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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Research

Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting

Authors: Evan J Lipson, William H Sharfman, Shuming Chen, Tracee L McMiller, Theresa S Pritchard, January T Salas, Susan Sartorius-Mergenthaler, Irwin Freed, Sowmya Ravi, Hao Wang, Brandon Luber, Janice Davis Sproul, Janis M Taube, Drew M Pardoll, Suzanne L Topalian

Published in: Journal of Translational Medicine | Issue 1/2015

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Abstract

Background

Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte–macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting.

Methods

Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m2 to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines.

Results

Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting.

Conclusion

Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents.
Trial registration: NCT01435499
Appendix
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Literature
1.
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14:7–17PubMed
2.
Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS et al (2000) High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444–2458PubMed
3.
Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS et al (2001) High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19:2370–2380PubMed
4.
Balch CM, Soong SJ, Atkins MB, Buzaid AC, Cascinelli N, Coit DG et al (2004) An evidence-based staging system for cutaneous melanoma. CA Cancer J Clin 54:131–149PubMedCrossRef
5.
6.
7.
Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA et al (2013) Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19:462–468PubMedCentralPubMedCrossRef
8.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH et al (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020–1030PubMedCrossRef
9.
Lee KH, Wang E, Nielsen MB, Wunderlich J, Migueles S, Connors M et al (1999) Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression. J Immunol 163:6292–6300PubMed
10.
11.
Sondak VK, Liu PY, Tuthill RJ, Kempf RA, Unger JM, Sosman JA et al (2002) Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol 20:2058–2066PubMedCrossRef
12.
Morton DL, Mozzillo N, Thompson JF, Kelley MC, Faries M, Wagner J et al (2007) An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites (abstract). J Clin Oncol 25:s8508
13.
Ahmad M, Rees RC, Ali SA (2004) Escape from immunotherapy: possible mechanisms that influence tumor regression/progression. Cancer Immunol Immunother 53:844–854PubMedCrossRef
14.
Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT et al (2009) The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 15:5323–5337PubMedCrossRef
15.
16.
17.
Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K et al (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90:3539–3543PubMedCentralPubMedCrossRef
18.
Soiffer R, Lynch T, Mihm M, Jung K, Rhuda C, Schmollinger JC et al (1998) Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci USA 95:13141–13146PubMedCentralPubMedCrossRef
19.
Chang AE, Li Q, Bishop DK, Normolle DP, Redman BD, Nickoloff BJ (2000) Immunogenetic therapy of human melanoma utilizing autologous tumor cells transduced to secrete granulocyte-macrophage colony-stimulating factor. Hum Gene Ther 11:839–850PubMedCrossRef
20.
Kusumoto M, Umeda S, Ikubo A, Aoki Y, Tawfik O, Oben R et al (2001) Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene. Cancer Immunol Immunother 50:373–381PubMedCrossRef
21.
Soiffer R, Hodi FS, Haluska F, Jung K, Gillessen S, Singer S et al (2003) Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J Clin Oncol 21:3343–3350PubMedCrossRef
22.
Luiten RM, Kueter EW, Mooi W, Gallee MP, Rankin EM, Gerritsen WR et al (2005) Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients. J Clin Oncol 23:8978–8991PubMedCrossRef
23.
Serafini P, Carbley R, Noonan KA, Tan G, Bronte V, Borrello I (2004) High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res 64:6337–6343PubMedCrossRef
24.
Bronte V, Serafini P, Apolloni E, Zanovello P (2001) Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J Immunother 24:431–446PubMedCrossRef
25.
Pan PY, Li Y, Li Q, Gu P, Martinet O, Thung S et al (2004) In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery. Cancer Immunol Immunother 53:17–25PubMedCrossRef
26.
Parmiani G, Castelli C, Pilla L, Santinami M, Colombo MP, Rivoltini L (2007) Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Ann Oncol 18:226–232PubMedCrossRef
27.
Drake CG, Jaffee E, Pardoll DM (2006) Mechanisms of immune evasion by tumors. Adv Immunol 90:51–81PubMedCrossRef
28.
Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761PubMedCrossRef
29.
Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218PubMed
30.
Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP (2005) Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med 201:1591–1602PubMedCentralPubMedCrossRef
31.
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL et al (1994) Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA 91:3515–3519PubMedCentralPubMedCrossRef
32.
Topalian SL, Rivoltini L, Mancini M, Markus NR, Robbins PF, Kawakami Y et al (1994) Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene. Proc Natl Acad Sci USA 91:9461–9465PubMedCentralPubMedCrossRef
