Abstract
While the use of genomic data has the potential to revolutionize patient care, there is still much work to be done with regard to the transformation of host-tumor interactions into favorable clinical outcomes for our patients. High-throughput technologies, such as next-generation sequencing (NGS), have rapidly advanced our understanding of oncology, and we are learning that most tumors do not simply possess consistently mutated genes that are responsible for tumorigenesis, facilitating the need for personalized cancer therapy. A T cell-dependent mechanism of cancer progression was discovered in 2012, providing a potential link to cancer immunotherapy. Since then, an antibody against cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), ipilimumab, and three programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq), were approved by the Food and Drug Administration (FDA) in the USA. In this review article, based on evidence that has been emerging in the literature over the last decade, we will discuss the basis for including genomic data in immunotherapy regimens, the current progress in identifying biomarkers targetable by immune checkpoint blockade, and the application of these therapies in modern oncology programs. Going forward, the clinical application of NGS in personalized oncology programs could include dose monitoring and adjustment or the development of individualized vaccines or other personalized therapies based on the mutational landscape. The continued identification of new neoantigens and the efficient mobilization of tumor-reactive lymphocytes in patients with cancer will promote the advancement of immunotherapy using personalized NGS-guided technologies.
Similar content being viewed by others
References
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319
Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J, Snyder ES, Ricart AD,Balakumaran A, Rose S, Moskowitz CH (2016) Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 34:3733–3739
Batlevi CL, Matsuki E, Brentjens RJ, Younes A (2016) Novel immunotherapies in lymphoid malignancies Nature reviews. Clin Oncol 13:25–40
Berman DM, Wolchok J, Weber J, Hamid O, O’Day S, Chasalow SD (2009) Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol 27:3020
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced Nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639
Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL (2010) 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
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 366:2455–2465
Bretscher P (1992) The two-signal model of lymphocyte activation twenty-one years later. Immunol Today 13:74–76
Budczies J, Bockmayr M, Denkert C, Klauschen F, Groschel S, Darb-Esfahani S, Pfarr N, Leichsenring J, Onozato ML, Lennerz JK, Dietel M, Frohling S, Schirmacher P, Iafrate AJ, Weichert W, Stenzinger A (2016) Pan-Cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival. Genes Chromosomes Cancer 55:626–639
Chen J, Feng Y, Lu L, Wang H, Dai L, Li Y, Zhang P (2012) Interferon-gamma-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. Immunobiology 217:385–393
Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, Zhang Y, He X, Zhou T, Qin T, Huang Y, Yi X, Zhang L (2015) Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol 10:910–923
Chen Y, McGee J, Chen X, Doman TN, Gong X, Zhang Y, Hamm N, Ma X, Higgs RE, Bhagwat SV, Buchanan S, Peng S-B, Staschke KA, Yadav V, Yue Y, Kouros-Mehr H (2014) Identification of Druggable cancer driver genes amplified across TCGA datasets. PLoS One 9:e98293
Clifton GT, Mittendorf EA, Peoples GE (2015) Adjuvant HER2/neu peptide cancer vaccines in breast cancer. Immunotherapy 7:1159–1168
Cohen CJ, Gartner JJ, Horovitz-Fried M, Shamalov K, Trebska-McGowan K, Bliskovsky VV, Parkhurst MR, Ankri C, Prickett TD, Crystal JS, Li YF, El-Gamil M, Rosenberg SA, Robbins PF (2015) Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest 125:3981–3991
