Immune Netw.  2015 Apr;15(2):58-65. 10.4110/in.2015.15.2.58.

Adoptive Cell Therapy of Melanoma with Cytokine-induced Killer Cells

Affiliations
  • 1College of Pharmacy, Chungbuk National University, Cheongju 362-763, Korea. shan@chungbuk.ac.kr

Abstract

Melanoma is the most aggressive skin cancer and its incidence is gradually increasing worldwide. Patients with metastatic melanoma have a very poor prognosis (estimated 5-year survival rate of <16%). In the last few years, several drugs have been approved for malignant melanoma, such as tyrosine kinase inhibitors and immune checkpoint blockades. Although new therapeutic agents have improved progression-free and overall survival, their use is limited by drug resistance and drug-related toxicity. At the same time, adoptive cell therapy of metastatic melanoma with tumor-infiltrating lymphocytes has shown promising results in preclinical and clinical studies. In this review, we summarize the currently available drugs for treatment of malignant melanoma. In addition, we suggest cytokine-induced killer (CIK) cells as another candidate approach for adoptive cell therapy of melanoma. Our preclinical study and several previous studies have shown that CIK cells have potent anti-tumor activity against melanomas in vitro and in an in vivo human tumor xenograft model without any toxicity.

Keyword

Melanoma; Preclinical study; Cytokine-induced killer cells

MeSH Terms

Cell- and Tissue-Based Therapy*
Cytokine-Induced Killer Cells*
Drug Resistance
Heterografts
Humans
Incidence
Lymphocytes, Tumor-Infiltrating
Melanoma*
Prognosis
Protein-Tyrosine Kinases
Skin Neoplasms
Survival Rate
Protein-Tyrosine Kinases

Figure

  • Figure 1 Efficacy of cytokine-induced killer (CIK) cells for melanoma treatment in a mouse model. Generation of CIK cells from human peripheral blood mononuclear cells (PBMCs) was induced by culturing them in the presence of IL-2 and anti-CD3 antibody for 14 days. The resulting CIK cells were stained with human monoclonal antibodies against CD3, CD56, CD4, and CD8 (A). in vitro cytotoxicity of CIK cells was examined by a 51Cr-release assay that used LOX-IMVI and K562 as target cells (B). Effector (E) and target (T) cells (1×104 cells/100µl/well) were mixed at different E:T ratios (1:1 to 100:1). The percentage of cytotoxicity was calculated as following: cytotoxicity=[(sample-spontaneous)/(maximum-spontaneous)] ×100. Spontaneous release was measured upon target cell incubation in medium alone, whereas maximal release was measured after treatment with 2% Nonidet P-40. Nude mice (n=7) were implanted subcutaneously with 1.5×106 LOX-IMVI cells. CIK cells (1 to 10×106 cells/mouse) were injected intravenously once a week. Adriamycin (ADR) was injected intravenously at 2 mg/kg. Tumor size was estimated as length (mm)×width (mm)×height (mm)/2 (C). Body weight was measured to estimate toxicity (D). Mice were sacrificed on day 15 and tumors were weighed (E). Statistical significance was determined by Student's t-test versus the PBS-treated control group (*p<0.01). All experimental procedures were approved by the Animal Experimentation Ethics Committee and by the Institutional Ethics Committee of Chungbuk National University. Informed consents have been obtained from volunteers.


