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Vaccination with NY-ESO-1 Protein and Cpg in Montanide Induces Integrated Antibody/Th1 Responses and CD8 T Cells Through Cross-Priming

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Vaccination with NY-ESO-1 Protein and Cpg in Montanide Induces Integrated Antibody/Th1 Responses and CD8 T Cells Through Cross-Priming Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming Danila Valmori*†, Naira E. Souleimanian*, Valeria Tosello*, Nina Bhardwaj‡, Sylvia Adams‡, David O’Neill‡, Anna Pavlick‡, Juliet B. Escalon‡, Crystal M. Cruz‡, Angelica Angiulli‡, Francesca Angiulli‡, Gregory Mears§, Susan M. Vogel§, Linda Pan¶, Achim A. Jungbluth¶, Eric W. Hoffmann¶, Ralph Venhaus¶, Gerd Ritter¶, Lloyd J. Old¶ʈ, and Maha Ayyoub*† *Ludwig Institute Clinical Trial Center, Columbia University, New York, NY 10032; ‡New York University School of Medicine, New York, NY 10016; §Division of Medical Oncology, Columbia University Medical Center, New York, NY 10032; and ¶Ludwig Institute for Cancer Research, New York, NY 10158 Contributed by Lloyd J. Old, April 12, 2007 (sent for review February 22, 2007) The use of recombinant tumor antigen proteins is a realistic helper type 1 (Th1)-type immunity (7). In humans, they can approach for the development of generic cancer vaccines, but the directly activate B lymphocytes and plasmacytoid dendritic cells ,(potential of this type of vaccines to induce specific CD8؉ T cell and also indirectly activate myeloid dendritic cells (mDCs responses, through in vivo cross-priming, has remained unclear. In increasing antigen cross-presentation and stimulating adaptive this article, we report that repeated vaccination of cancer patients immune responses (8–10). with recombinant NY-ESO-1 protein, Montanide ISA-51, and CpG In this study, we have assessed the immune response elicited ODN 7909, a potent stimulator of B cells and T helper type 1 by repeated vaccination with a NY-ESO-1 recombinant protein (Th1)-type immunity, resulted in the early induction of specific (rNY-ESO-1) administered with CpG 7909 in a water–oil emul- integrated CD4؉ Th cells and antibody responses in most vacci- sion with Montanide ISA-51. We show that cancer patients nated patients, followed by the development of later CD8؉ T cell receiving this vaccine developed integrated Ab and CD4ϩ T cell responses in a fraction of them. The correlation between antibody responses to NY-ESO-1 at an early phase of the vaccination and T cell responses, together with the ability of vaccine-induced protocol. A fraction of the patients also developed specific CD8ϩ antibodies to promote in vitro cross-presentation of NY-ESO-1 by T cell responses at a later time point. Assessment of the dendritic cells to vaccine-induced CD8؉ T cells, indicated that correlation between the development of Ab and T cell responses elicitation of NY-ESO-1-specific CD8؉ T cell responses by cross- suggested that the presence of sufficient levels of NY-ESO-1- priming in vivo was associated with the induction of adequate specific antibodies was determinant for the cross-priming of ϩ levels of specific antibodies. Together, our data provide clear CD8 T cells to occur in vivo. In line with this concept, we found evidence of in vivo cross-priming of specific cytotoxic T lympho- that in vitro cross-presentation of NY-ESO-1 protein to vaccine- ϩ cytes by a recombinant tumor antigen vaccine, underline the induced CD8 T cells by dendritic cells was enhanced by importance of specific antibody induction for the cross-priming to vaccine-induced Ab. occur, and support the use of this type of formulation for the further development of efficient cancer vaccines. Results Serological Response to Vaccination with rNY-ESO-1, CpG 7909, and cancer vaccine Montanide ISA-51. Study patients received four s.c. injections of NY-ESO-1/Montanide/CpG vaccine at 3-week intervals. The ␮ key step in the development of generic cancer vaccines is study included two arms receiving 100 or 400 g of rNY-ESO-1 IMMUNOLOGY Athe implementation of vaccination strategies allowing for per injection, together with 2.5 mg of CpG emulsified in Mon- the consistent induction of immune responses to tumor antigens. tanide. CpG 7909 belongs to the CpG-B class, which potently In this respect, the choice of appropriate antigens, based on both stimulates B cells (11). All patients developed significant sero- the frequency and the specificity of their expression in cancer logical responses to NY-ESO-1 (Fig. 1A). Specific IgG responses tissues, is of paramount importance. The group of cancer/testis became significant after the second injection and further in- antigens (CTA) (1, 2), including the NY-ESO-1 antigen (3), is creased after the third and fourth injections, without generally emerging among the most promising candidates. Because many reaching a plateau. Specific IgG titers were variable among CTA are not expressed on the surface of cancer cells but rather