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01-02-2016 | Original Article

A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer

Authors: Masanori Noguchi, Fukuko Moriya, Noriko Koga, Satoko Matsueda, Tetsuro Sasada, Akira Yamada, Tatsuyuki Kakuma, Kyogo Itoh

Published in: Cancer Immunology, Immunotherapy | Issue 2/2016

Abstract

This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL) and immunoglobulin G responses were measured before and after PPV. The incidence of grade 3 or 4 hematologic adverse events was higher in the PPV plus CPA arm than in the PPV alone arm. Decrease in Treg and increase in MDSC were more pronounced in PPV plus CPA treatment than in PPV alone (p = 0.036 and p = 0.048, respectively). There was no correlation between the changes in Treg or MDSC and CTL response. There was no difference in positive immune responses between the two arms, although overall survival in patients with positive immune responses was longer than in those with negative immune responses (p = 0.001). Significant differences in neither progression-free survival nor overall survival were observed between the two arms. Low-dose CPA showed no change in the antitumor effect of PPV, possibly due to the simultaneous decrease in Treg and increase in MDSC, in patients under PPV.

Quatromoni JG, Eruslanov E (2012) Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res 4:376–389PubMedCentralPubMed

Miller AM, Lundberg K, Ozenci V, Banham AH, Hellström M, Eqevad L et al (2006) CD4⁺CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol 177:7398–7405CrossRefPubMed

Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM et al (2008) Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 14:3254–3261PubMedCentralCrossRefPubMed

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949CrossRefPubMed

Karagöz B, Bilgi O, Gümüs M, Erikçi AA, Sayan O, Türken O, Gumus M et al (2010) CD8⁺CD28⁻ cells and CD4⁺CD25⁺ regulatory T cells in the peripheral blood of advanced stage lung cancer patients. Med Oncol 27:29–33CrossRefPubMed

Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4⁺CD25⁺ regulatory T cells in patients with gastro-intestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98:1089–1099CrossRefPubMed

Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM (2006) Intratumoral CD4⁺CD25⁺ regulatory T-cell-mediated suppression of infiltrating CD4⁺ T cells in B-cell non-Hodgkin lymphoma. Blood 107:3639–3646PubMedCentralCrossRefPubMed

Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68:5439–5449PubMedCentralCrossRefPubMed

Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59PubMedCentralCrossRefPubMed

10.

Sasada T, Komatsu N, Suekane S, Yamada A, Noguchi M, Itoh K (2010) Overcoming the hurdles of randomized clinical trials of therapeutic cancer vaccine. Eur J Cancer 46:1514–1519CrossRefPubMed

11.

Noguchi M, Sasada T, Itoh K (2013) Personalized peptide vaccination: a new approach for advanced cancer as therapeutic cancer vaccine. Cancer Immunol Immunother 62:919–929CrossRefPubMed

12.

Noguchi M, Kobayashi K, Suetsugu N, Tomiyasu K, Suekane S, Yamada A et al (2003) Induction of cellular and humoral immune responses to tumor cells and peptides in HLA-A24 positive hormone-refractory prostate cancer patients by peptide vaccination. Prostate 57:80–92CrossRefPubMed

13.

Noguchi M, Itoh K, Suekane S, Yao A, Suetsugu N, Katagiri K et al (2004) Phase I trial of patient-oriented vaccination in HLA-A2 positive patients with metastatic hormone refractory prostate cancer. Cancer Sci 95:77–84CrossRefPubMed

14.

Noguchi M, Uemura H, Naito S, Akaza H, Yamada A, Itoh K (2011) A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low-dose estramustine in HLA-A24-positive patients with castration-resistant prostate cancer. Prostate 71:470–479CrossRefPubMed

15.

Noguchi M, Kakuma T, Uemura H, Nasu Y, Kumon H, Hirao Y et al (2010) A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer. Cancer Immunol Immunother 59:1001–1009CrossRefPubMed

16.

Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H (2005) Inhibition of CD4⁺25⁺ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105:2862–2868CrossRefPubMed

17.

Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J et al (2004) Thrombospondin-1 associated with tumor microenvironment contributed to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 64:1570–1574CrossRefPubMed

18.

