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Immunotherapy for advanced melanoma: future directions

    Sara Valpione

    *Author for correspondence:

    E-mail Address: sara.valpione@christie.nhs.uk

    Christie Hospital NHS Foundation Trust, 550 Wilmslow Rd, Manchester, M20 4BX, UK

    &
    Luca G Campana

    Department of Surgery, Oncology & Gastroenterology, University of Padova, via Gattamelata 64, 35128 Padova, Italy

    Published Online:https://doi.org/10.2217/imt.15.111

    As calculated by the meta-analysis of Korn et al., the prognosis of metastatic melanoma in the pretarget and immunological therapy era was poor, with a median survival of 6.2 and a 1-year life expectancy of 25.5%. Nowadays, significant advances in melanoma treatment have been gained, and immunotherapy is one of the promising approaches to get to durable responses and survival improvement. The aim of the present review is to highlight the recent innovations in melanoma immunotherapy and to propose a critical perspective of the future directions of this enthralling oncology subspecialty.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin. Orthop. Relat. Res. (262), 3–11 (1991).
    • 2 Thomas L. Cellular and Humoral Aspects of the Hypersensitive States. Lawrence HS (Ed.). Hoeber-Harper Publishing, NY, USA, 529–532 (1959).
    • 3 Burnet FM. The concept of immunological surveillance. Prog. Exp. Tumor Res. 13, 1–27 (1970).
    • 4 Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004).
    • 5 Teng MW, Galon J, Fridman WH, Smyth MJ. From mice to humans: developments in cancer immunoediting. J. Clin. Invest. 125(9), 3338–3346 (2015).
    • 6 Finak G, Bertos N, Pepin F et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14(5), 518–527 (2008).
    • 7 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011). • A comprehensive theory of cancer genesis.
    • 8 Pol J, Vacchelli E, Aranda F et al. Trial watch: immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology 4(4), e1008866 (2015).
    • 9 Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
    • 10 Martins I, Wang Y, Michaud M et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 21(1), 79–91 (2014).
    • 11 Kepp O, Galluzzi L, Martins I et al. Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy. Cancer Metastasis Rev. 30(1), 61–69 (2011).
    • 12 Vinay DS, Ryan EP, Pawelec G et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 35(Suppl.), S185–S198 (2015).
    • 13 Tai T, Cahan LD, Tsuchida T, Saxton RE, Irie RF, Morton DL. Immunogenicity of melanoma-associated gangliosides in cancer patients. Int. J. Cancer 35(5), 607–612 (1985).
    • 14 Van Der Bruggen P, Traversari C, Chomez P et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254(5038), 1643–1647 (1991).
    • 15 Boel P, Wildmann C, Sensi ML et al. BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 2(2), 167–175 (1995).
    • 16 Real FX, Furukawa KS, Mattes MJ et al. Class 1 (unique) tumor antigens of human melanoma: identification of unique and common epitopes on a 90-kDa glycoprotein. Proc. Natl Acad. Sci. USA 85(11), 3965–3969 (1988).
    • 17 Seigler HF, Wallack MK, Vervaert CE et al. Melanoma patient antibody responses to melanoma tumor-associated antigens defined by murine monoclonal antibodies. J. Biol. Response Mod. 8(1), 37–52 (1989).
    • 18 Boussiotis VA. Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma. N. Engl. J. Med. 371(23), 2230–2232 (2014).
    • 19 Lawrence MS, Stojanov P, Polak P et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457), 214–218 (2013). •• The neoantigen load in different cancer histologies may vary consistently and influence immunogenicity.
    • 20 Galon J, Costes A, Sanchez-Cabo F et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795), 1960–1964 (2006).
    • 21 Mlecnik B, Tosolini M, Charoentong P et al. Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 138(4), 1429–1440 (2010).
    • 22 Hamid O, Schmidt H, Nissan A et al. 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 (2011).
    • 23 Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12(4), 298–306 (2012).
    • 24 Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 161(7), 1681–1696 (2015).
    • 25 Schatton T, Scolyer RA, Thompson JF, Mihm MC Jr. Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. Methods Mol. Biol. 1102, 287–324 (2014).
    • 26 Chi M, Dudek AZ. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res. 21(3), 165–174 (2011).
