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1. Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial

Author

Bol, Kalijn F., Schreibelt, Gerty, Bloemendal, Martine, van Willigen, Wouter W., Hins-de Bree, Simone, de Goede, Anna L., de Boer, Annemiek J., Bos, Kevin J. H., Duiveman-de Boer, Tjitske, Olde Nordkamp, Michel A. M., van Oorschot, Tom G. M., Popelier, Carlijn J., Pots, Jeanne M., Scharenborg, Nicole M., van de Rakt, Mandy W. M. M., de Ruiter, Valeska, van Meeteren, Wilmy S., van Rossum, Michelle M., Croockewit, Sandra J., Koeneman, Bouke J., Creemers, Jeroen H. A., Wortel, Inge M. N., Angerer, Caroline, Brüning, Mareke, Petry, Katja, Dzionek, Andrzej, van der Veldt, Astrid A., van Grünhagen, Dirk J., Werner, Johanna E. M., Bonenkamp, Johannes J., Haanen, John B. A. G., Boers-Sonderen, Marye J., Koornstra, Rutger H. T., Boomsma, Martijn F., Aarntzen, Erik H. J., Gotthardt, Martin, Nagarajah, James, de Witte, Theo J. M., Figdor, Carl G., de Wilt, Johannes H. W., Textor, Johannes, de Groot, Jan Willem B., Gerritsen, Winald R., and de Vries, I. Jolanda M.

Published
2024
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2. Fully closed and automated enrichment of primary blood dendritic cells for cancer immunotherapy

Author

Schreibelt, Gerty, primary, Duiveman-de Boer, Tjitske, additional, Pots, Jeanette M., additional, van Oorschot, Tom G.M., additional, de Boer, Annemiek J., additional, Scharenborg, Nicole M., additional, van de Rakt, Mandy W.M.M., additional, Bos, Kevin, additional, de Goede, Anna L., additional, Petry, Katja, additional, Brüning, Mareke, additional, Angerer, Caroline, additional, Schöggl, Carola, additional, Dzionek, Andreas, additional, and de Vries, I. Jolanda M., additional

Published
2023
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3. Adjuvant dendritic cell therapy in stage IIIB/C melanoma:the MIND-DC randomized phase III trial

Author

Bol, Kalijn F., Schreibelt, Gerty, Bloemendal, Martine, van Willigen, Wouter W., Hins-de Bree, Simone, de Goede, Anna L., de Boer, Annemiek J., Bos, Kevin J.H., Duiveman-de Boer, Tjitske, Olde Nordkamp, Michel A.M., van Oorschot, Tom G.M., Popelier, Carlijn J., Pots, Jeanne M., Scharenborg, Nicole M., van de Rakt, Mandy W.M.M., de Ruiter, Valeska, van Meeteren, Wilmy S., van Rossum, Michelle M., Croockewit, Sandra J., Koeneman, Bouke J., Creemers, Jeroen H.A., Wortel, Inge M.N., Angerer, Caroline, Brüning, Mareke, Petry, Katja, Dzionek, Andrzej, van der Veldt, Astrid A., van Grünhagen, Dirk J., Werner, Johanna E.M., Bonenkamp, Johannes J., Haanen, John B.A.G., Boers-Sonderen, Marye J., Koornstra, Rutger H.T., Boomsma, Martijn F., Aarntzen, Erik H.J., Gotthardt, Martin, Nagarajah, James, de Witte, Theo J.M., Figdor, Carl G., de Wilt, Johannes H.W., Textor, Johannes, de Groot, Jan Willem B., Gerritsen, Winald R., de Vries, I. Jolanda M., Bol, Kalijn F., Schreibelt, Gerty, Bloemendal, Martine, van Willigen, Wouter W., Hins-de Bree, Simone, de Goede, Anna L., de Boer, Annemiek J., Bos, Kevin J.H., Duiveman-de Boer, Tjitske, Olde Nordkamp, Michel A.M., van Oorschot, Tom G.M., Popelier, Carlijn J., Pots, Jeanne M., Scharenborg, Nicole M., van de Rakt, Mandy W.M.M., de Ruiter, Valeska, van Meeteren, Wilmy S., van Rossum, Michelle M., Croockewit, Sandra J., Koeneman, Bouke J., Creemers, Jeroen H.A., Wortel, Inge M.N., Angerer, Caroline, Brüning, Mareke, Petry, Katja, Dzionek, Andrzej, van der Veldt, Astrid A., van Grünhagen, Dirk J., Werner, Johanna E.M., Bonenkamp, Johannes J., Haanen, John B.A.G., Boers-Sonderen, Marye J., Koornstra, Rutger H.T., Boomsma, Martijn F., Aarntzen, Erik H.J., Gotthardt, Martin, Nagarajah, James, de Witte, Theo J.M., Figdor, Carl G., de Wilt, Johannes H.W., Textor, Johannes, de Groot, Jan Willem B., Gerritsen, Winald R., and de Vries, I. Jolanda M.

