Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53-DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non-expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non-expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC.
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Zou W . Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5: 263–274.
Khong HT, Restifo NP . Natural selection of tumor variants in the generation of "tumor escape" phenotypes. Nat Immunol 2002; 3: 999–1005.
Bilgin B, Sendur MA, Bülent Akıncı M, Şener Dede D, Yalçın B . Targeting the PD-1 pathway: a new hope for gastrointestinal cancers. Curr Med Res Opin 2017; 31: 1–11.
Ilie M, Hofman V, Dietel M, Soria JC, Hofman P . Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Arch 2016; 468: 511–525.
O'Donnell JS, Smyth MJ, Teng MW . Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade? Genome Med 2016; 8: 111.
O'Donnell JS, Long GV, Scolyer RA, Teng MW, Smyth MJ . Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev 2017; 52: 71–81.
Sawada Y, Yoshikawa T, Shimomura M, Iwama T, Endo I, Nakatsura T . Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes. Int J Oncol 2015; 46: 28–36.
Reyes D, Salazar L, Espinoza E, Pereda C, Castellón E, Valdevenito R et al. Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients. Br J Cancer 2013; 109: 1488–1497.
Lee JH, Lee Y, Lee M, Heo MK, Song JS, Kim KH et al. A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Br J Cancer 2015; 113: 1666–1676.
Xi HB, Wang GX, Fu B, Liu WP, Li Y . Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer. Biol Pharm Bull 2015; 38: 827–835.
Kadowaki N . Dendritic cells: a conductor of T cell differentiation. Allergol Int 2007; 56: 193–199.
Manicassamy S, Pulendran B . Dendritic cell control of tolerogenic responses. Immunol Rev 2011; 241: 206–227.
Sakai K, Shimodaira S, Maejima S, Udagawa N, Sano K, Higuchi Y et al. Dendritic cell-based immunotherapy targeting Wilms' tumor 1 in patients with recurrent malignant glioma. J Neurosurg 2015; 123: 989–997.
Anassi E, Ndefo UA . Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer. P T 2011; 36: 197–202.
Schuler PJ, Harasymczuk M, Visus C, Deleo A, Trivedi S, Lei Y et al. Phase I dendritic cell p53 peptide vaccine for head and neck cancer. Clin Cancer Res 2014; 20: 2433–2444.
DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ . Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A 1979; 76: 2420–2424.
Levine AJ . p53, the cellular gatekeeper for growth and division. Cell 1997; 88: 323–331.
Vogelstein B, Lane D, Levine AJ . Surfing the p53 network. Nature 2000; 408: 307–310.
Gabrilovich DI, Nadaf S, Corak J, Berzofsky JA, Carbone DP . Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. Cell Immunol 1996; 170: 111–119.
Zitvogel L, Mayordomo JI, Tjandrawan T, DeLeo AB, Clarke MR, Lotze MT et al. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med. 1996; 183: 87–97.
Noguchi Y, Chen YT, Old LJ . A mouse mutant p53 product recognized by CD4+ and CD8+ T cells. Proc Natl Acad Sci U S A. 1994; 91: 3171–3175.
Theobald M, Biggs J, Dittmer D, Levine AJ, Sherman LA . Targeting p53 as a general tumor antigen. Proc Natl Acad Sci U S A 1995; 92: 11993–11997.
Röpke M, Hald J, Guldberg P, Zeuthen J, Nørgaard L, Fugger L et al. Spontaneous human squamous cell carcinomas are killed by a human cytotoxic T lymphocyte clone recognizing a wild-type p53-derived peptide. Proc Natl Acad Sci U S A 1996; 93: 14704–14707.
Nijman HW, Van der Burg SH, Vierboom MP, Houbiers JG, Kast WM, Melief CJ . p53, a potential target for tumor-directed T cells. Immunol Lett 1994; 40: 171–178.
Gnjatic S, Cai Z, Viguier M, Chouaib S, Guillet JG, Choppin J . Accumulation of the p53 protein allows recognition by human CTL of a wild-type p53 epitope presented by breast carcinomas and melanomas. J Immunol 1998; 160: 328–333.
Papadopoulos KP, Hesdorffer CS, Suciu-Foca N, Hibshoosh H, Harris PE . Wild-type p53 epitope naturally processed and presented by an HLA-B haplotype on human breast carcinoma cells. Clin Cancer Res 1999; 5: 2089–2093.
Chikamatsu K, Nakano K, Storkus WJ, Appella E, Lotze MT, Whiteside TL et al. Generation of anti-p53 cytotoxic T lymphocytes from human peripheral blood using autologous dendritic cells. Clin Cancer Res 1999; 5: 1281–1288.