Reference

1. Gordon R. Skin cancer: an overview of epidemiology and risk factors. Semin Oncol Nurs. 2013; 29:160–169.
2. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol. 2012; 166:1069–1080.
Article
3. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007; 445:851–857.
Article
4. Marks R. Epidemiology of melanoma. Clin Exp Dermatol. 2000; 25:459–463.
Article
5. Whiteman DC, Whiteman CA, Green AC. Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies. Cancer Causes Control. 2001; 12:69–82.
6. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS. High frequency of BRAF mutations in nevi. Nat Genet. 2003; 33:19–20.
Article
7. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin. 2014; 64:9–29.
8. Ko JM, Fisher DE. A new era: melanoma genetics and therapeutics. J Pathol. 2011; 223:241–250.
Article
9. Tsao H, Goel V, Wu H, Yang G, Haluska FG. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004; 122:337–341.
Article
10. 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 R, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002; 417:949–954.
Article
11. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker B, LeBoit PE, Pinkel D, Bastian BC. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005; 353:2135–2147.
Article
12. 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. BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364:2507–2516.
Article
13. Straussman RT, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012; 487:500–504.
Article
14. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366:707–714.
Article
15. Sullivan RJ, Flaherty KT. Resistance to BRAFtargeted therapy in melanoma. Eur J Cancer. 2013; 49:1297–1304.
Article
16. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005; 25:9543–9553.
Article
17. Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE. Reversal of the TCR stop signal by CTLA-4. Science. 2006; 313:1972–1975.
Article
18. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12:252–264.
Article
19. Laurent S, Queirolo P, Boero S, Salvi S, Piccioli P, Boccardo S, Minghelli S, Morabito A, Fontana V, Pietra G, Carrega P, Ferrari N, Tosetti F, Chang LJ, Mingari MC, Ferlazzo G, Poggi A, Pistillo MP. The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-alpha production. J Transl Med. 2013; 11:108.
20. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992; 11:3887–3895.
Article
21. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000; 192:1027–1034.
Article
22. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006; 203:883–895.
Article
23. Chapon M, Randriamampita C, Maubec E, Badoual C, Fouquet S, Wang SF, Marinho E, Farhi D, Garcette M, Jacobelli S, Rouquette A, Carlotti A, Girod A, Prevost-Blondel A, Trautmann A, Avril MF, Bercovici N. Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes. J Invest Dermatol. 2011; 131:1300–1307.
Article
24. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013; 369:134–144.
Article
25. Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, Marshall MA, Gomez-Navarro J, Liang JQ, Bulanhagui CA. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010; 16:1042–1048.
Article
26. 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. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366:2443–2454.
Article
27. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengelov L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR. CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014; 15:700–712.
Article
28. Teply BA, Lipson EJ. Identification and management of toxicities from immune checkpoint-blocking drugs. Oncology (Williston Park). 2014; Suppl 3. 30–38.
29. Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know. Nat Rev Clin Oncol. 2011; 8:577–585.
Article
30. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008; 26:5233–5239.
Article
31. Heylmann D, Bauer M, Becker H, van GS, Bacher N, Steinbrink K, Kaina B. Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response. PLoS One. 2013; 8:e83384.
Article
32. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005; 11:6713–6721.
Article
33. Phan GQ, Rosenberg SA. Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy. Cancer Control. 2013; 20:289–297.
Article
34. Cormier JN, Abati A, Fetsch P, Hijazi YM, Rosenberg SA, Marincola FM, Topalian SL. Comparative analysis of the in vivo expression of tyrosinase, MART-1/Melan-A, and gp100 in metastatic melanoma lesions: implications for immunotherapy. J Immunother. 1998; 21:27–31.
Article
35. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De PE, Van den Eynde BJ, Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. J Immunol. 2007; 178:2617–2621.
Article
36. 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. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006; 314:126–129.
Article
37. 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. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009; 114:535–546.
Article
38. Miller JS. The biology of natural killer cells in cancer, infection, and pregnancy. Exp Hematol. 2001; 29:1157–1168.
Article
39. Seliger B. Different regulation of MHC class I antigen processing components in human tumors. J Immunotoxicol. 2008; 5:361–367.
Article
40. Seliger B, Cabrera T, Garrido F, Ferrone S. HLA class I antigen abnormalities and immune escape by malignant cells. Semin Cancer Biol. 2002; 12:3–13.