Abstract

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88−1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73−2.38; p = 0.44). Grade 3−4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.

Published
2024

5. Supplementary Table 1 from Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients

Author

Lesterhuis, W. Joost, primary, de Vries, I. Jolanda M., primary, Schreibelt, Gerty, primary, Lambeck, Annechien J.A., primary, Aarntzen, Erik H.J.G., primary, Jacobs, Joannes F.M., primary, Scharenborg, Nicole M., primary, van de Rakt, Mandy W.M.M., primary, de Boer, Annemiek J., primary, Croockewit, Sandra, primary, van Rossum, Michelle M., primary, Mus, Roel, primary, Oyen, Wim J.G., primary, Boerman, Otto C., primary, Lucas, Sophie, primary, Adema, Gosse J., primary, Punt, Cornelis J.A., primary, and Figdor, Carl G., primary

Published
2023
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6. Supplementary Figure 2 from Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Author

Schreibelt, Gerty, primary, Bol, Kalijn F., primary, Westdorp, Harm, primary, Wimmers, Florian, primary, Aarntzen, Erik H.J.G., primary, Duiveman-de Boer, Tjitske, primary, van de Rakt, Mandy W.M.M., primary, Scharenborg, Nicole M., primary, de Boer, Annemiek J., primary, Pots, Jeanette M., primary, Olde Nordkamp, Michel A.M., primary, van Oorschot, Tom G.M., primary, Tel, Jurjen, primary, Winkels, Gregor, primary, Petry, Katja, primary, Blokx, Willeke A.M., primary, van Rossum, Michelle M., primary, Welzen, Marieke E.B., primary, Mus, Roel D.M., primary, Croockewit, Sandra A.J., primary, Koornstra, Rutger H.T., primary, Jacobs, Joannes F.M., primary, Kelderman, Sander, primary, Blank, Christian U., primary, Gerritsen, Winald R., primary, Punt, Cornelis J.A., primary, Figdor, Carl G., primary, and de Vries, I. Jolanda M., primary

Published
2023
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7. Supplementary Figure 3 from Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Author

Schreibelt, Gerty, primary, Bol, Kalijn F., primary, Westdorp, Harm, primary, Wimmers, Florian, primary, Aarntzen, Erik H.J.G., primary, Duiveman-de Boer, Tjitske, primary, van de Rakt, Mandy W.M.M., primary, Scharenborg, Nicole M., primary, de Boer, Annemiek J., primary, Pots, Jeanette M., primary, Olde Nordkamp, Michel A.M., primary, van Oorschot, Tom G.M., primary, Tel, Jurjen, primary, Winkels, Gregor, primary, Petry, Katja, primary, Blokx, Willeke A.M., primary, van Rossum, Michelle M., primary, Welzen, Marieke E.B., primary, Mus, Roel D.M., primary, Croockewit, Sandra A.J., primary, Koornstra, Rutger H.T., primary, Jacobs, Joannes F.M., primary, Kelderman, Sander, primary, Blank, Christian U., primary, Gerritsen, Winald R., primary, Punt, Cornelis J.A., primary, Figdor, Carl G., primary, and de Vries, I. Jolanda M., primary

Published
2023
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8. Supplementary Figure 2 from Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients

