, VanWaes C, Davis JL, Mathur A, Ripley RT, Nathan DA, Laurencot CM, Rosenberg SA (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3):535–546. doi:10.1182/blood-2009-03-211714
146. Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM, Hughes MS, Kammula US, Phan GQ, Lim RM, Wank SA, Restifo NP, Robbins PF, Laurencot CM, Rosenberg SA (2011) T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther J Am Soc Gene Ther 19(3):620–626. doi:10.1038/mt.2010.272
147. Chinnasamy N, Wargo JA, Yu Z, Rao M, Frankel TL, Riley JP, Hong JJ, Parkhurst MR, Feldman SA, Schrump DS, Restifo NP, Robbins PF, Rosenberg SA, Morgan RA (2011) A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J Immunol 186 (2):685–696. doi:10.4049/jimmunol.1001775
148. Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, Litzky L, Bagg A, Carreno BM, Cimino PJ, Binder-Scholl GK, Smethurst DP, Gerry AB, Pumphrey NJ, Bennett AD, Brewer JE, Dukes J, Harper J, Tayton-Martin HK, Jakobsen BK, Hassan NJ, Kalos M, June CH (2013) Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122(6):863– 871. doi:10.1182/blood-2013-03-490565
149. Wooldridge L, Ekeruche-Makinde J, van den Berg HA, Skowera A, Miles JJ, Tan MP, Dolton G, Clement M, Llewellyn-Lacey S, Price DA, Peakman M, Sewell AK (2012) A single autoimmune T cell receptor recognizes more than a million different peptides. J Biol Chem 287(2):1168–1177. doi:10.1074/jbc.M111.289488
150. Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, Feldman SA, Yang JC, Dudly ME, Wunderlich JR, Sherry RM, Kammula US, Hughes MS, Restifo NP, Raffeld M Lee CR, Li YF, El-Gamil M, Rosenberg SA (2014) A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: long term follow up and correlates with response. Clin Cancer Res Official J Am Assoc Cancer Res. doi:10.1158/1078-0432.CCR-14-2708
151. Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R, Rosenberg SA, Eshhar Z (1993) Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J Exp Med 178(1):361–366
152. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res Official J Am Assoc Cancer Res 12(20 Pt 1):6106–6115. doi:10.1158/1078-0432.CCR-06-1183
153. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M (2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5(177):177ra138. doi:10.1126/scitranslmed.3005930
154. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6(224):224ra225. doi:10.1126/scitranslmed.3008226
155. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3(95):95ra73. doi:10.1126/scitranslmed.3002842
156. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL (2014) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. doi:10.1016/S0140-6736(14)61403-3
157. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517. doi:10.1056/NEJMoa1407222
158. Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, Rossig C, Russell HV, Diouf O, Liu E, Liu H, Wu MF, Gee AP, Mei Z, Rooney CM, Heslop HE, Brenner MK (2011) Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118(23):6050–6056. doi:10.1182/blood-2011-05-354449
159. Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM, Kalos M, June CH (2014) Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2(2):112–120. doi:10.1158/2326-6066.CIR-13-0170
160. Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH (2013) T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 1(1):26–31. doi:10.1158/2326-6066.CIR-13-0006
161. Maude SL, Barrett D, Teachey DT, Grupp SA (2014) Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20(2):119–122. doi:10.1097/PPO.0000000000000035
162. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther J Am Soc Gene Ther 18(4):843– 851. doi:10.1038/mt.2010.24
163. Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M(2010) Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther J Am Soc Gene Ther 18(4):666–668. doi:10.1038/mt.2010.31
164. Beard RE, Zheng Z, Lagisetty KH, Burns WR, Tran E, Hewitt SM, Abate-Daga D, Rosati SF, Fine HA, Ferrone S, Rosenberg SA, Morgan RA (2014) Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells. J Immunother Cancer 2:25. doi:10.1186/2051-1426-2-25
165. Burns WR, Zhao Y, Frankel TL, Hinrichs CS, Zheng Z, Xu H, Feldman SA, Ferrone S, Rosenberg SA, Morgan RA (2010) A high molecular weight melanoma-associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas. Cancer Res 70(8):3027–3033. doi:10.1158/0008-5472.CAN-09-2824
166. Heemskerk B, Liu K, Dudley ME, Johnson LA, Kaiser A, Downey S, Zheng Z, Shelton TE, Matsuda K, Robbins PF, Morgan RA, Rosenberg SA (2008) Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther 19(5):496–510. doi:10.1089/hum.2007.0171
167. Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z, Palmer DC, Reger RN, Borman ZA, Zhang L, Morgan RA, Gattinoni L, Rosenberg SA, Trinchieri G, Restifo NP (2010) Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res 70(17):6725–6734. doi:10.1158/0008-5472.CAN-10-0735
168. Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF, Sadelain M, Brentjens RJ (2012) Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119(18):4133–4141. doi:10.1182/blood-2011-12-400044
169. Zhang L, Morgan RA, Beane JD, Zheng Z, Dudley ME, Kassim SH, Nahvi AV, Ngo LT, Sherry RM, Phan GQ, Hughes MS, Kammula US, Feldman SA, Toomey MA, Kerkar SP, Restifo NP, Yang JC, Rosenberg SA (2015) Tumor Infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res Official J Am Assoc Cancer Res. doi:10.1158/1078-0432.CCR-14-2085
170. Foster AE, Dotti G, Lu A, Khalil M, Brenner MK, Heslop HE, Rooney CM, Bollard CM(2008) Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor. J Immunother 31(5):500–505. doi:10.1097/CJI.0b013e318177092b
171. Zhang L, Yu Z, Muranski P, Palmer DC, Restifo NP, Rosenberg SA, Morgan RA (2013) Inhibition of TGF-beta signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther 20(5):575–580. doi:10.1038/gt.2012.75
172. Kershaw MH, Wang G, Westwood JA, Pachynski RK, Tiffany HL, Marincola FM, Wang E, Young HA, Murphy PM, Hwu P (2002) Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum Gene Ther 13(16): 1971–1980. doi:10.1089/10430340260355374
173. Sapoznik S, Ortenberg R, Galore-Haskel G, Kozlovski S, Levy D, Avivi C, Barshack I, Cohen CJ, Besser MJ, Schachter J, Markel G (2012) CXCR1 as a novel target for directing reactive T cells toward melanoma: implications for adoptive cell transfer immunotherapy. Cancer Immunol Immunother CII 61(10):1833–1847. doi:10.1007/s00262-012-1245-1
174. Peng W, Ye Y, Rabinovich BA, Liu C, Lou Y, Zhang M, Whittington M, Yang Y, Overwijk WW, Lizee G, Hwu P (2010) Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin Cancer Res Official J Am Assoc Cancer Res 16(22):5458–5468. doi:10.1158/1078-0432.CCR-10-0712
175. Ji Y, Wrzesinski C, Yu Z, Hu J, Gautam S, Hawk NV, Telford WG, Palmer DC, Franco Z, Sukumar M, Roychoudhuri R, Clever D, Klebanoff CA, Surh CD, Waldmann TA, Restifo NP, Gattinoni L (2015) miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic gammac cytokines. Proc Natl Acad Sci USA 112(2):476–481. doi:10.1073/pnas.1422916112
176. Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizee G, Radvanyi L, Hwu P (2012) PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res 72(20):5209–5218. doi:10.1158/0008-5472.CAN-12-1187