Collins FS, Varmus H (2015) A new initiative on precision medicine. N Engl J Med 372:793–795
Damle NK, Doyle LV, Grosmaire LS, Ledbetter JA (1988) Differential regulatory signals delivered by antibody binding to the CD28 (Tp44) molecule during the activation of human T lymphocytes. J Immunol 140:1753–1761
Dronca RS, Liu X, Harrington SM, Chen L, Cao S, Kottschade LA, McWilliams RR, Block MS, NevalaWK, Thompson MA, Mansfield AS, Park SS, Markovic SN, Dong H (2016) T cell Bim levels reflect responses to anti-PD-1 cancer therapy. JCI Insight 1:e86014
Gajewski TF (2012) Cancer immunotherapy. Mol Oncol 6:242–250
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (New York, NY) 313:1960–1964
Gandini S, Massi D, Mandala M (2016) PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol 100:88–98
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028
Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, Gerber DE, Shepherd FA, Antonia S, Goldman JW, Juergens RA, Laurie SA, Nathan FE, Shen Y, Harbison CT, Hellmann MD (2016) Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34:2980–2987
Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A, Ajarim D, Al-Tweigeri T, Dermime S (2006) The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 8:190–198
Greene JM, Schneble EJ, Jackson DO, Hale DF, Vreeland TJ, Flores M, Martin J, Herbert GS, Hardin MO, Yu X, Wagner TE, Peoples GE (2016) A phase I/IIa clinical trial in stage IV melanoma of an autologous tumor-dendritic cell fusion (dendritoma) vaccine with low dose interleukin-2. Cancer Immunol Immunother 65:383–392
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 515:577–581
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 104:3360–3365
Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gomez H, Bastholt L, Chasalow SD, Berman D (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204
Hannani D, Vetizou M, Enot D, Rusakiewicz S, Chaput N, Klatzmann D, Desbois M, Jacquelot N, Vimond N, Chouaib S, Mateus C, Allison JP, Ribas A, Wolchok JD, Yuan J, Wong P, Postow M, Mackiewicz A, Mackiewicz J, Schadendorff D, Jaeger D, Zornig I, Hassel J, Korman AJ, Bahjat K, Maio M, Calabro L, Teng MW, Smyth MJ, Eggermont A, Robert C, Kroemer G, Zitvogel L (2015) Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res 25:208–224
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–567
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116:1757–1766
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. N Engl J Med 363:711–723
Hoos A, Ibrahim R, Korman A, Abdallah K, Berman D, Shahabi V, Chin K, Canetta R, Humphrey R (2010) Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 37:533–546
Ikeda S, Okamoto T, Okano S, Umemoto Y, Tagawa T, Morodomi Y, Kohno M, Shimamatsu S, Kitahara H, Suzuki Y, Fujishita T, Maehara Y (2016) PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. J Thorac Oncol 11:62–71
Ilie M, Hofman V, Dietel M, Soria JC, Hofman P (2016) Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Arch 468:511–525
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 11:3887–3895
Ivashko IN, Kolesar JM (2016) Pembrolizumab and nivolumab: PD-1 inhibitors for advanced melanoma. Am J Health Syst Pharm 73:193–201
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MDM, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339
Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, Keegan P, Pazdur R (2016) FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist 21:634–642
Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704
Kelderman S, Heemskerk B, van Tinteren H, van den Brom RR, Hospers GA, van den Eertwegh AJ, Kapiteijn EW, de Groot JW, Soetekouw P, Jansen RL, Fiets E, Furness AJ, Renn A, Krzystanek M, Szallasi Z, Lorigan P, Gore ME, Schumacher TN, Haanen JB, Larkin JM, Blank CU (2014) Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 63:449–458
Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA, Fauci AS (2008) 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
