Personalized Peptide-based Vaccination for Treatment of Colorectal Cancer: Rational and Progress

Author(s): Seyed Mostafa Parizadeh, Reza Jafarzadeh-Esfehani, Maryam Ghandehari, Afsaneh Rezaei-Kalat, Seyed Mohammad Reza Parizadeh, Afsane Javanbakht, Seyed Mahdi Hassanian, Gordon A. Ferns, Majid Khazaei, Amir Avan*

Journal Name: Current Drug Targets

Volume 20 , Issue 14 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Colorectal cancer (CRC) is one of the most common cancers globally and is associated with a high rate of morbidity and mortality. A large proportion of patients with early stage CRC, who undergo conventional treatments develop local recurrence or distant metastasis and in this group of advanced disease, the survival rate is low. Furthermore there is often a poor response and/or toxicity associated with chemotherapy and chemo-resistance may limit continuing conventional treatment alone. Choosing novel and targeted therapeutic approaches based on clinicopathological and molecular features of tumors in combination with conventional therapeutic approach could be used to eradicate residual micrometastasis and therefore improve patient prognosis and also be used preventively. Peptide- based vaccination therapy is one class of cancer treatment that could be used to induce tumorspecific immune responses, through the recognition of specific antigen-derived peptides in tumor cells, and this has emerged as a promising anti-cancer therapeutic strategy. The aim of this review was to summarize the main findings of recent studies in exciting field of peptide-based vaccination therapy in CRC patients as a novel therapeutic approach in the treatment of CRC.

Keywords: Peptide, vaccine, immunotherapy, colorectal cancer, treatment, clinicopathological.

[1]
Parizadeh SM, Jafarzadeh-Esfehani R, Hassanian SM, et al. Targeting cancer stem cells as therapeutic approach in the treatment of colorectal cancer. Int J Biochem Cell Biol 2019; 110: 75-83.
[http://dx.doi.org/10.1016/j.biocel.2019.02.010] [PMID: 30818083]
[2]
Kuipers EJ, Grady WM, Lieberman D, et al. Colorectal cancer. Nat Rev Dis Primers 2015; 1(15065): 15065.
[http://dx.doi.org/10.1038/nrdp.2015.65] [PMID: 27189416]
[3]
Coppedè F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol 2014; 20(4): 943-56.
[http://dx.doi.org/10.3748/wjg.v20.i4.943] [PMID: 24574767]
[4]
Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin 2009; 59(6): 366-78.
[http://dx.doi.org/10.3322/caac.20038] [PMID: 19897840]
[5]
Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 2009; 22(4): 191-7.
[http://dx.doi.org/10.1055/s-0029-1242458] [PMID: 21037809]
[6]
Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014; 383(9927): 1490-502.
[http://dx.doi.org/10.1016/S0140-6736(13)61649-9] [PMID: 24225001]
[7]
Johnson CM, Wei C, Ensor JE, et al. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control 2013; 24(6): 1207-22.
[http://dx.doi.org/10.1007/s10552-013-0201-5] [PMID: 23563998]
[8]
Kim GA, Lee HC, Choe J, et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol 2017.; S0168-8278(17): 32294-8..
[PMID: 29150142]
[9]
Parizadeh SM, Parizadeh SA, Alizade-Noghani M, et al. Association between non-alcoholic fatty liver disease and colorectal cancer. Expert Rev Gastroenterol Hepatol 2019; 13(7): 633-41.
[http://dx.doi.org/10.1080/17474124.2019.1617696] [PMID: 31092057]
[10]
Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal cancer incidence patterns in the United States, 1974–2013. JNCI. J Natl Cancer Inst 2017; 109(8)djw322
[http://dx.doi.org/10.1093/jnci/djw322]
[11]
Berry J, Vreeland T, Trappey A, et al. Cancer vaccines in colon and rectal cancer over the last decade: Lessons learned and future directions. Expert Rev Clin Immunol 2017; 13(3): 235-45.
[http://dx.doi.org/10.1080/1744666X.2016.1226132] [PMID: 27552944]
[12]
Patel SG, Ahnen DJ. Colorectal Cancer in the Young. Curr Gastroenterol Rep 2018; 20(4): 15.
[http://dx.doi.org/10.1007/s11894-018-0618-9] [PMID: 29616330]
[13]
Parizadeh SM, Jafarzadeh-Esfehani R, Ghandehari M, et al. Epigenetic drug therapy in the treatment of colorectal cancer. Curr Pharm Des 2018; 24(23): 2701-9.
