Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer

Journal of Translational Medicine

Mitsukazu Gotoh²  Kazuyoshi Takeda¹  Kazuya Ise²  Yutaka Shio²  Mitsunori Higuchi²  Takashi Kimura²  Mika Hoshino²  Jun Osugi²  Atsushi Yonechi²  Takeo Hasegawa²  Hiroshi Yaginuma²  Naoyuki Okabe²  Satoshi Mutoh²  Takumi Yamaura²  Mitsuro Fukuhara²  Hiroyuki Suzuki² 

[1] Department of Immunology, Juntendo University, School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan;Department of Regenerative Surgery, Fukushima Medical University, School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan

关键词: Non-small cell lung cancer;    Prognosis;    Multiple peptides;    Cancer vaccine;   

Others  :  827677
DOI  :  10.1186/1479-5876-11-97

 received in 2012-11-12, accepted in 2013-03-20,  发布年份 2013

【 摘 要 】

Background

Vaccine treatment using multiple peptides derived from multiple proteins is considered to be a promising option for cancer immune therapy, but scientific evidence supporting the therapeutic efficacy of multiple peptides is limited.

Methods

We conducted phase I trials using a mixture of multiple therapeutic peptide vaccines to evaluate their safety, immunogenicity and clinical response in patients with advanced/recurrent NSCLC. We administered two different combinations of four HLA-A24-restricted peptides. Two were peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2), and the third was a peptide derived from up-regulated lung cancer 10 (URLC10, which is also called lymphocyte antigen 6 complex locus K [LY6K]). The fourth peptide used was derived from TTK protein kinase (TTK) or cell division associated 1 (CDCA1). Vaccines were administered weekly by subcutaneous injection into the axillary region of patients with montanide ISA-51 incomplete Freund’s adjuvant, until the disease was judged to have progressed or patients requested to be withdrawn from the trial. Immunological responses were primarily evaluated using an IFN-gamma ELiSPOT assay.

Results

Vaccinations were well tolerated with no severe treatment-associated adverse events except for the reactions that occurred at the injection sites. Peptide-specific T cell responses against at least one peptide were observed in 13 of the 15 patients enrolled. Although no patient exhibited complete or partial responses, seven patients (47%) had stable disease for at least 2 months. The median overall survival time was 398 days, and the 1- and 2-year survival rates were 58.3% and 32.8%, respectively.

Conclusion

Peptide vaccine therapy using a mixture of four novel peptides was found to be safe, and is expected to induce strong specific T cell responses.

Trial registration

These studies were registered with ClinicalTrials.gov NCT00633724 and NCT00874588.