Kreiter S, Vormehr M, van de Roemer N, Diken M, Lower M, Diekmann J, Boegel S, Schrors B, Vascotto F, Castle JC, Tadmor AD, Schoenberger SP, Huber C, Tureci O, Sahin U (2015) Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520:692–696
Krishnadas DK, Shusterman S, Bai F, Diller L, Sullivan JE, Cheerva AC, George RE, Lucas KG (2015) A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol Immunother 64:1251–1260
Kwek SS, Dao V, Roy R, Hou Y, Alajajian D, Simko JP, Small EJ, Fong L (2012) Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients. J Immunol 189:3759–3766
Lane BR, Bissonnette J, Waldherr T, Ritz-Holland D, Chesla D, Cottingham SL, Alberta S, Liu C, Thompson AB, Graveel C, MacKeigan JP, Noyes SL, Smith J, Lakhani N, Steensma MR (2015) Development of a Center for Personalized Cancer Care at a regional cancer Center: feasibility trial of an institutional tumor sequencing advisory board. J Mol Diagn 17:695–704
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34
Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268
Le DT UJN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520
Leung AM, Lee AF, Ozao-Choy J, Ramos RI, Hamid O, O’Day SJ, Shin-Sim M, Morton DL, Faries MB, Sieling PA, Lee DJ (2014) Clinical benefit from Ipilimumab therapy in melanoma patients may be associated with serum CTLA4 levels. Front Oncol 4:110
Linch SN, Kasiewicz MJ, McNamara MJ, Hilgart-Martiszus IF, Farhad M, Redmond WL (2016) Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. Proc Natl Acad Sci U S A 113:E319–E327
Ma C, Armstrong AW (2014) Severe adverse events from the treatment of advanced melanoma: a systematic review of severe side effects associated with ipilimumab, vemurafenib, interferon alfa-2b, dacarbazine and interleukin-2. J Dermatolog Treat 25:401–408
Mack SJ, Milius RP, Gifford BD, Sauter J, Hofmann J, Osoegawa K, Robinson J, Groeneweg M, Turenchalk GS, Adai A, Holcomb C, Rozemuller EH, Penning MT, Heuer ML, Wang C, Salit ML, Schmidt AH, Parham PR, Müller C, Hague T, Fischer G, Fernandez-Viňa M, Hollenbach JA, Norman PJ, Maiers M (2015) Minimum information for reporting next generation sequence genotyping (MIRING): guidelines for reporting HLA and KIR genotyping via next generation sequencing. Hum Immunol 76:954–962
Martens A, Wistuba-Hamprecht K, Yuan J, Postow MA, Wong P, Capone M, Madonna G, Khammari A, Schilling B, Sucker A, Schadendorf D, Martus P, Dreno B, Ascierto PA, Wolchok JD, Pawelec G, Garbe C, Weide B (2016) Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with Ipilimumab. Clin Cancer Res 22:4848–4858
Martin SD, Brown SD, Wick DA, Nielsen JS, Kroeger DR, Twumasi-Boateng K, Holt RA, Nelson BH (2016) Low mutation burden in ovarian cancer may limit the utility of Neoantigen-targeted vaccines. PLoS One 11:e0155189
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 482:400–404
McCoy KD, Le Gros G (1999) The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol 77:1–10
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34:2460–2467
Ng Tang D, Shen Y, Sun J, Wen S, Wolchok JD, Yuan J, Allison JP, Sharma P (2013) Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 1:229–234
Olszanski AJ (2015) Principles of immunotherapy. J Natl Compr Canc Netw 13:670–672
Ortiz MV, Kobos R, Walsh M, Slotkin EK, Roberts S, Berger MF, Hameed M, Solit D, Ladanyi M, Shukla N, Kentsis A (2016) Integrating genomics into clinical pediatric oncology using the molecular tumor Board at the Memorial Sloan Kettering Cancer Center. Pediatr Blood Cancer 63:1368–1374
Pico de Coana Y, Poschke I, Gentilcore G, Mao Y, Nystrom M, Hansson J, Masucci GV, Kiessling R (2013) Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production. Cancer Immunol Res 1:158–162
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–562
Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ (2014) Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother 63:721–735
Rajan A, Kim C, Heery CR, Guha U, Gulley JL (2016) Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: role in advanced cancers. Hum Vaccin Immunother 12:2219–2231
