Dendritic Cells (White Blood Cells) Vaccination for Advanced Melanoma

Melanoma Clinical Trial

Official title:

Mature Dendritic Cell Vaccination Against gp100 in Patients With Advanced Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00683670
• Other study ID #: 07-0652 / 826850
• Status: Completed
• Phase: Phase 1
• First received: May 19, 2008
• Last updated: February 21, 2017
• Start date: August 2008
• Est. completion date: June 2016

Study information

• Verified date: February 2017
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate a method of using dendritic cells (a kind of white blood cell) as a vaccine to stimulate your own immune system to react to your melanoma cells.

Description:

Eligible patients that provide written informed consent will undergo apheresis to collect blood mononuclear cells for vaccine production. All patients will be given cyclophosphamide 300mg/m2 IV three days prior to vaccine dose #1 in order to deplete regulatory T cells. All patients will receive mature DC for each dose of vaccine. For each dose all patients will receive autologous dendritic cells pulsed with 2 gp100 melanoma peptides (G209-2M and G280-9V) plus up to an additional 10 unique melanoma tumor-specific peptides. All patients will receive booster doses with mature DC. The DC vaccine will be given intravenously every three weeks for a total of six vaccine doses. Peripheral blood (16 ml) will be taken weekly to monitor the immune response to each peptide by tetramer assay. Apheresis is repeated after vaccine dose #3 and dose #6 in order to collect PBMC for immune monitoring. Restaging is performed after three and six vaccine doses. Patients with stable disease or better (partial response/complete response) after six doses will be eligible to receive additional vaccinations as maintenance therapy every 2 months until progression.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Unresectable stage III and stage IV M1a/M1b/M1c melanoma including patients with uveal melanoma

• Age = 18 years

• Life expectancy = 4 months

• ECOG performance status 0-2

• At least 28 days from prior treatment (including adjuvant interferon) except in cases of a BRAF inhibitor (such as vemurafenib); concurrent treatment with a BRAF inhibitor +/- MEK inhibitor is permitted

• Required initial laboratory values (submitted within 14 days prior to registration):

• WBC >3,000/mm3

• Hg = 9.0 gm/dl

• Platelets >75,000/mm3

• Serum Bilirubin < 2.0 mg/dl

• Serum Creatinine < 2.0 mg/dl

• Sexually active women of childbearing potential must use effective birth control during the trial and for at least two months following the trial, and sexually active men must be willing to avoid fathering a new child while receiving therapy.

Exclusion Criteria:

• Prior treatment with more than one line of cytotoxic chemotherapy; prior treatment with one line of cytotoxic chemotherapy is permitted. Prior treatment with targeted therapy (such as ipilumumab, anti-PD1, and BRAF inhibitor) is permitted.

• Active untreated CNS metastasis

• Active infection

• Prior malignancy (except non-melanoma skin cancer) within 3 years

• Pregnant or nursing

• Concurrent treatment with corticosteroids; local (inhaled or topical) steroids are permitted.

• Inability to provide adequate informed consent

• Known allergy to eggs

• Prior history or uveitis or autoimmune inflammatory eye disease.

• Known positivity for hepatitis BsAg, hepatitis C antibody, or HIV antibody.

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• cyclophosphamide

Biological:
• Mature dendritic cell vaccine

Locations

Country	Name	City	State
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
University of Pennsylvania

Country where clinical trial is conducted

United States, 

References & Publications (51)

Antony PA, Restifo NP. CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2. J Immunother. 2005 Mar-Apr;28(2):120-8. Review. — View Citation

Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. Review. — View Citation

Bakker AB, Schreurs MW, de Boer AJ, Kawakami Y, Rosenberg SA, Adema GJ, Figdor CG. Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J Exp Med. 1994 Mar 1;179(3):1005-9. — View Citation

Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res. 2001 Sep 1;61(17):6451-8. — View Citation

Banchereau J, Schuler-Thurner B, Palucka AK, Schuler G. Dendritic cells as vectors for therapy. Cell. 2001 Aug 10;106(3):271-4. Review. — View Citation

Bass KK, Mastrangelo MJ. Immunopotentiation with low-dose cyclophosphamide in the active specific immunotherapy of cancer. Cancer Immunol Immunother. 1998 Sep;47(1):1-12. Review. — View Citation

Belardelli F, Ferrantini M, Parmiani G, Schlom J, Garaci E. International meeting on cancer vaccines: how can we enhance efficacy of therapeutic vaccines? Cancer Res. 2004 Sep 15;64(18):6827-30. — View Citation

Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. — View Citation

Cox AL, Skipper J, Chen Y, Henderson RA, Darrow TL, Shabanowitz J, Engelhard VH, Hunt DF, Slingluff CL Jr. Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science. 1994 Apr 29;264(5159):716-9. — View Citation

Eggermont AM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? Eur J Cancer. 2004 Aug;40(12):1825-36. Review. — View Citation

Ernsdorf MS, C.T., and L Titus-Ernsdorf. 2003. Update: Medical therapy for cutaneous melanoma. ASCO Educational Book 39:198-207.

Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med. 2004 May;10(5):475-80. Review. — View Citation

Golub SH, Morton DL. Sensitisation of lymphocytes in vitro against human melanoma-associated antigens. Nature. 1974 Sep 13;251(5471):161-3. — View Citation

Grover A, Kim GJ, Lizée G, Tschoi M, Wang G, Wunderlich JR, Rosenberg SA, Hwang ST, Hwu P. Intralymphatic dendritic cell vaccination induces tumor antigen-specific, skin-homing T lymphocytes. Clin Cancer Res. 2006 Oct 1;12(19):5801-8. — View Citation

Hoon DS, Foshag LJ, Nizze AS, Bohman R, Morton DL. Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res. 1990 Sep 1;50(17):5358-64. — View Citation

Huncharek M, Caubet JF, McGarry R. Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res. 2001 Feb;11(1):75-81. — View Citation

Ingram SB, O'Rourke MG. DC therapy for metastatic melanoma. Cytotherapy. 2004;6(2):148-53. Review. — View Citation

Jemal, A., T. Murray, E. Ward, A. Samuels, R.C. Tiwari, A. Ghafoor, E.J. Feuer, and M.J. Thun. 2007. Cancer statistics, 2007. CA Cancer J Clin 57:42-59.

Kawakami Y, Eliyahu S, Jennings C, Sakaguchi K, Kang X, Southwood S, Robbins PF, Sette A, Appella E, Rosenberg SA. Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression. J Immunol. 1995 Apr 15;154(8):3961-8. — View Citation

Kawakami Y, Robbins PF, Wang RF, Parkhurst M, Kang X, Rosenberg SA. The use of melanosomal proteins in the immunotherapy of melanoma. J Immunother. 1998 Jul;21(4):237-46. Review. — View Citation

Keilholz U, Weber J, Finke JH, Gabrilovich DI, Kast WM, Disis ML, Kirkwood JM, Scheibenbogen C, Schlom J, Maino VC, Lyerly HK, Lee PP, Storkus W, Marincola F, Worobec A, Atkins MB. Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy. J Immunother. 2002 Mar-Apr;25(2):97-138. Review. — View Citation

Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, Shimizu J, Nomura T, Chiba T, Sakaguchi S. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med. 2005 Oct 3;202(7):885-91. Erratum in: J Exp Med. 2012 Feb 13;209(2):423. — View Citation

Lin AM, Hershberg RM, Small EJ. Immunotherapy for prostate cancer using prostatic acid phosphatase loaded antigen presenting cells. Urol Oncol. 2006 Sep-Oct;24(5):434-41. Review. — View Citation

Linette GP, Zhang D, Hodi FS, Jonasch EP, Longerich S, Stowell CP, Webb IJ, Daley H, Soiffer RJ, Cheung AM, Eapen SG, Fee SV, Rubin KM, Sober AJ, Haluska FG. Immunization using autologous dendritic cells pulsed with the melanoma-associated antigen gp100-derived G280-9V peptide elicits CD8+ immunity. Clin Cancer Res. 2005 Nov 1;11(21):7692-9. — View Citation

Lotze, M.T., R.M. Dallal, J.M. Kirkwood, and J.C. Flickinger. 2001. Cutaneous Melanoma. In Cancer:Principles and Practice of Oncology. V.T. DeVita, S. Hellman, and S.A. Rosenberg, editors. Lippincott, Williams, & Wilkins, Philadelphia. 2012-2069.

Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005 Apr 1;105(7):2862-8. — View Citation

Marincola FM, Hijazi YM, Fetsch P, Salgaller ML, Rivoltini L, Cormier J, Simonis TB, Duray PH, Herlyn M, Kawakami Y, Rosenberg SA. Analysis of expression of the melanoma-associated antigens MART-1 and gp100 in metastatic melanoma cell lines and in in situ lesions. J Immunother Emphasis Tumor Immunol. 1996 May;19(3):192-205. — View Citation

Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell. 2001 Aug 10;106(3):255-8. Review. — View Citation

Miles DW, Towlson KE, Graham R, Reddish M, Longenecker BM, Taylor-Papadimitriou J, Rubens RD. A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer. Br J Cancer. 1996 Oct;74(8):1292-6. — View Citation

Mocellin S, Mandruzzato S, Bronte V, Lise M, Nitti D. Part I: Vaccines for solid tumours. Lancet Oncol. 2004 Nov;5(11):681-9. Review. Erratum in: Lancet Oncol. 2005 Jan;6(1):4. — View Citation

Morton DL, Eilber FR, Joseph WL, Wood WC, Trahan E, Ketcham AS. Immunological factors in human sarcomas and melanomas: a rational basis for immunotherapy. Ann Surg. 1970 Oct;172(4):740-9. — View Citation

Moss P, Khan N. CD8(+) T-cell immunity to cytomegalovirus. Hum Immunol. 2004 May;65(5):456-64. Review. — View Citation

Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998 Mar;4(3):328-32. — View Citation