Author

Lesterhuis, W. Joost, primary, de Vries, I. Jolanda M., primary, Schreibelt, Gerty, primary, Lambeck, Annechien J.A., primary, Aarntzen, Erik H.J.G., primary, Jacobs, Joannes F.M., primary, Scharenborg, Nicole M., primary, van de Rakt, Mandy W.M.M., primary, de Boer, Annemiek J., primary, Croockewit, Sandra, primary, van Rossum, Michelle M., primary, Mus, Roel, primary, Oyen, Wim J.G., primary, Boerman, Otto C., primary, Lucas, Sophie, primary, Adema, Gosse J., primary, Punt, Cornelis J.A., primary, and Figdor, Carl G., primary

Published
2023
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9. Supplementary Figure 1 from Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients

Author

Lesterhuis, W. Joost, primary, de Vries, I. Jolanda M., primary, Schreibelt, Gerty, primary, Lambeck, Annechien J.A., primary, Aarntzen, Erik H.J.G., primary, Jacobs, Joannes F.M., primary, Scharenborg, Nicole M., primary, van de Rakt, Mandy W.M.M., primary, de Boer, Annemiek J., primary, Croockewit, Sandra, primary, van Rossum, Michelle M., primary, Mus, Roel, primary, Oyen, Wim J.G., primary, Boerman, Otto C., primary, Lucas, Sophie, primary, Adema, Gosse J., primary, Punt, Cornelis J.A., primary, and Figdor, Carl G., primary

Published
2023
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10. Supplementary Figure 1 from Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Author

Schreibelt, Gerty, primary, Bol, Kalijn F., primary, Westdorp, Harm, primary, Wimmers, Florian, primary, Aarntzen, Erik H.J.G., primary, Duiveman-de Boer, Tjitske, primary, van de Rakt, Mandy W.M.M., primary, Scharenborg, Nicole M., primary, de Boer, Annemiek J., primary, Pots, Jeanette M., primary, Olde Nordkamp, Michel A.M., primary, van Oorschot, Tom G.M., primary, Tel, Jurjen, primary, Winkels, Gregor, primary, Petry, Katja, primary, Blokx, Willeke A.M., primary, van Rossum, Michelle M., primary, Welzen, Marieke E.B., primary, Mus, Roel D.M., primary, Croockewit, Sandra A.J., primary, Koornstra, Rutger H.T., primary, Jacobs, Joannes F.M., primary, Kelderman, Sander, primary, Blank, Christian U., primary, Gerritsen, Winald R., primary, Punt, Cornelis J.A., primary, Figdor, Carl G., primary, and de Vries, I. Jolanda M., primary

Published
2023
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11. Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity

Author

Bol, Kalijn F., Aarntzen, Erik H. J. G., Pots, Jeanette M., Olde Nordkamp, Michel A. M., van de Rakt, Mandy W. M. M., Scharenborg, Nicole M., de Boer, Annemiek J., van Oorschot, Tom G. M., Croockewit, Sandra A. J., Blokx, Willeke A. M., Oyen, Wim J. G., Boerman, Otto C., Mus, Roel D. M., van Rossum, Michelle M., van der Graaf, Chantal A. A., Punt, Cornelis J. A., Adema, Gosse J., Figdor, Carl G., de Vries, I. Jolanda M., and Schreibelt, Gerty

Published
2016
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13. Maturation of monocyte-derived dendritic cells with Toll-like receptor 3 and 7/8 ligands combined with prostaglandin E2 results in high interleukin-12 production and cell migration

Author

Boullart, A. C. Inge, Aarntzen, Erik H. J. G., Verdijk, Pauline, Jacobs, Joannes F. M., Schuurhuis, Danita H., Benitez-Ribas, Daniel, Schreibelt, Gerty, van de Rakt, Mandy W. M. M., Scharenborg, Nicole M., de Boer, Annemiek, Kramer, Matthijs, Figdor, Carl G., Punt, Cornelis J. A., Adema, Gosse J., and de Vries, I. Jolanda M.