33.
Zakut R, Topalian SL, Kawakami Y, Mancini M, Eliyahu S, Rosenberg SA (1993) Differential expression of MAGE-1, -2, and -3 messenger RNA in transformed and normal human cell lines. Cancer Res 53:5–8PubMed
34.
Mullins DW, Sheasley SL, Ream RM, Bullock TN, Fu YX, Engelhard VH (2003) Route of immunization with peptide-pulsed dendritic cells controls the distribution of memory and effector T cells in lymphoid tissues and determines the pattern of regional tumor control. J Exp Med 198:1023–1034PubMedCentralPubMedCrossRef
35.
Jaffee EM, Thomas MC, Huang AY, Hauda KM, Levitsky HI, Pardoll DM (1996) Enhanced immune priming with spatial distribution of paracrine cytokine vaccines. J Immunother Emphasis Tumor Immunol 19:176–183PubMedCrossRef
36.
Couch M, Saunders JK, O’Malley BW Jr, Pardoll D, Jaffee E (2003) Spatial distribution of tumor vaccine improves efficacy. Laryngoscope 113:1401–1405PubMedCrossRef
37.
Chen S, Li Y, Depontieu FR, McMiller TL, English AM, Shabanowitz J et al (2013) Structure-based design of altered MHC class II-restricted peptide ligands with heterogeneous immunogenicity. J Immunol 191:5097–5106PubMedCrossRef
38.
Lindsey KR, Gritz L, Sherry R, Abati A, Fetsch PA, Goldfeder LC et al (2006) Evaluation of prime/boost regimens using recombinant poxvirus/tyrosinase vaccines for the treatment of patients with metastatic melanoma. Clin Cancer Res 12:2526–2537PubMedCentralPubMedCrossRef
39.
Hu Y, Petroni GR, Olson WC, Czarkowski A, Smolkin ME, Grosh WW et al (2014) Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine. Cancer Immunol Immunother 63:779–786PubMedCrossRef
40.
Depontieu FR, Qian J, Zarling AL, McMiller TL, Salay TM, Norris A et al (2009) Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy. Proc Natl Acad Sci USA 106:12073–12078PubMedCentralPubMedCrossRef
41.
Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B et al (2008) Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res 14:1455–1463PubMedCentralPubMedCrossRef
42.
Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR et al (2001) Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 19:145–156PubMed
43.
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 27:5911–5918PubMedCentralPubMedCrossRef
44.
Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C et al (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261PubMedCrossRef
45.
Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199PubMedCentralPubMedCrossRef
46.
Cox AL, Skipper J, Chen Y, Henderson RA, Darrow TL, Shabanowitz J et al (1994) Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science 264:716–719PubMedCrossRef
47.
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E et al (1994) Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci USA 91:6458–6462PubMedCentralPubMedCrossRef
48.
Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129PubMedCentralPubMedCrossRef
49.
Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME et al (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29:917–924PubMedCentralPubMedCrossRef
50.
Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G et al (2015) Safety and survival with GVAX pancreas prime and listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. doi:10.​1200/​JCO.​2014.​57.​4244
51.
van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar RJ, van der Sluis TM et al (2012) Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 13:509–517PubMedCrossRef
52.
Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA et al (2014) Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA 312:1744–1753PubMedCentralPubMedCrossRef
53.
Kaufman HL, Andtbacka RHI, Collichio FA, Amatruda T, Senzer NN, Chesney J et al (2014) Primary overall survival (OS) from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol 32:s9008a
54.
Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M et al (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546–2553PubMedCrossRef
55.
Quezada SA, Peggs KS, Curran MA, Allison JP (2006) CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116:1935–1945PubMedCentralPubMedCrossRef
56.
Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A et al (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA 105:3005–3010PubMedCentralPubMedCrossRef
57.
Klein O, Davis ID, McArthur GA, Chen L, Haydon A, Parente P et al (2015) Low-dose cyclophosphamide enhances antigen-specific CD4 T cell responses to NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. Cancer Immunol Immunother. doi:10.​1007/​s00262-015-1656-x PubMed
58.
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 105:2862–2868PubMedCrossRef
59.
Berd D, Maguire HC Jr, Mastrangelo MJ (1986) Induction of cell-mediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res 46:2572–2577PubMed
60.
Chen G, Gupta R, Petrik S, Laiko M, Leatherman JM, Asquith JM et al (2014) A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol Res 2:949–961PubMedCrossRef
Metadata
Title
Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting
Authors
Evan J Lipson
William H Sharfman
Shuming Chen
Tracee L McMiller
Theresa S Pritchard
January T Salas
Susan Sartorius-Mergenthaler
Irwin Freed
Sowmya Ravi
Hao Wang
Brandon Luber
Janice Davis Sproul
Janis M Taube
Drew M Pardoll
Suzanne L Topalian
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0572-3

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