    • 27 Mocellin S, Mandruzzato S, Bronte V, Lise M, Nitti D. Part I: vaccines for solid tumours. Lancet Oncol. 5(11), 681–689 (2004).
    • 28 Amedei A, Prisco D, Mm DE. The use of cytokines and chemokines in the cancer immunotherapy. Recent Pat. Anticancer Drug Discov. 8(2), 126–142 (2013).
    • 29 Nicholas C, Lesinski GB. Immunomodulatory cytokines as therapeutic agents for melanoma. Immunotherapy 3(5), 673–690 (2011).
    • 30 Payne KK, Bear HD, Manjili MH. Adoptive cellular therapy of cancer: exploring innate and adaptive cellular crosstalk to improve anti-tumor efficacy. Future Oncol. 10(10), 1779–1794 (2014).
    • 31 Gilham DE. Effective adoptive T-cell therapy for cancer in the absence of host lymphodepletion. Immunotherapy 3(2), 177–179 (2011).
    • 32 Wu R, Forget MA, Chacon J et al. Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer J. 18(2), 160–175 (2012).
    • 33 Rosenberg SA, Yang JC, Sherry RM et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer. Res. 17(13), 4550–4557 (2011).
    • 34 Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12(4), 269–281 (2012).
    • 35 Besser MJ, Shapira-Frommer R, Itzhaki O et al. 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. 19(17), 4792–4800 (2013).
    • 36 Duong CP, Yong CS, Kershaw MH, Slaney CY, Darcy PK. Cancer immunotherapy utilizing gene-modified T cells: from the bench to the clinic. Mol. Immunol. 67(2 Pt A), 46–57 (2015).
    • 37 Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348(6230), 62–68 (2015).
    • 38 Wilde S, Geiger C, Milosevic S et al. Generation of allo-restricted peptide-specific T cells using RNA-pulsed dendritic cells: a three phase experimental procedure. Oncoimmunology 1(2), 129–140 (2012).
    • 39 Li LP, Lampert JC, Chen X et al. Transgenic mice with a diverse human T cell antigen receptor repertoire. Nat. Med. 16(9), 1029–1034 (2010).
    • 40 Voss RH, Thomas S, Pfirschke C et al. Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells. Blood 115(25), 5154–5163 (2010).
    • 41 Stone JD, Harris DT, Soto CM et al. A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control. Cancer Immunol. Immunother. 63(11), 1163–1176 (2014).
    • 42 Beard RE, Zheng Z, Lagisetty KH et al. Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells. J. Immunother. Cancer 2, 25 (2014).
    • 43 Krishnamurthy J, Rabinovich BA, Mi T et al. Genetic engineering of T cells to target HERV-K, an ancient retrovirus on melanoma. Clin. Cancer Res. 21(14), 3241–3251 (2015).
    • 44 Gargett T, Brown MP. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235 (2014).
    • 45 Wu MR, Zhang T, Alcon A, Sentman CL. DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma. Cancer Immunol. Immunother. 64(4), 409–418 (2015).
    • 46 Song DG, Ye Q, Poussin M et al. A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity. Oncotarget 6(25), 21533–21546 (2015).
    • 47 Greco R, Oliveira G, Stanghellini MT et al. Improving the safety of cell therapy with the TK-suicide gene. Front. Pharmacol. 6, 95 (2015).
    • 48 Beatty GL, Moon EK. Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment. Oncoimmunology 3(11), e970027 (2014).
    • 49 Moon EK, Wang LC, Dolfi DV et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin. Cancer Res. 20(16), 4262–4273 (2014).
    • 50 Ankri C, Shamalov K, Horovitz-Fried M, Mauer S, Cohen CJ. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J. Immunol. 191(8), 4121–4129 (2013).
    • 51 Jensen MC, Riddell SR. Designing chimeric antigen receptors to effectively and safely target tumors. Curr. Opin. Immunol. 33, 9–15 (2015).
    • 52 Kim JS, Kim YG, Pyo M et al. Adoptive cell therapy of melanoma with cytokine-induced killer cells. Immune Netw. 15(2), 58–65 (2015).
    • 53 Besser MJ, Shoham T, Harari-Steinberg O et al. Development of allogeneic NK cell adoptive transfer therapy in metastatic melanoma patients: in vitro preclinical optimization studies. PLoS ONE 8(3), e57922 (2013).