[http://dx.doi.org/10.2174/1381612824666180730151904] [PMID: 30062956]
[14]
Zhang Y, Du Z, Zhang M. Biomarker development in MET-targeted therapy. Oncotarget 2016; 7(24): 37370-89.
[http://dx.doi.org/10.18632/oncotarget.8276] [PMID: 27013592]
[15]
Dermime S, Armstrong A, Hawkins RE, Stern PL. Cancer vaccines and immunotherapy. Br Med Bull 2002; 62: 149-62.
[http://dx.doi.org/10.1093/bmb/62.1.149] [PMID: 12176857]
[16]
Grenier JM, Yeung ST, Khanna KM. Combination immunotherapy: taking cancer vaccines to the next level. Front Immunol 2018; 9: 610.
[http://dx.doi.org/10.3389/fimmu.2018.00610] [PMID: 29623082]
[17]
Tanaka H, Hazama S, Iida M, et al. miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. Cancer Sci 2017; 108(11): 2229-38.
[http://dx.doi.org/10.1111/cas.13390] [PMID: 28859241]
[18]
Sasada T, Kibe S, Akagi Y, Itoh K. Personalized peptide vaccination for advanced colorectal cancer. OncoImmunology 2015; 4(5)e1005512
[http://dx.doi.org/10.1080/2162402X.2015.1005512] [PMID: 26155407]
[19]
Bahrami A, Hassanian SM, Shahid Sales S, et al. Targeting RAS signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. J Cell Physiol 2018; 233(3): 2058-66.
[http://dx.doi.org/10.1002/jcp.25890] [PMID: 28262927]
[20]
Bahrami A, Khazaei M, Hasanzadeh M, et al. Therapeutic potential of targeting pi3k/akt pathway in treatment of colorectal cancer: rational and progress. J Cell Biochem 2018; 119(3): 2460-9.
[http://dx.doi.org/10.1002/jcb.25950] [PMID: 28230287]
[21]
van de Velde CJ, Boelens PG, Borras JM, et al. EURECCA colorectal: multidisciplinary management: European consensus conference colon & rectum. Eur J Cancer 2014; 50(1)e34
[22]
van de Velde CJ, Boelens PG, Tanis PJ, et al. Experts reviews of the multidisciplinary consensus conference colon and rectal cancer 2012: science, opinions and experiences from the experts of surgery. Eur J Surg Oncol 2014; 40(4): 454-68.
[http://dx.doi.org/10.1016/j.ejso.2013.10.013] [PMID: 24268926]
[23]
Breugom AJ, Boelens PG, van den Broek CB, et al. Quality assurance in the treatment of colorectal cancer: the EURECCA initiative. Ann Oncol 2014; 25(8): 1485-92.
[http://dx.doi.org/10.1093/annonc/mdu039] [PMID: 24671742]
[24]
Shinagawa T, Tanaka T, Nozawa H, et al. Comparison of the guidelines for colorectal cancer in Japan, the USA and Europe. Annals of gastroenterological surgery 2018; 2(1): 6-12..
[http://dx.doi.org/10.1002/ags3.12047]
[25]
Watanabe T, Muro K, Ajioka Y, et al. Japanese Society for Cancer of the Colon and Rectum. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. Int J Clin Oncol 2018; 23(1): 1-34.
[http://dx.doi.org/10.1007/s10147-017-1101-6] [PMID: 28349281]
[26]
Mitchell MS, Kan-Mitchell J, Kempf RA, et al. Active specific immunotherapy for melanoma: phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res 1988; 48(20): 5883-93.
[PMID: 3262416]
[27]
Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res 2011; 17(11): 3520-6.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-3126] [PMID: 21471425]
[28]
Guo Y, Lei K, Tang L. Neoantigen vaccine delivery for personalized anticancer immunotherapy. Front Immunol 2018; 9: 1499.
[http://dx.doi.org/10.3389/fimmu.2018.01499] [PMID: 30013560]
[29]
Kajihara M, Takakura K, Kanai T, et al. Dendritic cell-based cancer immunotherapy for colorectal cancer. World J Gastroenterol 2016; 22(17): 4275-86.
[http://dx.doi.org/10.3748/wjg.v22.i17.4275] [PMID: 27158196]
[30]
Toh HC, Wang WW, Chia WK, et al. Clinical benefit of allogeneic melanoma cell lysate-pulsed autologous dendritic cell vaccine in mage-positive colorectal cancer patients. Clin Cancer Res 2009; 15(24): 7726-36.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1537] [PMID: 19996212]
[31]
Garg AD, Coulie PG, Van den Eynde BJ, Agostinis P. Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape. Trends Immunol 2017; 38(8): 577-93.