Komatsu N, Shichijo S, Nakagawa M, Itoh K (2004) New multiplexed flow cytometric assay to measure anti-peptide antibody: a novel tool for monitoring immune responses to peptides used for immunization. Scand J Clin Lab Invest 64:535–545CrossRefPubMed

19.

Yoshiyama K, Terazaki Y, Matsueda S, Shichijo S, Noguchi M, Yamada A et al (2012) Personalized peptide vaccination in patients with refractory non-small cell lung cancer. Int J Oncol 40:1492–1500PubMed

20.

Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F et al (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13:73–80CrossRefPubMed

21.

Scharovsky OG, Mainetti LE, Rozados VR (2009) Metronomic chemotherapy: changing the paradigm that more is better. Curr Oncol 16:7–15PubMedCentralCrossRefPubMed

22.

Nelius T, Rinard K, Filleur S (2011) Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer—review of the literature. Cancer Treat Rev 37:444–455CrossRefPubMed

23.

Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C et al (2004) CD4⁺CD25⁺ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34:336–344CrossRefPubMed

24.

Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F et al (2007) Metronomic cyclophosphamide regimen selectively depletes CD4⁺CD25⁺ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56:641–648CrossRefPubMed

25.

Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S et al (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res 67:425PubMedCentralCrossRefPubMed

26.

Angulo I, de las Heras FG, Garcia-Bustos JF, Gargallo D, Muñoz-Fernández MA, Fresno M (2000) Nitric oxide-producing CD11b(+)Ly-6G(Gr-1)(+)CD31(ER-MP12)(+) cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice. Blood 95:212–220PubMed

27.

Peláez B, Campillo JA, López-Asenjo JA, Subiza JL (2001) Cyclophosphamide induces the development of early myeloid cells suppressing tumor cell growth by a nitric oxide-dependent mechanism. J Immunol 166:6608–6615CrossRefPubMed

28.

Shimizu J, Yamasaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25⁺CD4⁺ T cells: a common basis between tumor immunity and auto immunity. J Immunol 163:5211–5218PubMed

29.

Shimizu J, Yamasaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25⁺CD4⁺ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142CrossRefPubMed

30.

Yang R, Cai Z, Zhng Yutzy WH 4th, Roby KF, Roden RB (2006) CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+ CD11b+ myeloid cells. Cancer Res 66:6807–6815CrossRefPubMed

31.

Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J et al (2006) Gr-1+ CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66:1123–1131CrossRefPubMed

32.

Salem ML, Kadima AN, El-Nagger SA, Rubinstein MP, Chen Y, Gillanders WE, Cole DJ (2007) Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD9⁺ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells. J Immunother 30:40–53CrossRefPubMed

33.

Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP et al (2005) Recruitment of latent pools of high-avidity CD8⁺ T cells to the antitumor immune response. J Exp Med 201:1591–1602PubMedCentralCrossRefPubMed

34.

Berd D, Maguire HC Jr, Mastrangelo MJ (1986) Induction of cell-mediated immunity to autologous melanoma cells and regression of metastasis after treatment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res 46:2572–2577PubMed

35.

Sahasrabudhe DM, deKernion JB, Pontes JE, Ryan DM, O’Donnell RW, Marquis DM et al (1986) Specific immunotherapy with suppressor function inhibition for metastatic renal carcinoma. J Biol Response Mod 5:581–594PubMed

36.

Audia S, Nicolas A, Cathelin D, Larmonier N, Ferrand C, Foucher P et al (2007) Increase of CD4⁺CD25⁺ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4⁺CD25⁺ T lymphocytes. Clin Exp Immunol 150:523–530PubMedCentralCrossRefPubMed

37.

Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M et al (2009) Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J Clin Oncol 27:5911–5918PubMedCentralCrossRefPubMed

38.

Ge Y, Domschke C, Stoiber N, Schott S, Heil J, Rom J et al (2012) Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother 61:353–362CrossRefPubMed

Title: A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer
Authors: Masanori Noguchi
Fukuko Moriya
Noriko Koga
Satoko Matsueda
Tetsuro Sasada
Akira Yamada
Tatsuyuki Kakuma
Kyogo Itoh
Publication date: 01-02-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 2/2016
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-015-1781-6

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