177. Liu C, Peng W, Xu C, Lou Y, Zhang M, Wargo JA, Chen JQ, Li HS, Watowich SS, Yang Y, Tompers Frederick D, Cooper ZA, Mbofung RM, Whittington M, Flaherty KT, Woodman SE, Davies MA, Radvanyi LG, Overwijk WW, Lizee G, Hwu P (2013) BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res Official J Am Assoc Cancer Res 19(2):393–403. doi:10.1158/1078-0432.CCR-12-1626
178. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263. doi:10.1016/j.cell.2012.06.024
179. Holderfield M, Deuker MM, McCormick F, McMahon M (2014) Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 14(7):455–467. doi:10.1038/nrc3760
180. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819. doi:10.1056/NEJMoa1002011
181. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516. doi:10.1056/NEJMoa1103782
182. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martin-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365. doi:10.1016/S0140-6736(12)60868-X
183. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi:10.1056/NEJMoa1200690
184. Sullivan RJ, Flaherty KT (2013) Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer 49(6):1297–1304. doi:10.1016/j.ejca.2012.11.019
185. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703. doi:10.1056/NEJMoa1210093
186. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi:10.1056/NEJMoa1200694
187. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma.NEngl J Med 363(8):711–723. doi:10.1056/NEJMoa1003466
188. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol Official J Am Soc Clin Oncol 32(10):1020–1030. doi:10.1200/JCO.2013.53.0105
189. Sumimoto H, Imabayashi F, Iwata T, Kawakami Y (2006) The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203 (7):1651–1656. doi:10.1084/jem.20051848
190. Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM, Ferrone CR, Flaherty KT, Lawrence DP, Fisher DE, Tsao H, Wargo JA (2010) Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 70(13):5213–5219. doi:10.1158/0008-5472.CAN-10-0118
191. Cooper ZA, Frederick DT, Juneja VR, Sullivan RJ, Lawrence DP, Piris A, Sharpe AH, Fisher DE, Flaherty KT, Wargo JA (2013) BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology 2(10):e26615. doi:10.4161/onci.26615
192. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, Newton LP, Liu C, Peng W, Sullivan RJ, Lawrence DP, Hodi FS, Overwijk WW, Lizee G, Murphy GF, Hwu P, Flaherty KT, Fisher DE, Wargo JA (2013) BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 19(5):1225–1231. doi:10.1158/1078-0432.CCR-12-1630
193. Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, Kefford RF, Hersey P, Scolyer RA (2012) Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 18 (5):1386–1394. doi:10.1158/1078-0432.CCR-11-2479
194. Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, Zhang M, Cooper ZA, Frederick DT, Li Y, Zhang M, Joseph RW, Bernatchez C, Ekmekcioglu S, Grimm E, Radvanyi LG, Davis RE, Davies MA, Wargo JA, Hwu P, Lizee G (2012) Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 18 (19):5329–5340. doi:10.1158/1078-0432.CCR-12-1632
195. Jiang X, Zhou J, Giobbie-Hurder A, Wargo J, Hodi FS (2013) The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res Official J Am Assoc Cancer Res 19(3):598–609. doi:10.1158/1078-0432.CCR-12-2731
196. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5(200):200ra116. doi:10.1126/scitranslmed.3006504
197. Cooper ZA, Juneja VR, Sage PT, Frederick DT, Piris A, Mitra D, Lo JA, Hodi FS, Freeman GJ, Bosenberg MW, McMahon M, Flaherty KT, Fisher DE, Sharpe AH, Wargo JA (2014) Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol Res 2(7):643–654. doi:10.1158/2326-6066.CIR-13-0215
198. Koya RC, Mok S, Otte N, Blacketor KJ, Comin-Anduix B, Tumeh PC, Minasyan A, Graham NA, Graeber TG, Chodon T, Ribas A (2012) BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res 72(16):3928–3937. doi:10.1158/0008-5472.CAN-11-2837