[http://dx.doi.org/10.1016/j.it.2017.05.006] [PMID: 28610825]
[32]
Hasson SSAA, Al-Busaidi JKZ, Sallam TA. The past, current and future trends in DNA vaccine immunisations. Asian Pac J Trop Biomed 2015; 5(5): 344-53.
[http://dx.doi.org/10.1016/S2221-1691(15)30366-X]
[33]
Staff C, Mozaffari F, Haller BK, Wahren B, Liljefors M. A Phase I safety study of plasmid DNA immunization targeting carcinoembryonic antigen in colorectal cancer patients. Vaccine 2011; 29(39): 6817-22.
[http://dx.doi.org/10.1016/j.vaccine.2010.12.063] [PMID: 21195077]
[34]
Khan KH. DNA vaccines: roles against diseases. Germs 2013; 3(1): 26-35.
[http://dx.doi.org/10.11599/germs.2013.1034] [PMID: 24432284]
[35]
McNamara MA, Nair SK, Holl EK. RNA-Based Vaccines in Cancer Immunotherapy. J Immunol Res 2015; 2015(10)794528
[PMID: 26665011]
[36]
Aurisicchio L, Mennuni C, Giannetti P, et al. Immunogenicity and safety of a DNA prime/adenovirus boost vaccine against rhesus CEA in nonhuman primates. Int J Cancer 2007; 120(11): 2290-300.
[http://dx.doi.org/10.1002/ijc.22555] [PMID: 17304509]
[37]
Bartlett DL, Liu Z, Sathaiah M, et al. Oncolytic viruses as therapeutic cancer vaccines. Mol Cancer 2013; 12(1): 103.
[http://dx.doi.org/10.1186/1476-4598-12-103] [PMID: 24020520]
[38]
Germic N, Frangez Z, Yousefi S, Simon HU. Regulation of the innate immune system by autophagy: Monocytes, macrophages, dendritic cells and antigen presentation. Cell Death Differ 2019; 26(4): 715-27.
[http://dx.doi.org/10.1038/s41418-019-0297-6] [PMID: 30737475]
[39]
Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: Function, dysfunction and human pathology. Nat Rev Immunol 2015; 15(6): 388-400.
[http://dx.doi.org/10.1038/nri3839] [PMID: 25998963]
[40]
Parmiani G, Russo V, Maccalli C, et al. Perforin and granzymes: Function, dysfunction and human pathology. Hum Vaccin Immunother 3175 10(11 ): 3175-8..
[http://dx.doi.org/10.4161/hv.29418]
[41]
Bijker MS, Melief CJ, Offringa R, van der Burg SH. Design and development of synthetic peptide vaccines: Past, present and future. Expert Rev Vaccines 2007; 6(4): 591-603.
[http://dx.doi.org/10.1586/14760584.6.4.591] [PMID: 17669012]
[42]
Tsuruma T, Hata F, Torigoe T, et al. Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer. J Transl Med 2004; 2(1): 19.
[http://dx.doi.org/10.1186/1479-5876-2-19] [PMID: 15193151]
[43]
Kibe S, Yutani S, Motoyama S, et al. Phase II study of personalized peptide vaccination for previously treated advanced colorectal cancer. Cancer Immunol Res 2014; 2(12): 1154-62.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0035] [PMID: 25351849]
[44]
Miyagi Y, Imai N, Sasatomi T, et al. Induction of cellular immune responses to tumor cells and peptides in colorectal cancer patients by vaccination with SART3 peptides. Clin Cancer Res 2001; 7(12): 3950-62.
[PMID: 11751487]
[45]
Sato Y, Maeda Y, Shomura H, et al. A phase I trial of cytotoxic T-lymphocyte precursor-oriented peptide vaccines for colorectal carcinoma patients. Br J Cancer 2004; 90(7): 1334-42.
[http://dx.doi.org/10.1038/sj.bjc.6601711] [PMID: 15054451]
[46]
Hayes SA, Clarke S, Pavlakis N, Howell VM. The role of proteomics in the age of immunotherapies. Mamm Genome 2018; 29(11-12): 757-69.
[http://dx.doi.org/10.1007/s00335-018-9763-6] [PMID: 30046851]
[47]
Khong H, Overwijk WW. Adjuvants for peptide-based cancer vaccines. J Immunother Cancer 2016; 4(1): 56.