Nomura T, Sakaguchi S. Naturally arising CD25+CD4+ regulatory T cells in tumor immunity. Curr Top Microbiol Immunol. 2005;293:287-302. Review. — View Citation

Parmiani G, Castelli C, Santinami M, Rivoltini L. Melanoma immunology: past, present and future. Curr Opin Oncol. 2007 Mar;19(2):121-7. Review. — View Citation

Pulendran B, Palucka K, Banchereau J. Sensing pathogens and tuning immune responses. Science. 2001 Jul 13;293(5528):253-6. Review. — View Citation

Queirolo P, Acquati M, Kirkwood JM, Eggermont AM, Rocca A, Testori A. Update: current management issues in malignant melanoma. Melanoma Res. 2005 Oct;15(5):319-24. Review. — View Citation

Randolph DA, Fathman CG. Cd4+Cd25+ regulatory T cells and their therapeutic potential. Annu Rev Med. 2006;57:381-402. Review. — View Citation

Roncador G, Brown PJ, Maestre L, Hue S, Martínez-Torrecuadrada JL, Ling KL, Pratap S, Toms C, Fox BC, Cerundolo V, Powrie F, Banham AH. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol. 2005 Jun;35(6):1681-91. — View Citation

Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med. 1998 Mar;4(3):321-7. — View Citation

Sakaguchi S, Sakaguchi N. Regulatory T cells in immunologic self-tolerance and autoimmune disease. Int Rev Immunol. 2005 May-Aug;24(3-4):211-26. Review. — View Citation

Salgaller ML, Marincola FM, Cormier JN, Rosenberg SA. Immunization against epitopes in the human melanoma antigen gp100 following patient immunization with synthetic peptides. Cancer Res. 1996 Oct 15;56(20):4749-57. — View Citation

Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000 Mar;19(1):21-34. — View Citation

Skipper JC, Gulden PH, Hendrickson RC, Harthun N, Caldwell JA, Shabanowitz J, Engelhard VH, Hunt DF, Slingluff CL Jr. Mass-spectrometric evaluation of HLA-A*0201-associated peptides identifies dominant naturally processed forms of CTL epitopes from MART-1 and gp100. Int J Cancer. 1999 Aug 27;82(5):669-77. — View Citation

Skipper JC, Kittlesen DJ, Hendrickson RC, Deacon DD, Harthun NL, Wagner SN, Hunt DF, Engelhard VH, Slingluff CL Jr. Shared epitopes for HLA-A3-restricted melanoma-reactive human CTL include a naturally processed epitope from Pmel-17/gp100. J Immunol. 1996 Dec 1;157(11):5027-33. — View Citation

Steinman RM, Pope M. Exploiting dendritic cells to improve vaccine efficacy. J Clin Invest. 2002 Jun;109(12):1519-26. Review. — View Citation

Thurner B, Haendle I, Röder C, Dieckmann D, Keikavoussi P, Jonuleit H, Bender A, Maczek C, Schreiner D, von den Driesch P, Bröcker EB, Steinman RM, Enk A, Kämpgen E, Schuler G. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med. 1999 Dec 6;190(11):1669-78. — View Citation

Torabian S, Kashani-Sabet M. Biomarkers for melanoma. Curr Opin Oncol. 2005 Mar;17(2):167-71. Review. — View Citation

van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13;254(5038):1643-7. — View Citation

Waldmann TA. Effective cancer therapy through immunomodulation. Annu Rev Med. 2006;57:65-81. Review. — View Citation

Yee C, Savage PA, Lee PP, Davis MM, Greenberg PD. Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J Immunol. 1999 Feb 15;162(4):2227-34. — View Citation

* Note: There are 51 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Immunological response based on measuring increased numbers of peptide specific CD8+ T cells as calculated by the tetramer assay.	Starting on Day 0, two tubes will be drawn weekly until Day 64. Thereafter, two tubes will be drawn every 21 days until Day 190. For patients receiving maintenance treatment, blood is drawn every month.; Data are presented as the percentage of CD8+ T cells positive for tetramer binding based on gating variables set using the iMASC reagent kit (Beckman Coulter).	Through completion of treatment
Primary	Safety and tolerability of the mature dendritic cell vaccine as measured by adverse events	The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for all toxicity reporting.	30 days after end of treatment
Secondary	Time to progression		Through completion of treatment or until progressive disease
Secondary	Regulatory T cell depletion after cyclophosphamide administration.	Regulatory T cells (Treg) are defined as CD4+CD25+foxP3+ (triple positive) cells. At the indicated time points, the percentage of Treg cells is determined by 3 color flow cytometry. The depletion of Treg is defined as follows [Treg baseline - Treg nadir/ Treg baseline x 100= % depletion].	Day -3 (72 hours prior to vaccine dose 1)
Secondary	Safety and side effect profile of mDC administered to patients given after a single dose of cyclophosphamide.		Day 0 (prior to vaccine dose 1)
Secondary	Clinical response rate using RECIST criteria		After third vaccine, sixth vaccine, and then every 8 weeks

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine