A melanoma helper peptide vaccine increases Th1 cytokine production by leukocytes in peripheral blood and immunized lymph nodes

Journal for ImmunoTherapy of Cancer

Craig L Slingluff³  Donna H Deacon³  Kimberly A Chianese-Bullock³  William W Grosh⁴  Mark Smolkin¹  Gina R Petroni¹  Andrea Czarkowski²  Walter C Olson³  Patrick M Dillon⁴ 

[1] Department of Public Health Sciences, University of Virginia Health System, Charlottesville, VA 22908, USA;Cancer Center, Charlottesville, VA 22908, USA;Department of Surgery/Division of Surgical Oncology, University of Virginia, Charlottesville, VA 22908, USA;Department of Medicine/Division of Hematology-Oncology, University of Virginia, Charlottesville, VA 22908, USA

关键词: Tumor vaccines;    Neoplasm;    Antigens;    Melanoma/im;    Cytotoxic;    T-Lymphocytes;    Cytokines;    Human;    Immunotherapy;   

Others  :  1138717
DOI  :  10.1186/2051-1426-2-23

 received in 2013-12-30, accepted in 2014-06-04,  发布年份 2014

【 摘 要 】

Background

Cancers produce soluble and cell-associated molecules that can suppress or alter antitumor immunity. Preclinical studies suggest the disease burden may alter the cytokine profile of helper T cell responses to cancer antigens. We studied cytokine production by helper T cells responding to vaccination with 6 melanoma helper peptides (6MHP) in blood and lymph nodes.

Methods

Twenty-three patients with stage IIIB-IV melanoma received a 6MHP vaccine. Antigen-reactive T cells from blood and draining lymph nodes were cultured, exposed to antigen, and then supernatants (days 2 and 5) were assayed for Th1 and Th2 cytokines. Results from 4 time points were compared to pre-vaccine levels.

Results

Cytokine responses to vaccinating peptides were observed in 83% of patients. Th1 favoring responses were most common (17 of 19 responders). The most abundant cytokines produced were IFN-γ and IL-5 in the PBMC’s. IL-2 responses predominated in cells obtained from draining lymph nodes in 2-day culture but not in 5-day cultures. Patients with clinically measurable disease produced similar levels of total cytokine and similar degree of Th1 polarization as patients with no evidence of disease (NED).

Conclusions

The MHC class II-associated peptides used in this study induced helper T cells with a Th1-biased cytokine response in both PBMC and sentinel immunized nodes. Most patients can mount a Th1 dominant response to these peptides. Future studies are needed to test newer vaccine adjuvants in combination with these peptides.

Trial registration

CDR0000378171, Clinicaltrials: NCT00089219.