[http://dx.doi.org/10.1186/s40425-016-0160-y] [PMID: 27660710]
[48]
Cox JC, Coulter AR. Adjuvants--a classification and review of their modes of action. Vaccine 1997; 15(3): 248-56.
[http://dx.doi.org/10.1016/S0264-410X(96)00183-1] [PMID: 9139482]
[49]
O’Hagan DT, Valiante NM. Recent advances in the discovery and delivery of vaccine adjuvants. Nat Rev Drug Discov 2003; 2(9): 727-35.
[http://dx.doi.org/10.1038/nrd1176] [PMID: 12951579]
[50]
Parizadeh SM, Ghandehari M, Heydari-Majd M, et al. Toll-like receptors signaling pathways as a potential therapeutic target in cardiovascular disease. Curr Pharm Des 2018; 24(17): 1887-98.
[http://dx.doi.org/10.2174/1381612824666180614090224] [PMID: 29898648]
[51]
Moradi-Marjaneh R, Hassanian SM, Fiuji H, et al. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J Cell Physiol 2018; 233(8): 5613-22.
[http://dx.doi.org/10.1002/jcp.26273] [PMID: 29150944]
[52]
Lindblad EB, Schønberg NE. Aluminum adjuvants: preparation, application, dosage, and formulation with antigen Vaccine Adjuvants 2010; 41-58.
[53]
Didierlaurent AM, Morel S, Lockman L, et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 2009; 183(10): 6186-97.
[http://dx.doi.org/10.4049/jimmunol.0901474] [PMID: 19864596]
[54]
Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008; 453(7198): 1122-6.
[http://dx.doi.org/10.1038/nature06939] [PMID: 18496530]
[55]
Reddy ST, Rehor A, Schmoekel HG, Hubbell JA, Swartz MA. In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J Control Release 2006; 112(1): 26-34.
[http://dx.doi.org/10.1016/j.jconrel.2006.01.006] [PMID: 16529839]
[56]
Walter E, Dreher D, Kok M, et al. Hydrophilic poly(DL-lactide-co-glycolide) microspheres for the delivery of DNA to human-derived macrophages and dendritic cells. J Control Release 2001; 76(1-2): 149-68.
[http://dx.doi.org/10.1016/S0168-3659(01)00413-8] [PMID: 11532321]
[57]
Johansen P, Mohanan D, Martínez-Gómez JM, Kündig TM, Gander B. Lympho-geographical concepts in vaccine delivery. J Control Release 2010; 148(1): 56-62.
[http://dx.doi.org/10.1016/j.jconrel.2010.05.019] [PMID: 20562028]
[58]
Sato Y, Fujiwara T, Mine T, et al. Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients. Cancer Sci 2007; 98(7): 1113-9.
[http://dx.doi.org/10.1111/j.1349-7006.2007.00498.x] [PMID: 17459063]
[59]
Hattori T, Mine T, Komatsu N, et al. Immunological evaluation of personalized peptide vaccination in combination with UFT and UZEL for metastatic colorectal carcinoma patients. Cancer Immunol Immunother 2009; 58(11): 1843-52.
[http://dx.doi.org/10.1007/s00262-009-0695-6] [PMID: 19396597]
[60]
Rahma OE, Hamilton JM, Wojtowicz M, et al. The immunological and clinical effects of mutated ras peptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors. J Transl Med 2014; 12(1): 55.
[http://dx.doi.org/10.1186/1479-5876-12-55] [PMID: 24565030]
[61]
Bahrami A, Khazaei M, Hassanian SM, et al. Targeting the tumor microenvironment as a potential therapeutic approach in colorectal cancer: Rational and progress. J Cell Physiol 2018; 233(4): 2928-36.
[http://dx.doi.org/10.1002/jcp.26041] [PMID: 28574572]
[62]
Bahrami A, Hassanian SM, Khazaei M, et al. The Therapeutic potential of targeting tumor microenvironment in breast cancer: rational strategies and recent progress. J Cell Biochem 2018; 119(1): 111-22.
[http://dx.doi.org/10.1002/jcb.26183] [PMID: 28574616]
[63]
Goydos JS, Elder E, Whiteside TL, Finn OJ, Lotze MT. A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma. J Surg Res 1996; 63(1): 298-304.
[http://dx.doi.org/10.1006/jsre.1996.0264] [PMID: 8667619]
[64]
González G, Crombet T, Catalá M, et al. A novel cancer vaccine composed of human-recombinant epidermal growth factor linked to a carrier protein: report of a pilot clinical trial. Ann Oncol 1998; 9(4): 431-5.