Rebelatto MC, Midha A, Mistry A, Sabalos C, Schechter N, Li X, Jin X, Steele KE, Robbins PB, Blake-Haskins JA, Walker J (2016) Development of a programmed cell death ligand-1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma. Diagn Pathol 11:95
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O’Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16:908–918
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, KowalskiDM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR (2016) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255–265
Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, Chow LQ, Gerber DE, Laurie SA, Goldman JW, Shepherd FA, Chen AC, Shen Y, Nathan FE, Harbison CT, Antonia S (2016) Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34:2969–2979
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science (New York, NY) 348:124–128
Roach C, Zhang N, Corigliano E, Jansson M, Toland G, Ponto G, Dolled-Filhart M, Emancipator K, Stanforth D, Kulangara K (2016) Development of a companion diagnostic PD-L1 immunohistochemistry assay for Pembrolizumab therapy in non–small-cell lung cancer. Appl Immunohistochem Mol Morphol 24:392–397
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 19:747–752
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) 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 (London, England) 387:1909–1920
Sakamoto S, Matsueda S, Takamori S, Toh U, Noguchi M, Yutani S, Yamada A, Shichijo S, Yamada T, Suekane S, Kawano K, Sasada T, Hattori N, Kohno N, Itoh K (2015) Immunological evaluation of peptide vaccination for cancer patients with the HLA-A26 allele. Cancer Sci 106:1257–1263
Santabarbara G, Maione P, Rossi A, Palazzolo G, Gridelli C (2016) Novel immunotherapy in the treatment of advanced non-small cell lung cancer. Expert Rev Clin Pharmacol 9:1571–1581
Santegoets SJ, Stam AG, Lougheed SM, Gall H, Scholten PE, Reijm M, Jooss K, Sacks N, Hege K, Lowy I, Cuillerot JM, von Blomberg BM, Scheper RJ, van den Eertwegh AJ, Gerritsen WR, de Gruijl TD (2013) T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment. Cancer Immunol Immunother 62:245–256
Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science (New York, NY) 348:69–74
Schwaederle M, Parker BA, Schwab RB, Fanta PT, Boles SG, Daniels GA, Bazhenova LA, Subramanian R, Coutinho AC, Ojeda-Fournier H, Datnow B, Webster NJ, Lippman SM, Kurzrock R (2014) Molecular tumor board: the University of California-san Diego Moores Cancer Center experience. Oncologist 19:631–636
Seifert AM, Zeng S, Zhang JQ, Kim TS, Cohen NA, Beckman MJ, Medina BD, Maltbaek JH, Loo JK,Crawley MH, Rossi F, Besmer P, Antonescu CR, DeMatteo RP (2016) PD-1/PD-L1 blockade enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors. Clin Cancer Res 23:454–465
Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 17:956–965
Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, Grasso CS, HugoW, Sandoval S, Torrejon DY, Palaskas N, Abril Rodriguez G, Parisi G, Azhdam A, Chmielowski B, Cherry G, Seja E, Berent-Maoz B, Shintaku IP, Le DT, Pardoll DM, Diaz LA, Tumeh PC, Graeber TG, Lo RS, Comin-Anduix B, Ribas A (2016) Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 7:188–201
Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caraco C, Curvietto M, Esposito A, Paone M, Palla M, Cavalcanti E, Sandomenico F, Petrillo A, Botti G, Fulciniti F, Palmieri G, Queirolo P, Marchetti P, Ferraresi V, Rinaldi G, Pistillo MP, Ciliberto G, Mozzillo N, Ascierto PA (2014) Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 63:675–683
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 371:2189–2199
Song M, Chen D, Lu B, Wang C, Zhang J, Huang L, Wang X, Timmons CL, Hu J, Liu B, Wu X, Wang L, Wang J, Liu H (2013) PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PLoS One 8:e65821
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 5:200ra116
Sunshine J, Taube JM (2015) PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 23:32–38