Article
41. Geller MA, Miller JS. Use of allogeneic NK cells for cancer immunotherapy. Immunotherapy. 2011; 3:1445–1459.
Article
42. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005; 105:3051–3057.
Article
43. Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res. 2011; 17:6287–6297.
Article
44. Schmidt-Wolf GD, Negrin RS, Schmidt-Wolf IG. Activated T cells and cytokine-induced CD3+CD56+ killer cells. Ann Hematol. 1997; 74:51–56.
45. Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991; 174:139–149.
Article
46. Franceschetti M, Pievani A, Borleri G, Vago L, Fleischhauer K, Golay J, Introna M. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol. 2009; 37:616–628.
47. Verneris MR, Baker J, Edinger M, Negrin RS. Studies of ex vivo activated and expanded CD8+ NK-T cells in humans and mice. J Clin Immunol. 2002; 22:131–136.
48. Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood. 2004; 103:3065–3072.
Article
49. Pievani A, Borleri G, Pende D, Moretta L, Rambaldi A, Golay J, Introna M. Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity. Blood. 2011; 118:3301–3310.
Article
50. Alvarnas JC, Linn YC, Hope EG, Negrin RS. Expansion of cytotoxic CD3+ CD56+ cells from peripheral blood progenitor cells of patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2001; 7:216–222.
Article
51. Schmidt-Wolf IG, Lefterova P, Johnston V, Scheffold C, Csipai M, Mehta BA, Tsuruo T, Huhn D, Negrin RS. Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells. Cell Immunol. 1996; 169:85–90.
Article
52. Zhang YS, Yuan FJ, Jia GF, Zhang JF, Hu LY, Huang L, Wang J, Dai ZQ. CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R. World J Gastroenterol. 2005; 11:3339–3345.
Article
53. Liu P, Chen L, Huang X. The antitumor effects of CIK cells combined with docetaxel against drug-resistant lung adenocarcinoma cell line SPC-A1/DTX in vitro and in vivo. Cancer Biother Radiopharm. 2009; 24:91–98.
Article
54. Zhao Q, Zhang H, Li Y, Liu J, Hu X, Fan L. Anti-tumor effects of CIK combined with oxaliplatin in human oxaliplatin-resistant gastric cancer cells in vivo and in vitro. J Exp Clin Cancer Res. 2010; 29:118.
Article
55. Zhu HH, Xu KL, Pan XY, Liu JQ, Chen FX, Huang YH. [Specific anti-leukemic cell effect mediated by dendritic cells pulsed with chronic myelogenous leukemia lysate antigen in vitro]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2003; 11:278–281.
56. Zhang S, Jiang SJ, Zhang CQ, Wang HM, Bai CX. Antitumour activities of cytokine-induced killer cells and dendritic cells in vitro andin vivo. Chin Med J (Engl). 2005; 118:1308–1312.
57. Wang FS, Liu MX, Zhang B, Shi M, Lei ZY, Sun WB, Du QY, Chen JM. Antitumor activities of human autologous cytokine-induced killer (CIK) cells against hepatocellular carcinoma cells in vitro and in vivo. World J Gastroenterol. 2002; 8:464–468.
Article
58. Kornacker M, Moldenhauer G, Herbst M, Weilguni E, Tita-Nwa F, Harter C, Hensel M, Ho AD. Cytokine-induced killer cells against autologous CLL: direct cytotoxic effects and induction of immune accessory molecules by interferon-gamma. Int J Cancer. 2006; 119:1377–1382.
Article
59. Kim HM, Lim J, Park SK, Kang JS, Lee K, Lee CW, Lee KH, Yun MJ, Yang KH, Han G, Kwon SW, Kim Y, Han SB. Antitumor activity of cytokine-induced killer cells against human lung cancer. Int Immunopharmacol. 2007; 7:1802–1807.
Article
60. Kim HM, Kang JS, Lim J, Park SK, Lee K, Yoon YD, Lee CW, Lee KH, Han G, Yang KH, Kim YJ, Kim Y, Han SB. Inhibition of human ovarian tumor growth by cytokine-induced killer cells. Arch Pharm Res. 2007; 30:1464–1470.
Article
61. Kim JS, Chung IS, Lim SH, Park Y, Park MJ, Kim JY, Kim YG, Hong JT, Kim Y, Han SB. Preclinical and clinical studies on cytokine-induced killer cells for the treatment of renal cell carcinoma. Arch Pharm Res. 2014; 37:559–566.
Article
62. Sun S, Li XM, Li XD, Yang WS. Studies on inducing apoptosis effects and mechanism of CIK cells for MGC-803 gastric cancer cell lines. Cancer Biother Radiopharm. 2005; 20:173–180.
Article
63. Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, Pisacane A, Zaccagna A, Volpe MG, Gallo S, Caravelli D, Giacone E, Venesio T, Balsamo A, Pignochino Y, Grignani G, Carnevale-Schianca F, Aglietta M, Sangiolo D. Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. Clin Cancer Res. 2013; 19:4347–4358.
Article
64. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005; 5:275–284.
Article
65. Tailor NK, Lee HB, Sharma M. Effective melanoma inhibition by synthetic pentacyclic triterpenoid 2-(3-phenylprop-2-en-1-ylidene)-22beta-hydroxy-3-oxoolean12-en-28-oic acid: an in vitro and in vivo study. J Environ Pathol Toxicol Oncol. 2013; 32:59–72.
Article
66. Schott S, Niessner H, Sinnberg T, Venturelli S, Berger A, Ikenberg K, Villanueva J, Meier F, Garbe C, Busch C. Cytotoxicity of new duplex drugs linking 3'-C-ethynylcytidine and 5-fluor-2'-deoxyuridine against human melanoma cells. Int J Cancer. 2012; 131:2165–2174.
Article
67. Choi WK, El-Gamal MI, Choi HS, Baek D, Oh CH. New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies. Eur J Med Chem. 2011; 46:5754–5762.
Article
68. Jakel CE, Schmidt-Wolf IG. An update on new adoptive immunotherapy strategies for solid tumors with cytokine-induced killer cells. Expert Opin Biol Ther. 2014; 14:905–916.
Article
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