[http://dx.doi.org/10.1023/A:1008261031034] [PMID: 9636835]
[65]
Moulton HM, Yoshihara PH, Mason DH, Iversen PL, Triozzi PL. Active specific immunotherapy with a β-human chorionic gonadotropin peptide vaccine in patients with metastatic colorectal cancer: antibody response is associated with improved survival. Clin Cancer Res 2002; 8(7): 2044-51.
[PMID: 12114402]
[66]
Mazzaferro V, Coppa J, Carrabba MG, et al. Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 2003; 9(9): 3235-45.
[PMID: 12960108]
[67]
Tsuruma T, Hata F, Torigoe T, et al. Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer. J Transl Med 2004; 2(1): 19.
[http://dx.doi.org/10.1186/1479-5876-2-19] [PMID: 15193151]
[68]
Mukherjee P, Pathangey LB, Bradley JB, et al. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model. Vaccine 2007; 25(9): 1607-18.
[http://dx.doi.org/10.1016/j.vaccine.2006.11.007] [PMID: 17166639]
[69]
Tan G-H, Li Y-N, Huang F-Y, et al. Combination of recombinant xenogeneic endoglin DNA and protein vaccination enhances anti-tumor effects. Immunol Invest 2007; 36(4): 423-40.
[http://dx.doi.org/10.1080/08820130701361103] [PMID: 17691024]
[70]
Seledtsov VI, Niza NA, Felde MA, et al. Xenovaccinotherapy for colorectal cancer. Biomed Pharmacother 2007; 61(2-3): 125-30.
[http://dx.doi.org/10.1016/j.biopha.2006.09.016] [PMID: 17258887]
[71]
Kaumaya PT, Foy KC, Garrett J, et al. Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors. J Clin Oncol 2009; 27(31): 5270-7.
[http://dx.doi.org/10.1200/JCO.2009.22.3883] [PMID: 19752336]
[72]
Okuno K, Sugiura F, Inoue K, Sukegawa Y. Clinical trial of a 7-peptide cocktail vaccine with oral chemotherapy for patients with metastatic colorectal cancer. Anticancer Res 2014; 34(6): 3045-52.
[PMID: 24922671]
[73]
Murahashi M, Hijikata Y, Yamada K, et al. Phase I clinical trial of a five-peptide cancer vaccine combined with cyclophosphamide in advanced solid tumors. Clin Immunol 2016; 166-167: 48-58.
[http://dx.doi.org/10.1016/j.clim.2016.03.015] [PMID: 27072896]
[74]
Correale P, Botta C, Martino EC, et al. Phase Ib study of poly-epitope peptide vaccination to thymidylate synthase (TSPP) and GOLFIG chemo-immunotherapy for treatment of metastatic colorectal cancer patients. OncoImmunology 2015; 5(4)e1101205
[http://dx.doi.org/10.1080/2162402X.2015.1101205] [PMID: 27141384]
[75]
Goodwin TJ, Huang L. Investigation of phosphorylated adjuvants co-encapsulated with a model cancer peptide antigen for the treatment of colorectal cancer and liver metastasis. Vaccine 2017; 35(19): 2550-7.
[http://dx.doi.org/10.1016/j.vaccine.2017.03.067] [PMID: 28385609]
[76]
Taniguchi H, Iwasa S, Yamazaki K, et al. Phase 1 study of OCV-C02, a peptide vaccine consisting of two peptide epitopes for refractory metastatic colorectal cancer. Cancer Sci 2017; 108(5): 1013-21.
[http://dx.doi.org/10.1111/cas.13227] [PMID: 28266765]
[77]
Kawamura J, Sugiura F, Sukegawa Y, et al. Multicenter, phase II clinical trial of peptide vaccination with oral chemotherapy following curative resection for stage III colorectal cancer. Oncol Lett 2018; 15(4): 4241-7.
[PMID: 29541190]
[78]
Ebrahimnezhad S, Jazayeri M, Hassanian SM, Avan A. Current status and prospective regarding the therapeutic potential of natural autoantibodies in cancer therapy. J Cell Physiol 2017; 232(10): 2649-52.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 14
Year: 2019
Published on: 14 October, 2019
Page: [1486 - 1495]
Pages: 10
DOI: 10.2174/1389450120666190619121658
Price: $65

Article Metrics

PDF: 35
HTML: 5
EPUB: 1
PRC: 1