Published
2008
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16. Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

Author

Boudewijns, Steve, primary, Bol, Kalijn F., additional, Schreibelt, Gerty, additional, Westdorp, Harm, additional, Textor, Johannes C., additional, van Rossum, Michelle M., additional, Scharenborg, Nicole M., additional, de Boer, Annemiek J., additional, van de Rakt, Mandy W. M. M., additional, Pots, Jeanne M., additional, van Oorschot, Tom G. M., additional, Duiveman-de Boer, Tjitske, additional, Olde Nordkamp, Michel A., additional, van Meeteren, Wilmy S. E. C., additional, van der Graaf, Winette T. A., additional, Bonenkamp, Johannes J., additional, de Wilt, Johannes H. W., additional, Aarntzen, Erik H. J. G., additional, Punt, Cornelis J. A., additional, Gerritsen, Winald R., additional, Figdor, Carl G., additional, and de Vries, I. Jolanda M., additional

Published
2016
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17. Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Author

Schreibelt, Gerty, primary, Bol, Kalijn F., additional, Westdorp, Harm, additional, Wimmers, Florian, additional, Aarntzen, Erik H.J.G., additional, Duiveman-de Boer, Tjitske, additional, van de Rakt, Mandy W.M.M., additional, Scharenborg, Nicole M., additional, de Boer, Annemiek J., additional, Pots, Jeanette M., additional, Olde Nordkamp, Michel A.M., additional, van Oorschot, Tom G.M., additional, Tel, Jurjen, additional, Winkels, Gregor, additional, Petry, Katja, additional, Blokx, Willeke A.M., additional, van Rossum, Michelle M., additional, Welzen, Marieke E.B., additional, Mus, Roel D.M., additional, Croockewit, Sandra A.J., additional, Koornstra, Rutger H.T., additional, Jacobs, Joannes F.M., additional, Kelderman, Sander, additional, Blank, Christian U., additional, Gerritsen, Winald R., additional, Punt, Cornelis J.A., additional, Figdor, Carl G., additional, and de Vries, I. Jolanda M., additional

Published
2016
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18. Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients

Author

Bol, Kalijn F, primary, Figdor, Carl G, additional, Aarntzen, Erik HJG, additional, Welzen, Marieke EB, additional, van Rossum, Michelle M, additional, Blokx, Willeke AM, additional, van de Rakt, Mandy WMM, additional, Scharenborg, Nicole M, additional, de Boer, Annemiek J, additional, Pots, Jeanette M, additional, olde Nordkamp, Michel AM, additional, van Oorschot, Tom GM, additional, Mus, Roel DM, additional, Croockewit, Sandra AJ, additional, Jacobs, Joannes FM, additional, Schuler, Gerold, additional, Neyns, Bart, additional, Austyn, Jonathan M, additional, Punt, Cornelis JA, additional, Schreibelt, Gerty, additional, and de Vries, I Jolanda M, additional

Published
2015
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19. Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA mRNA for vaccination of colorectal cancer patients

Author

Lesterhuis, W. Joost, Vries, I. Jolanda M., Gerty Schreibelt, Schuurhuis, Danita H., Aarntzen, Erik H., Boer, Annemiek, Scharenborg, Nicole M., Rakt, Mandy, Hesselink, Erik J., Figdor, Carl G., Adema, Gosse J., Punt, Cornelis J. A., and Other departments

Subjects
chemical and pharmacologic phenomena
Abstract

Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. We have demonstrated that vaccination of autologous ex vivo cultured DCs results in the induction of tumor-specific immune responses in cancer patients, which correlates with clinical response. Optimization of antigen loading is one of the possibilities for further improving the efficacy of DC vaccination. Theoretically, transfection of DCs with RNA encoding a tumor-specific antigen may induce a broader immune response as compared to the most widely used technique of peptide pulsing. In this clinical study, RNA transfection was compared with peptide pulsing as an antigen loading strategy for DC vaccination. Patients with resectable liver metastases of colorectal cancer were vaccinated intravenously and intradermally 3 times weekly with either carcinoembryogenic antigen (CEA)-derived HLA-A2 binding peptide-loaded or CEA mRNA electroporated DCs prior to surgical resection of the metastases. All DCs were loaded with keyhole limpet hemocyanin (KLH) as a control protein. Evaluation of vaccine-induced immune reactivity consisted of T-cell proliferative responses and B-cell antibody responses against KLH in peripheral blood. CEA reactivity was determined in T-cell cultures of biopsies of post-treatment delayed type hypersensitivity skin tests. Sixteen patients were included. All patients showed T-cell responses against KLH upon vaccination. CEA peptide-specific T-cells were detected in 8 out of 11 patients in the peptide group, but in none of the 5 patients in the RNA group. In our study, DC CEA mRNA transfection was not superior to DC CEA peptide pulsing in the induction of a tumor-specific immune response in colorectal cancer patients