【 授权许可】

   
2013 Suzuki et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, Byers T, Colditz GA, Gould MK, Jett JR, Sabichi AL, Smith-Bindman R, Wood DE, Qaseem A, Detterbeck FC: Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 2012, 307:2418-2429.
• [3]Min JH, Lee HY, Lim H, Ahn MJ, Park K, Chung MP, Lee KS: Drug-induced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell lung cancer: a review on current insight. Cancer Chemother Pharmacol 2011, 68:1099-1109.
• [4]Ricciardi S, Tomao S, de Marinis F: Toxicity of targeted therapy in non-small-cell lung cancer management. Clin Lung Cancer 2009, 10:28-35.
• [5]Vansteenkiste J, Zielinski M, Linder A, Dahabre J, Esteban E, Malinowski W, Jassem J, Passlick B, Lehmann F, Brichard VG: Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2007, 25:s7554.
• [6]Butts C, Murray N, Maksymiuk A, Goss G, Marshall E, Soulières D, Cormier Y, Ellis P, Price A, Sawhney R, Davis M, Mansi J, Smith C, Vergidis D, Ellis P, MacNeil M, Palmer M: Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 2005, 23:6674-6681.
• [7]Bae J, Smith R, Daley J, Mimura N, Tai YT, Anderson KC, Munshi NC: Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: A potential therapeutic application in multiple myeloma and other plasma cell disorders. Clin Cancer Res 2012, 18:4850-4860.
• [8]Kono K, Mizukami Y, Daigo Y, Takano A, Masuda K, Yoshida K, Tsunoda T, Kawaguchi Y, Nakamura Y, Fujii H: Vaccination with multiple peptides derived from novel cancer-testis antigens can induce specific T-cell responses and clinical responses in advanced esophageal cancer. Cancer Sci 2009, 100:1502-1509.
• [9]Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, Ito H, Miyagi Y, Nakayama H, Fujita M, Hosokawa M, Tsuchiya E, Kohno N, Nakamura Y, Daigo Y: Cancer-testis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res 2007, 67:11601-11611.
• [10]Suda T, Tsunoda T, Daigo Y, Nakamura Y, Tahara H: Identification of human leukocyte antigen HLA-A24-restricted epitope-peptides derived from gene products up-regulated in lung and esophageal cancers as novel targets for immunotherapy. Cancer Sci 2007, 98:1803-1808.
• [11]Ishizaki H, Tsunoda T, Wada S, Yamauchi M, Shibuya M, Tahara H: Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res 2006, 12:5841-5849.
• [12]Hayama S, Daigo Y, Kato T, Ishikawa N, Yamabuki T, Miyamoto M, Ito T, Tsuchiya E, Kondo S, Nakamura Y: Activation of CDCA1-KNTC2, members of centromere protein complex, involved in pulmonary carcinogenesis. Cancer Res 2006, 66:10339-10348.
• [13]Wada S, Tsunoda T, Baba T, Primus FJ, Kuwano H, Shibuya M, Tahara H: Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res 2005, 65:4939-4946.
• [14]Kono K, Iinuma H, Akutsu Y, Tanaka H, Hayashi N, Uchikado Y, Noguchi T, Fujii H, Okinaka K, Fukushima R, Matsubara H, Ohira M, Baba H, Natsugoe S, Kitano S, Takeda K, Yoshida K, Tsunoda T, Nakamura Y: Multicenter, phase II clinical trial of cancer vaccination for advanced esophageal cancer with three peptides derived from novel cancer-testis antigens. J Transl Med 2012, 10:141-149. BioMed Central Full Text
• [15]Shepherd FA, Douillard JY, Blumenschein GR Jr: Immunotherapy for non-small cell lung cancer: novel approaches to improve patient outcome. J Thorac Oncol 2011, 6:1763-1773.
• [16]Kabaker K, Shell K, Kaufman HL: Vaccines for colorectal cancer and renal cell carcinoma. Cancer J 2011, 17:283-293.
• [17]Sienel W, Varwerk C, Linder A, Kaiser D, Teschner M, Delire M, Stamatis G, Passlick B: Melanoma associated antigen (MAGE)-A3 expression in Stages I and II non-small cell lung cancer: results of a multi-center study. Eur J Cardiothorac Surg 2004, 25:131-134.
• [18]Shigematsu Y, Hanagiri T, Shiota H, Kuroda K, Baba T, Mizukami M, So T, Ichiki Y, Yasuda M, So T, Takenoyama M, Yasumoto K: Clinical significance of cancer/testis antigens expression in patients with non-small cell lung cancer. Lung Cancer 2010, 68:105-110.
• [19]Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, Tong A, Kumar P, Pappen B, Hamilton C, DeVol E, Maples PB, Liu L, Chamberlin T, Shawler DL, Fakhrai H: Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 2006, 24:4721-4730.
• [20]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: Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 2012, 18:1254-1261.
• [21]Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar M, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004, 22:1589-1597.
• [22]Ulahannan SV, Brahmer JR: Antiangiogenic agents in combination with chemotherapy in patients with advanced non-small cell lung cancer. Cancer Invest 2011, 29:325-337.
• [23]Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl JMed 2003, 349:427-434.
• [24]Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355:2542-2550.
• [25]Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol 2009, 27:1227-1234.
• [26]Bubeník J: MHC class I down-regulation: tumour escape from immune surveillance? (review). Int J Oncol 2004, 25:487-491.
• [27]Kikuchi E, Yamazaki K, Torigoe T, Cho Y, Miyamoto M, Oizumi S, Hommura F, Dosaka-Akita H, Nishimura M: HLA class I antigen expression is associated with a favorable prognosis in early stage non-small cell lung cancer. Cancer Sci 2007, 98:1424-1430.
• [28]Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS: Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009, 15:7412-7420.
• [29]Butterfield LH, Disis ML, Fox BA, Lee PP, Khleif SN, Thurin M, Trinchieri G, Wang E, Wigginton J, Chaussabel D, Coukos G, Dhodapkar M, Håkansson L, Janetzki S, Kleen TO, Kirkwood JM, Maccalli C, Maecker H, Maio M, Malyguine A, Masucci G, Palucka AK, Potter DM, Ribas A, Rivoltini L, Schendel D, Seliger B, Selvan S, Slingluff CL Jr, Stroncek DF: A systematic approach to biomarker discovery; preamble to “the iSBTc-FDA taskforce on immunotherapy biomarkers”. J Transl Med 2008, 6:81-91. BioMed Central Full Text
• [30]Quoix E, Ramlau R, Westeel V, Papai Z, Madroszyk A, Riviere A, Koralewski P, Breton JL, Stoelben E, Braun D, Debieuvre D, Lena H, Buyse M, Chenard MP, Acres B, Lacoste G, Bastien B, Tavernaro A, Bizouarne N, Bonnefoy JY, Limacher JM: Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol 2011, 12:1125-1133.
• [31]Sawada Y, Yoshikawa T, Nobuoka D, Shirakawa H, Kuronuma T, Motomura Y, Mizuno S, Ishii H, Nakachi K, Konishi M, Nakagohri T, Takahashi S, Gotohda N, Takayama T, Yamao K, Uesaka K, Furuse J, Kinoshita T, Nakatsura T: Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: Immunologic evidence and potential for improving overall survival. Clin Cancer Res 2012, 18:3686-3696.
• [32]Dillman RO, Fogel GB, Cornforth AN, Selvan SR, Schiltz PM, DePriest C: Features associated with survival in metastatic melanoma patients treated with patient-specific dendritic cell vaccines. Cancer Biother Radiopharm 2011, 26:407-415.
• [33]Lukaszewicz-Zając M, Mroczko B, Gryko M, Kędra B, Szmitkowski M: Comparison between clinical significance of serum proinflammatory proteins (IL-6 and CRP) and classic tumor markers (CEA and CA 19–9) in gastric cancer. Clin Exp Med 2011, 11:89-96.
• [34]Kwon KA, Kim SH, Oh SY, Lee S, Han JY, Kim KH, Goh RY, Choi HJ, Park KJ, Roh MS, Kim HJ, Kwon HC, Lee JH: Clinical significance of preoperative serum vascular endothelial growth factor, interleukin-6, and C-reactive protein level in colorectal cancer. BMC Cancer 2010, 10:203-210. BioMed Central Full Text