    • 54 Gammaitoni L, Giraudo L, Leuci V et al. Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. Clin. Cancer Res. 19(16), 4347–4358 (2013).
    • 55 US FDA. www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/default.htm.
    • 56 Defrancesco L. CAR-T cell therapy seeks strategies to harness cytokine storm. Nat. Biotechnol. 32(7), 604 (2014).
    • 57 Vanseggelen H, Hammill JA, Dvorkin-Gheva A et al. T cells engineered with chimeric antigen receptors targeting NKG2D ligands display lethal toxicity in mice. Mol. Ther. 23(10), 1600–1610 (2015).
    • 58 Hombach AA, Holzinger A, Abken H. The weal and woe of costimulation in the adoptive therapy of cancer with chimeric antigen receptor (CAR)-redirected T cells. Curr. Mol. Med. 13(7), 1079–1088 (2013).
    • 59 Maio M, Grob JJ, Aamdal S et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a Phase III trial. J. Clin. Oncol. 33(10), 1191–1196 (2015).
    • 60 Mocellin S, Benna C, Pilati P. Coinhibitory molecules in cancer biology and therapy. Cytokine Growth Factor Rev. 24(2), 147–161 (2013).
    • 61 Hodi FS, O'day SJ, Mcdermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).
    • 62 Snyder A, Makarov V, Merghoub T et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371(23), 2189–2199 (2014).
    • 63 Van Allen EM, Miao D, Schilling B et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257), 207–211 (2015).
    • 64 Lebbe C, Weber JS, Maio M et al. Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior Phase II studies. Ann. Oncol. 25(11), 2277–2284 (2014).
    • 65 Shahabi V, Whitney G, Hamid O et al. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol. Immunother. 61(5), 733–737 (2012).
    • 66 S SA, Qian W, Ellis S et al. Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients. Melanoma Res. 25(5), 432–442 (2015).
    • 67 Wong RM, Scotland RR, Lau RL et al. Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int. Immunol. 19(10), 1223–1234 (2007).
    • 68 Kleffel S, Posch C, Barthel SR et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162(6), 1242–1256 (2015).
    • 69 Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372(4), 320–330 (2015).
    • 70 Weber JS, D'angelo SP, Minor D et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, Phase 3 trial. Lancet Oncol. 16(4), 375–384 (2015).
    • 71 Ribas A, Puzanov I, Dummer R et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, Phase 2 trial. Lancet Oncol. 16(8), 908–918 (2015).
    • 72 Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372(26), 2521–2532 (2015). •• A Phase III trial demonstrating the superiority of anti-programmed death-1 treatment versus anti-cytotoxic T-lymphocyte antigen-4 treatment as first-line therapy for metastatic melanoma.
    • 73 Loo D, Alderson RF, Chen FZ et al. Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Clin. Cancer Res. 18(14), 3834–3845 (2012).
    • 74 Hemon P, Jean-Louis F, Ramgolam K et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J. Immunol. 186(9), 5173–5183 (2011).
    • 75 Curti BD, Kovacsovics-Bankowski M, Morris N et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73(24), 7189–7198 (2013).
    • 76 Li SY, Liu Y. Immunotherapy of melanoma with the immune costimulatory monoclonal antibodies targeting CD137. Clin. Pharmacol. 5(Suppl. 1), 47–53 (2013).
    • 77 Hernandez-Chacon JA, Li Y, Wu RC et al. Costimulation through the CD137/4–1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function. J. Immunother. 34(3), 236–250 (2011).
    • 78 Yonezawa A, Dutt S, Chester C, Kim J, Kohrt HE. Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin. Cancer Res. 21(14), 3113–3120 (2015).
    • 79 Roberts DJ, Franklin NA, Kingeter LM et al. Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells. J. Immunother. 33(8), 769–779 (2010).
    • 80 Pepe CA, Ricci R, Cortelazzi C et al. The vast majority of lymphocytes infiltrating primary cutaneous melanoma express the CD27 costimulatory receptor: implications for melanoma progression. Eur. J. Dermatol. 21(2), 178–183 (2011).
    • 81 Song DG, Ye Q, Poussin M et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood 119(3), 696–706 (2012).
    • 82 Zhu LX, Davoodi M, Srivastava MK et al. GITR agonist enhances vaccination responses in lung cancer. Oncoimmunology 4(4), e992237 (2015).