Syn NL, Yong WP, Goh BC, Lee SC (2016) Evolving landscape of tumor molecular profiling for personalized cancer therapy: a comprehensive review. Expert Opin Drug Metab Toxicol 12:911–922
Tafe LJ, Gorlov IP, de Abreu FB, Lefferts JA, Liu X, Pettus JR, Marotti JD, Bloch KJ, Memoli VA, Suriawinata AA, Dragnev KH, Fadul CE, Schwartz GN, Morgan CR, Holderness BM, Peterson JD, Tsongalis GJ, Miller TW, Chamberlin MD (2015) Implementation of a molecular tumor board: the impact on treatment decisions for 35 patients evaluated at Dartmouth-Hitchcock Medical Center. Oncologist 20:1011–1018
Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, Reimand J, Lawrence MS, Getz G, Bader GD, Ding L, Lopez-Bigas N (2013) Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep 3:2650
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074
Tie Y, Ma X, Zhu C, Mao Y, Shen K, Wei X, Chen Y, Zheng H (2017) Safety and efficacy of nivolumab in the treatment of cancers: a meta-analysis of 27 prospective clinical trials. Int J Cancer 140:948–958
Topalian SL, Drake CG, Pardoll DM (2012) Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24:207–212
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 366:2443–2454
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 32:1020–1030
Tran B, Brown AM, Bedard PL, Winquist E, Goss GD, Hotte SJ, Welch SA, Hirte HW, Zhang T, Stein LD, Ferretti V, Watt S, Jiao W, Ng K, Ghai S, Shaw P, Petrocelli T, Hudson TJ, Neel BG, Onetto N, Siu LL, McPherson JD, Kamel-Reid S, Dancey JE (2013) Feasibility of real time next generation sequencing of cancer genes linked to drug response: results from a clinical trial. Int J Cancer 132:1547–1555
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571
Van Allen EM, Golay HG, Liu Y, Koyama S, Wong K, Taylor-Weiner A, Giannakis M, Harden M, Rojas-Rudilla V, Chevalier A, Thai T, Lydon C, Mach S, Avila AG, Wong JA, Rabin AR, Helmkamp J, Sholl L, Carter SL, Oxnard G, Janne P, Getz G, Lindeman N, Hammerman PS, Garraway LA, Hodi FS, Rodig SJ, Dranoff G, Wong KK, Barbie DA (2015) Long-term benefit of PD-L1 blockade in lung cancer associated with JAK3 activation. Cancer Immunol Res 3:855–863
Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MHG, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science (New York, NY) 350:207–211
van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, van Dijk LJ, Behjati S, Hilkmann H, El Atmioui D, Nieuwland M, Stratton MR, Kerkhoven RM, Kesmir C, Haanen JB, Kvistborg P, Schumacher TN (2013) Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31:e439–e442
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science (New York, NY) 339:1546–1558
Wang L, Ren F, Wang Q, Baldridge LA, Monn MF, Fisher KW, Sheng W, Zhou X, Du X, Cheng L (2016) Significance of programmed death ligand 1 (PD-L1) Immunohistochemical expression in colorectal cancer. Mol Diagn Ther 20:175–181
Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77:4911–4927
Yuan J, Zhou J, Dong Z, Tandon S, Kuk D, Panageas KS, Wong P, Wu X, Naidoo J, Page DB, Wolchok JD, Hodi FS (2014) Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res 2:127–132
Zaragoza J, Caille A, Beneton N, Bens G, Christiann F, Maillard H, Machet L (2016) High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol 174:146–151
Zhang G, Liu WL, Zhang L, Wang JY, Kuang MH, Liu P, Lin YH, Dai SQ, Du J (2011) Involvement of indoleamine 2,3-dioxygenase in impairing tumor-infiltrating CD8 T-cell functions in esophageal squamous cell carcinoma. Clin Dev Immunol 2011:384726
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
RCS declares that I have no conflict of interest.
SH attended a 1-day advisory board meeting for Bristol-Myers.
Rights and permissions
About this article
Cite this article
Siniard, R.C., Harada, S. Immunogenomics: using genomics to personalize cancer immunotherapy. Virchows Arch 471, 209–219 (2017). https://doi.org/10.1007/s00428-017-2140-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-017-2140-0