【 授权许可】

   
2014 Dillon et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Mortara L, Gras-Masse H, Rommens C, Venet A, Guillet JG, Bourgault-Villada I: Type 1 CD4 (+) T-cell help is required for induction of antipeptide multispecific cytotoxic T lymphocytes by a lipopeptidic vaccine in rhesus macaques. J Virol 1999, 73:4447-4451.
• [2]Schoenberger SP, Toes RE, van der Voort EL, Offringa R, Melief CJ: T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998, 393:480-483.
• [3]Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H: The central role of CD4+ T-cells in the antitumor immune response. JEM 1998, 188:2357-2368.
• [4]Matsui S, Ahlers JD, Vortmeyer AO, Terabe M, Tsukui T, Carbone DP, Carbone DP, Liotta LA, Berzofsky JA: A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL. JI 1999, 163:184-193.
• [5]Slingluff CL Jr, Petroni GR, Yamshchikov GV, Hibbitts S, Grosh WW, Chianese-Bullock KA, Bissonette EA, Barnd DL, Deacon DH, Patterson JW, Parekh J, Neese PY, Woodson EM, Wiernasz CJ, Merrill P: Immunologic and clinical outcomes of vaccination with a multiepitope melanoma peptide vaccine plus low-dose interleukin-2 administered either concurrently or on a delayed schedule. J Clin Oncol 2004, 22:4474-4485.
• [6]Slingluff CL Jr, Petroni GR, Olson W, Czarkowski AR, Grosh WW, Smolkin M, Chianese-Bullock KA, Neese PY, Deacon DH, Nail C, Merrill P, Fink R, Patterson JW, Rehm PK: Helper T cell responses and clinical activity of a melanoma vaccine with multiple peptides from MAGE and melanocytic differentiation antigens. J Clin Oncol 2008, 26:4973-4980.
• [7]Hu Y, Petroni GR, Olson WC, Czarkowski A, Smolkin ME, Grosh WW, Chianese-Bullock KA, Slingluff CL Jr: Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine. Cancer Immunol Immunother 2014. [Epub ahead of print]
• [8]Tatsumi T, Kierstead LS, Ranieri E, Gesualdo L, Schena FP, Finke JH, Bukowski RM, Mueller-Berghaus J, Kirkwood JM, Kwok WW, Storkus WJ: Disease-associated bias in T helper type 1 (Th1)/Th2 CD4 (+) T cell responses against MAGE-6 in HLA-DRB10401 (+) patients with renal cell carcinoma or melanoma. JEM 2002, 196:619-628.
• [9]Rackowski JL, Haggarty BS, Gaulton GN, Hoxie: T4 endocytosis and phosphorylation induced by phorbol esters but not by mitogen or HIV infection. J Immunolo 1988, 140:786-795.
• [10]Slingluff CL Jr, Petroni GR, Chianese-Bullock KA, Smolkin ME, Hibbitts S, Murphy C, Johansen N, Grosh WW, Yamshchikov GV, Neese PY, Patterson JW, Fink R, Rehm PK: Immunologic and clinical outcomes of a randomized phase II trial of two multipeptide vaccines for melanoma in the adjuvant setting. Clin Cancer Res 2007, 13:6386-6395.
• [11]Deacon DH, Hogan KT, Swanson EM, Chianese-Bullock KA, Denlinger CE, Czarkowski AR, Schrecengost RS, Patterson JW, Teague MW, Slingluff CL Jr: The use of gamma-irradiation and ultraviolet-irradiation in the preparation of human melanoma cells for use in autologous whole-cell vaccines. BMC Cancer 2008, 8:360.
• [12]Slingluff CL Jr, Yamshchikov G, Neese P, Galavotti H, Eastham S, Engelhard VH, Kittlesen D, Deacon D, Hibbitts S, Grosh WW, Petroni G, Cohen R, Wiernasz C, Patterson JW, Conway BP, Ross WG: Phase I trial of a melanoma vaccine with gp100 (280-288) peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes. Clin Cancer Res 2001, 7:3012-3024.
• [13]Slingluff CL Jr, Lee S, Zhao F, Chianese-Bullock KA, Olson WC, Butterfield LH, Whiteside TL, Leming PD, Kirkwood J: A randomized phase II trial of multiepitope vaccination with melanoma peptides for cytotoxic T cells and helper T cells for patients with metastatic melanoma (E1602). Clin Cancer Res 2013, 19(15):4228-4238.
• [14]Claret E, Renversez JC, Zheng X, Bonnefoix T, Sotto JJ: Valid estimation of IL2 secretion by PHA-stimulated T-cell clones absolutely requires the use of anti-CD25 monoclonal antibody to prevent IL2 consumption. Immunol Lett 1992, 33(2):179-85.
• [15]Kallies A: Distinct regulation of effector and memory T-cell differentiation. Immunol Cell Biol 2008, 86:325-32.
• [16]Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, Robbins PF: Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. JEM 1996, 183:1965-1971.
• [17]Kobayashi H, Kokubo T, Sato K, Kimura S, Asano K, Takahashi H, Iizuka H, Miyokawa N, Katagiri M: CD4+ T cells from peripheral blood of a melanoma patient recognize peptides derived from nonmutated tyrosinase. Cancer Res 1998, 58:296-301.
• [18]Zarour HM, Kirkwood JM, Kierstead LS, Herr W, Brusic V, Slingluff CL Jr, Sidney J, Sette A, Storkus WJ: Melan-A/MART-1 (51-73) represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4 (+) T cells. Proc Natl Acad Sci U S A 2000, 97:400-405.
• [19]Manici S, Sturniolo T, Imro MA, Hammer J, Sinigaglia F, Noppen C, Spagnoli G, Mazzi B, Bellone M, Dellabona P, Protti MP: Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in association with histocompatibility leukocyte antigen DR11. JEM 1999, 189:871-876.
• [20]Chaux P, Vantomme V, Stroobant V, Thielemans K, Corthals J, Luiten R, Eggermont AM, Boon T, van der Bruggen P: Identification of MAGE-3 epitopes presented by HLA-DR molecules to CD4 (+) T lymphocytes. JEM 1999, 189:767-778.
• [21]Halder T, Pawelec G, Kirkin AF, Zeuthen J, Meyer HE, Kun L, Kalbacker H: Isolation of novel HLA-DR restricted potential tumor-associated antigens from the melanoma cell line FM3. Cancer Res 1997, 57:3238-3244.
• [22]Li K, Adibzadeh M, Halder T, Kalbacher H, Heinzel S, Muller C, Zeuthen J, Pawelec G: Tumour-specific MHC-class-II-restricted responses after in vitro sensitization to synthetic peptides corresponding to gp100 and Annexin II eluted from melanoma cells. Cancer Immunol Immunother 1998, 47:32-38.
• [23]Thompson LW, Hogan KT, Caldwell JA, Pierce RA, Hendrickson RC, Deacon DH, Settlage RE, Brinckerhoff LH, Engelhard VH, Shabanowitz J, Hunt DF, Slingluff CL Jr: Preventing the spontaneous modification of an HLA-A2-restricted peptide at an N-terminal glutamine or an internal cysteine residue enhances peptide antigenicity. J Immunother 2004, 27:177-183.
• [24]Johnson RP, Trocha A, Yang L, Mazzara GP, Panicali DL, Buchanan TM, Walker BD: HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes: Fine specificity of the gag-specific response defined by using unstimulated peripheral blood mononuclear cells and cloned effector cells. JI 1991, 147:1512-1521.
• [25]Yamshchikov GV, Barnd DL, Eastham S, Galavotti H, Patterson JW, Deacon DH, Teates D, Neese P, Grosh WW, Petroni G, Engelhard VH, Slingluff CL Jr: Evaluation of peptide vaccine immunogenicity in draining lymph nodes and blood of melanoma patients. Int J Cancer 2001, 92:703-711.
• [26]Slingluff CL Jr, Yamshchikov GV, Hogan KT, Hibbitts SC, Petroni GR, Bissonette EA, Patterson JW, Neese PY, Grosh WW, Chianese-Bullock KA, Czarkowski A, Rehm PK, Parekh J: Evaluation of the sentinel immunized node for immune monitoring of cancer vaccines. Ann Surg Oncol 2008, 15:3538-3549.