    • 83 Lee GH, Askari A, Malietzis G et al. The role of CD40 expression in dendritic cells in cancer biology; a systematic review. Curr. Cancer Drug Targets 14(7), 610–620 (2014).
    • 84 Richard AC, Ferdinand JR, Meylan F, Hayes ET, Gabay O, Siegel RM. The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator. J. Leukoc. Biol. 98(3), 333–345 (2015).
    • 85 Schaer DA, Murphy JT, Wolchok JD. Modulation of GITR for cancer immunotherapy. Curr. Opin. Immunol. 24(2), 217–224 (2012).
    • 86 Vinay DS, Kwon BS. Immunotherapy of cancer with 4–1BB. Mol. Cancer Ther. 11(5), 1062–1070 (2012).
    • 87 Shibahara I, Saito R, Zhang R et al. OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy. Mol. Cancer 14, 41 (2015).
    • 88 Jacobs J, Deschoolmeester V, Zwaenepoel K et al. CD70: an emerging target in cancer immunotherapy. Pharmacol. Ther. 155, 1–10 (2015).
    • 89 Zhao R, Chinai JM, Buhl S et al. HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc. Natl Acad. Sci. USA 110(24), 9879–9884 (2013).
    • 90 Aspord C, Leccia MT, Charles J, Plumas J. Plasmacytoid dendritic cells support melanoma progression by promoting Th2 and regulatory immunity through OX40L and ICOSL. Cancer Immunol. Res. 1(6), 402–415 (2013).
    • 91 Tirapu I, Huarte E, Guiducci C et al. Low surface expression of B7–1 (CD80) is an immunoescape mechanism of colon carcinoma. Cancer Res. 66(4), 2442–2450 (2006).
    • 92 Ray A, Das DS, Song Y et al. Targeting PD1–PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia 29(6), 1441–1444 (2015).
    • 93 Zhang Y, Chung Y, Bishop C et al. Regulation of T cell activation and tolerance by PDL2. Proc. Natl Acad. Sci. USA 103(31), 11695–11700 (2006).
    • 94 Swanson RM, Gavin MA, Escobar SS et al. Butyrophilin-like 2 modulates B7 costimulation to induce Foxp3 expression and regulatory T cell development in mature T cells. J. Immunol. 190(5), 2027–2035 (2013).
    • 95 Zhang W, Wang J, Wang Y et al. B7-H3 silencing by RNAi inhibits tumor progression and enhances chemosensitivity in U937 cells. Onco Targets Ther. 8, 1721–1733 (2015).
    • 96 Leong SR, Liang WC, Wu Y et al. An anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. Mol. Pharm. 12(6), 1717–1729 (2015).
    • 97 Yamazaki T, Goya I, Graf D et al. A butyrophilin family member critically inhibits T cell activation. J. Immunol. 185(10), 5907–5914 (2010).
    • 98 Boles NC, Lin KK, Lukov GL et al. CD48 on hematopoietic progenitors regulates stem cells and suppresses tumor formation. Blood 118(1), 80–87 (2011).
    • 99 Hokuto D, Sho M, Yamato I et al. Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma. Eur. J. Cancer 51(2), 157–165 (2015).
    • 100 Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat. Rev. Immunol. 14(10), 653–666 (2014).
    • 101 Liu GY, Li ZJ, Li QL et al. Enhanced growth suppression of TERT-positive tumor cells by oncolytic adenovirus armed with CCL20 and CD40L. Int. Immunopharmacol. 28(1), 487–493 (2015).
    • 102 Lambracht-Washington D, Rosenberg RN. Co-stimulation with TNF receptor superfamily 4/25 antibodies enhances in-vivo expansion of CD4+CD25+Foxp3+ T cells (Tregs) in a mouse study for active DNA Abeta42 immunotherapy. J. Neuroimmunol. 278, 90–99 (2015).
    • 103 Yu N, Fu S, Xu Z et al. Synergistic antitumor responses by combined GITR activation and sunitinib in metastatic renal cell carcinoma. Int. J. Cancer doi:10.1002/ijc.29713 (2015) (Epub ahead of print).
    • 104 Bartkowiak T, Curran MA. 4–1BB agonists: multi-potent potentiators of tumor immunity. Front. Oncol. 5, 117 (2015).
    • 105 Buchan SL, Manzo T, Flutter B et al. OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. J. Immunol. 194(1), 125–133 (2015).
    • 106 Van De Ven K, Borst J. Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential. Immunotherapy 7(6), 655–667 (2015).
    • 107 Xiao Y, Freeman GJ. A new B7:CD28 family checkpoint target for cancer immunotherapy: HHLA2. Clin. Cancer Res. 21(10), 2201–2203 (2015).
    • 108 Fu T, He Q, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 71(16), 5445–5454 (2011).
    • 109 Leung J, Suh WK. The CD28-B7 family in anti-tumor immunity: emerging concepts in cancer immunotherapy. Immune Netw. 14(6), 265–276 (2014).
    • 110 Kanodia S, Da Silva DM, Karamanukyan T et al. Expression of LIGHT/TNFSF14 combined with vaccination against human papillomavirus Type 16 E7 induces significant tumor regression. Cancer Res. 70(10), 3955–3964 (2010).
    • 111 Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3–potential mechanisms of action. Nat. Rev. Immunol. 15(1), 45–56 (2015).
    • 112 Altvater B, Landmeier S, Pscherer S et al. 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin. Cancer Res. 15(15), 4857–4866 (2009).
    • 113 Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK. Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 32(8), 345–349 (2011).
    • 114 Gertner-Dardenne J, Fauriat C, Olive D. BTLA, a key regulator of Vgamma9Vdelta2 T-cell proliferation. Oncoimmunology 2(9), e25853 (2013).
    • 115 Cai G, Freeman GJ. The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol. Rev. 229(1), 244–258 (2009).
    • 116 Abeler-Dorner L, Swamy M, Williams G, Hayday AC, Bas A. Butyrophilins: an emerging family of immune regulators. Trends Immunol. 33(1), 34–41 (2012).
    • 117 Carlsten M, Norell H, Bryceson YT et al. Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells. J. Immunol. 183(8), 4921–4930 (2009).
    • 118 Lines JL, Sempere LF, Broughton T, Wang L, Noelle R. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol. Res. 2(6), 510–517 (2014).
    • 119 Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372(21), 2006–2017 (2015).
    • 120 Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015). •• A Phase III trial devaluating anti-programmed death-1 treatment versus anti-cytotoxic T-lymphocyte antigen-4 treatment versus combination of both as first-line therapy for metastatic melanoma.
    • 121 Kroemer G, Galluzzi L. Combinatorial immunotherapy with checkpoint blockers solves the problem of metastatic melanoma-An exclamation sign with a question mark. Oncoimmunology 4(7), e1058037 (2015).
    • 122 Weber JS, Kudchadkar RR, Yu B et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J. Clin. Oncol. 31(34), 4311–4318 (2013).
    • 123 Hugo W, Shi H, Sun L et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162(6), 1271–1285 (2015).
    • 124 Nefedova Y, Fishman M, Sherman S et al. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 67(22), 11021–11028 (2007).
    • 125 Kusmartsev S, Cheng F, Yu B et al. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 63(15), 4441–4449 (2003).
    • 126 Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368(14), 1365–1366 (2013).
    • 127 Eggermont AM, Chiarion-Sileni V, Grob JJ. Correction to Lancet Oncol 2015; 16: 522–30. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 16(6), e262 (2015).
    • 128 Eggermont AM, Chiarion-Sileni V, Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, Phase 3 trial. Lancet Oncol. 16(5), 522–530 (2015).
    • 129 Kelderman S, Heemskerk B, Van Tinteren H et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol. Immunother. 63(5), 449–458 (2014).
    • 130 Valpione S, Martinoli C, Fava P et al. Personalised medicine: development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab. Eur. J. Cancer 51(14), 2086–2094 (2015).
    • 131 Wilgenhof S, Du Four S, Vandenbroucke F et al. Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma. J. Immunother. 36(3), 215–222 (2013).
    • 132 Simeone E, Gentilcore G, Giannarelli D et al. 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(7), 675–683 (2014).
    • 133 Sabel MS, Lee J, Wang A, Lao C, Holcombe S, Wang S. Morphomics predicts response to ipilimumab in patients with stage IV melanoma. J. Surg. Oncol. 112(4), 333–337 (2015).