199. Hooijkaas A, Gadiot J, Morrow M, Stewart R, Schumacher T, Blank CU (2012) Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma. Oncoimmunology 1(5):609–617. doi:10.4161/onci.20226
200. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J (2013) Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 368(14):1365–1366. doi:10.1056/NEJMc1302338
201. Puzanov I, Callahan M, Linette GP, Patel S, Luke J, Sosman JA, Wolchok J, Hamid O, Minor D, Orford K, Hug B, Ma B, Matthys G, Hoos A (2014) Phase I study of the BRAF inhibitor dabrafenib (D)± the MEK inhibitor trametinib (T) in combination with ipilimumab (I) for V600E/K mutation-positive unresectable or metastatic melanoma (MM). In: 2014 ASCO Annual Meeting
202. Vella LJ, Pasam A, Dimopoulos N, Andrews M, Knights A, Puaux AL, Louahed J, Chen W, Woods K, Cebon JS (2014) MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells. Cancer Immunol Res 2(4):351–360. doi:10.1158/2326-6066.CIR-13-0181
203. Shindo T, Kim TK, Benjamin CL, Wieder ED, Levy RB, Komanduri KV (2013) MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner. Blood 121(23):4617–4626. doi:10.1182/blood-2012-12-476218
204. Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, Yang J, Seestaller-Wehr L, Zhang SY, Hopson C, Tsvetkov L, Jing J, Zhang S, Smothers J, Hoos A (2015) The BRAF and MEK Inhibitors Dabrafenib and Trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD1, PD-L1 and CTLA-4. Clin Cancer Res Official J Am Assoc Cancer Res. doi:10.1158/1078-0432.CCR-14-2339
205. Basile KJ, Le K, Hartsough EJ, Aplin AE (2014) Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res 27 (3):479–484. doi:10.1111/pcmr.12218
206. Wong DJ, Robert L, Atefi MS, Lassen A, Avarappatt G, Cerniglia M, Avramis E, Tsoi J, Foulad D, Graeber TG, Comin-Anduix B, Samatar A, Lo RS, Ribas A (2014) Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma. Mol Cancer 13:194. doi:10.1186/1476-4598-13-194
207. Shtivelman E, Davies MQ, Hwu P, Yang J, Lotem M, Oren M, Flaherty KT, Fisher DE (2014) Pathways and therapeutic targets in melanoma. Oncotarget 5(7):1701–1752
208. Maertens O, Johnson B, Hollstein P, Frederick DT, Cooper ZA, Messiaen L, Bronson RT, McMahon M, Granter S, Flaherty K, Wargo JA, Marais R, Cichowski K (2013) Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov. doi:10.1158/2159-8290.CD-12-0313
209. Whittaker SR, Theurillat JP, Van Allen E, Wagle N, Hsiao J, Cowley GS, Schadendorf D, Root DE, Garraway LA (2013) A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov 3(3):350–362. doi:10.1158/2159-8290.CD-12-0470
210. Kwong LN, Davies MA (2013) Navigating the therapeutic complexity of PI3K pathway inhibition in melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 19(19): 5310–5319. doi:10.1158/1078-0432.CCR-13-0142
211. Deng W, Gopal YN, Scott A, Chen G, Woodman SE, Davies MA (2012) Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res 25(2):248–258. doi:10.1111/j.1755-148X.2011.00950.x
212. Aziz SA, Jilaveanu LB, Zito C, Camp RL, Rimm DL, Conrad P, Kluger HM (2010) Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 16(24):6029–6039. doi:10.1158/1078-0432.CCR-10-1490
213. Marsh Durban V, Deuker MM, Bosenberg MW, Phillips W, McMahon M (2013) Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma. J Clin Investig 123(12):5104–5118. doi:10.1172/JCI69619
214. Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, Stegmeier F, Yao YM, Lengauer C (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA 105(35):13057–13062. doi:10.1073/pnas.0802655105
215. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454(7205):776–779. doi:10.1038/nature07091
216. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353(20):2135–2147. doi:10.1056/NEJMoa050092
217. Sheppard KE, McArthur GA (2013) The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res Official J Am Assoc Cancer Res 19(19):5320–5328. doi:10.1158/1078-0432.CCR-13-0259
218. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P, Neuberg DS, Martin P, Millenson MM, Ely SA, Courtney R, Shaik N, Wilner KD, Randolph S, Van den Abbeele AD, Chen-Kiang SY, Yap JT, Shapiro GI (2012) Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119(20):4597–4607. doi:10.1182/blood-2011-10-388298
219. Joshi KS, Rathos MJ, Mahajan P, Wagh V, Shenoy S, Bhatia D, Chile S, Sivakumar M, Maier A, Fiebig HH, Sharma S (2007) P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol Cancer Ther 6(3):926–934. doi:10.1158/1535-7163.MCT-06-0614
220. Joshi KS, Rathos MJ, Joshi RD, Sivakumar M, Mascarenhas M, Kamble S, Lal B, Sharma S (2007) In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol Cancer Ther 6(3):918–925. doi:10.1158/1535-7163.MCT-06-0613
221. Tate SC, Cai S, Ajamie RT, Burke T, Beckmann RP, Chan EM, De Dios A, Wishart GN, Gelbert LM, Cronier DM (2014) Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res Official J Am Assoc Cancer Res 20(14):3763–3774. doi:10.1158/1078-0432.CCR-13-2846
222. Dickson MA (2014) Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res Official J Am Assoc Cancer Res 20(13):3379–3383. doi:10.1158/1078-0432.CCR-13-1551
223. Yadav V, Chen SH, Yue YG, Buchanan S, Beckmann RP, Peng SB (2014) Co-targeting BRAF and cyclin dependent kinases 4/6 for BRAF mutant cancers. Pharmacol Ther. doi:10.1016/j.pharmthera.2014.12.003
224. Yadav V, Burke TF, Huber L, Van Horn RD, Zhang Y, Buchanan SG, Chan EM, Starling JJ, Beckmann RP, Peng SB (2014) The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol Cancer Ther 13(10):2253–2263. doi:10.1158/1535-7163.MCT-14-0257
225. Lai F, Jin L, Gallagher S, Mijatov B, Zhang XD, Hersey P (2012) Histone deacetylases (HDACs) as mediators of resistance to apoptosis in melanoma and as targets for combination therapy with selective BRAF inhibitors. Adv Pharmacol 65:27–43. doi:10.1016/B978-0-12-397927-8.00002-6
226. Lai F, Guo ST, Jin L, Jiang CC, Wang CY, Croft A, Chi MN, Tseng HY, Farrelly M, Atmadibrata B, Norman J, Liu T, Hersey P, Zhang XD (2013) Cotargeting histone deacetylases and oncogenic BRAF synergistically kills human melanoma cells by necrosis independently of RIPK1 and RIPK3. Cell Death Dis 4:e655. doi:10.1038/cddis.2013.192
227. Johannessen CM, Johnson LA, Piccioni F, Townes A, Frederick DT, Donahue MK, Narayan R, Flaherty KT, Wargo JA, Root DE, Garraway LA (2013) A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504(7478):138–142. doi:10.1038/nature12688
228. Smyth T, Paraiso KH, Hearn K, Rodriguez-Lopez AM, Munck JM, Haarberg HE, Sondak VK, Thompson NT, Azab M, Lyons JF, Smalley KS, Wallis NG (2014) Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in melanoma models. Mol Cancer Ther 13 (12):2793–2804. doi:10.1158/1535-7163.MCT-14-0452
229. Paraiso KH, Haarberg HE, Wood E, Rebecca VW, Chen YA, Xiang Y, Ribas A, Lo RS, Weber JS, Sondak VK, John JK, Sarnaik AA, Koomen JM, Smalley KS (2012) The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res Official J Am Assoc Cancer Res 18(9):2502–2514. doi:10.1158/1078-0432.CCR-11-2612
230. Haarberg HE, Paraiso KH, Wood E, Rebecca VW, Sondak VK, Koomen JM, Smalley KS (2013) Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma. Mol Cancer Ther 12(6):901–912. doi:10.1158/1535-7163.MCT-12-1003
231. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. doi:10.1038/nrc3239