Nikitina EY, Clark JI, Van Beynen J, Chada S, Virmani AK, Carbone DP et al. Dendritic cells transduced with full-length wild-type p53 generate antitumor cytotoxic T lymphocytes from peripheral blood of cancer patients. Clin Cancer Res 2001; 7: 127–135.
Marks JR, Davidoff AM, Kerns BJ, Humphrey PA, Pence JC, Dodge RK et al. Overexpression and mutation of p53 in epithelial ovarian cancer. Cancer Res 1991; 51: 2979–2984.
Tolcher AW, Hao D, de Bono J, Miller A, Patnaik A, Hammond LA et al. Phase I, pharmacokinetic, and pharmacodynamic study of intravenously administered Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene, in patients with advanced cancer. J Clin Oncol 2006; 24: 2052–2058.
Kanegae Y, Makimura M, Saito I . A simple and efficient method for purification of infectious recombinant adenovirus. Jpn J Med Sci Biol 1994; 47: 157–166.
Osugi Y, Vuckovic S, Hart DN . Myeloid blood CD11c(+) dendritic cells and monocyte-derived dendritic cells differ in their ability to stimulate T lymphocytes. Blood 2002; 100: 2858–2866.
Russell PJ, Kingsley EA . Human prostate cancer cell lines. Methods Mol Med 2003; 81: 21–39.
Yaginuma Y, Westphal H . Analysis of the p53 gene in human uterine carcinoma cell lines. Cancer Res 1991; 51: 6506–6509.
Sasaki R, Shirakawa T, Zhang ZJ, Tamekane A, Matsumoto A, Sugimura K et al. Additional gene therapy with Ad5CMV-p53 enhanced the efficacy of radiotherapy in human prostate cancer cells. Int J Radiat Oncol Biol Phys 2001; 51: 1336–1345.
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–422.
Liu Y, Kulesz-Martin M . P53 regulation and function in normal cells and tumors. Medicina (B Aires) 2000; 60: 9–11.
Ashcroft M, Vousden KH . Regulation of p53 stability. Oncogene 1999; 18: 7637–7643.
Eastham JA, Stapleton AM, Gousse AE, Timme TL, Yang G, Slawin KM et al. Association of p53 mutations with metastatic prostate cancer. Clin Cancer Res 1995; 1: 1111–1118.
Chappell WH, Lehmann BD, Terrian DM, Abrams SL, Steelman LS, McCubrey JA . p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3. Cell Cycle 2012; 11: 4579–4588.
Pisters LL, Pettaway CA, Troncoso P, McDonnell TJ, Stephens LC, Wood CG et al. Evidence that transfer of functional p53 protein results in increased apoptosis in prostate cancer. Clin Cancer Res 2004; 10: 2587–2593.
Svane IM, Pedersen AE, Johansen JS, Johnsen HE, Nielsen D, Kamby C et al. Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers. Cancer Immunol Immunother 2007; 56: 1485–1499.
Chiappori AA, Soliman H, Janssen WE, Antonia SJ, Gabrilovich DI . INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect. Expert Opin Biol Ther 2010; 10: 983–991.
Antonia SJ, Mirza N, Fricke I, Chiappori A, Thompson P, Williams N et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res 2006; 12: 878–887.
Thomas DJ, Robinson M, King P, Hasan T, Charlton R, Martin J et al. p53 expression and clinical outcome in prostate cancer. Br J Urol 1993; 72: 778–781.
Shirakawa T, Gotoh A, Gardner TA, Kao C, Zhang ZJ, Matsubara S et al. p53 adenoviral vector (Ad-CMV-p53) induced prostatic growth inhibition of primary cultures of human prostate and an experimental rat model. J Gene Med 2000; 2: 426–432.
Shayakhmetov D.M, Gaggar A, Ni S, Li ZY, Lieber A . Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol 2005; 79: 7478–7491.
This work was partially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 26461503.The materials including rAd-p53, rAd-LacZ, p53-DCs, and LacZ-DCs, were constructed only for this study, and were not commercially available.
The authors declare no conflict of interest.
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Saito, H., Kitagawa, K., Yoneda, T. et al. Combination of p53-DC vaccine and rAd-p53 gene therapy induced CTLs cytotoxic against p53-deleted human prostate cancer cells in vitro. Cancer Gene Ther 24, 289–296 (2017) doi:10.1038/cgt.2017.21
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