patients: at the last time point, NY-ESO-1 reciprocal Ab titers had reached an average 42.429 Ϯ 29.080 in the 400 ␮g group and intracellularly, it is important that vaccination induces specific Ϯ ␮ CD8ϩ T cells able to directly recognize antigen-expressing tumor 24.091 10.737 in the 100 g group. Serological responses to an cells. Recombinant proteins can be produced in large scale and at relatively low cost, are commonly used in the development of Author contributions: D.V., L.J.O., and M.A. designed research; D.V., N.E.S., V.T., N.B., S.A., antiviral vaccines, and are therefore attractive candidate anti- D.O., A.P., J.B.E., C.M.C., A.A., F.A., G.M., S.M.V., A.A.J., and M.A. performed research; L.P., tumor vaccines. The potential of tumor antigen recombinant E.W.H., R.V., G.R., and L.J.O. contributed new reagents/analytic tools; D.V. and M.A. protein vaccines, however, relies on their ability not only to elicit analyzed data; and D.V. and M.A. wrote the paper. antibody (Ab) and CD4ϩ T cell responses but also to efficiently The authors declare no conflict of interest. prime naive CD8ϩ T cells through cross-priming (4), which Abbreviations: CTL, cytotoxic T lymphocyte; APC, antigen-presenting cell; TLR, Toll-like generally is inefficient during spontaneous immune responses to receptors; Th, T helper; mDC, myeloid dendritic cell; PBMC, peripheral blood mononuclear cell; ADCC, antibody-dependent cellular cytotoxicity. tumor antigens (5). Professional antigen-presenting cells (APCs) †To whom correspondence may be sent at the present address: Institut National de la detect pathogens through a variety of receptors such as the Sante´ et de la Recherche Me´dicale, Unite 601, Centre de Lutte Contre le Cancer Rene´ Toll-like receptors (TLR), which recognize pathogen-associated Gauducheau, Boulevard Jacques Monod, 44800 Saint Herblain, France. E-mail: molecular patterns including CpG dinucleotides within defined [email protected] or [email protected]. flanking sequences (CpG ODN) (6). Synthetic CpG ODN able ʈTo whom correspondence may be addressed. E-mail: [email protected]. to trigger TLR9 are potent vaccine adjuvants, stimulating T © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0703395104 PNAS ͉ May 22, 2007 ͉ vol. 104 ͉ no. 21 ͉ 8947–8952 Downloaded by guest on September 25, 2021 Fig. 1. Serological responses. (A) Serological responses were assessed by ELISA at baseline and at the indicated study week after vaccination. (B) The isotype of vaccine-induced IgG (week 12, serum dilution of 1:100) was assessed by ELISA using isotype-specific antibodies. (C) Linear B cell epitopes were determined by using patients’ immune sera and a panel of 30-aa-long pep- tides spanning the protein sequence. unrelated recombinant protein (MAGE-A4) generally were low in both groups (4.957 Ϯ 3.594 in the group receiving 400 ␮g and 2.735 Ϯ 2.519 in the group receiving 100 ␮g). Isotype of Vaccine-Induced IgG and Mapping of B Cell Epitopes. To investigate further the serological responses induced by the Fig. 2. Assessment of CD4ϩ and CD8ϩ T cell responses after in vitro stimu- vaccine, we assessed the isotype of vaccine-induced IgG by using lation. (A) The presence of specific CD4ϩ and CD8ϩ T cells in stimulated cultures isotype-specific antibodies. As illustrated in Fig. 1B, the vaccine from vaccinated patients was assessed by intracellular staining with anti-IFN-␥ preferentially induced specific IgG of types 1 and 3, which are monoclonal Ab after stimulation in the absence or presence of the NY-ESO-1 peptide pool. Numbers in the upper right quadrant are the percentages of associated, in humans, with type 1 immune responses. We ϩ ϩ mapped the linear B cell epitopes recognized by the vaccine- IFN-␥-producing cells in CD4 or CD8 T cells. As an example, data are shown induced Ab with a panel of peptides spanning the protein for one responder patient. (B) Summary of the results obtained for all patients. Values correspond to the percentage of CD4ϩ or CD8ϩ T cells specifically sequence (12). The analysis identified a dominant region located producing IFN-␥ in response to stimulation with the peptide pool. (C) Cultures in the central part of the protein and comprising amino acids 80– were stimulated with single peptides in the NY-ESO-1 pool. The proportion of 110, which was recognized strongly by Abs from all patients (Fig. IFN-␥-producing cells was assessed by intracellular staining as above. Symbols 1C). Consistent with the previous identification of B cell epitopes are as given in the Fig. 1 key. located in the N-terminal half of the protein and recognized by specific Abs from cancer patients with spontaneous serological ϩ responses to NY-ESO-1 (12, 13), the immune sera from vacci- CD4 T cells recognized sequences located in two distinct nated patients reacted to peptides in the amino acids 1–70 region regions of the protein, corresponding to peptides 81–100 and of the protein.
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