Published
2010

20. Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients

Author

de Vries, I. Jolanda M., Lesterhuis, W. Joost, Scharenborg, Nicole M., Engelen, Linda P. H., Ruiter, Dirk J., Gerritsen, Marie-Jeanne P., Croockewit, Sandra, Britten, Cedrik M., Torensma, Ruurd, Adema, Gosse J., Figdor, Carl G., Punt, Cornelis J. A., and Other departments

Subjects
hemic and immune systems, chemical and pharmacologic phenomena
Abstract

We have investigated the capacity of immature and mature monocyte-derived DCs pulsed with melanoma-associated peptides (gp100 and tyrosinase) to induce a primary cytotoxic T-lymphocyte response in vivo. Advanced HLA-A2.1(+) melanoma patients were vaccinated with peptide- and keyhole limpet hemocyanin (KLH)-pulsed DCs, either immature (9 patients) or matured by monocyte-conditioned medium/tumor necrosis factor alpha/prostaglandin E(2) (10 patients). All patients vaccinated with mature DCs showed a pronounced proliferative T-cell and humoral response against KLH. By contrast, KLH responses were absent in most of the patients vaccinated with immature DCs. Delayed-type hypersensitivity (DTH) reactions against antigen-pulsed DCs were only observed in patients vaccinated with mature DCs and not in patients vaccinated with immature DCs. MHC-peptide tetramer staining of DTH-derived T cells revealed the presence of specific T cells recognizing the melanoma-associated peptides in 1 patient. In a second patient, DTH-derived T cells showed specific lysis of tumor cells expressing the antigens used for DC pulsing. Only patients vaccinated with mature DCs showed objective clinical responses. Interestingly, both patients with long-term progression-free survival (22 and >40 months) were both vaccinated with mature DCs and demonstrated antigen-specific T-cell reactivity of DTH-derived T cells. We conclude that mature DC are superior to immature DC in the induction of immunological responses in melanoma patients, which may translate into improved clinical results

Published
2003

21. Route of administration modulates the induction of dendritic cell vaccine-induced antigen-specific T cells in advanced melanoma patients.

Author

UCL - SSS/DDUV - Institut de Duve, Lesterhuis, W Joost, de Vries, I Jolanda M, Schreibelt, Gerty, Lambeck, Annechien J A, Aarntzen, Erik H J G, Jacobs, Joannes F M, Scharenborg, Nicole M, van de Rakt, Mandy W M M, de Boer, Annemiek J, Croockewit, Sandra, van Rossum, Michelle M, Mus, Roel, Oyen, Wim J G, Boerman, Otto C, Lucas, Sophie, Adema, Gosse J, Punt, Cornelis J A, Figdor, Carl G, UCL - SSS/DDUV - Institut de Duve, Lesterhuis, W Joost, de Vries, I Jolanda M, Schreibelt, Gerty, Lambeck, Annechien J A, Aarntzen, Erik H J G, Jacobs, Joannes F M, Scharenborg, Nicole M, van de Rakt, Mandy W M M, de Boer, Annemiek J, Croockewit, Sandra, van Rossum, Michelle M, Mus, Roel, Oyen, Wim J G, Boerman, Otto C, Lucas, Sophie, Adema, Gosse J, Punt, Cornelis J A, and Figdor, Carl G

Abstract

Intradermal vaccination resulted in superior antitumor T-cell induction when compared with intranodal vaccination. No advantage of additional IL-2 treatment could be shown.

Published
2011

22. Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used.

Author

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands - Department of Medical Oncology, Lesterhuis, W Joost, Schreibelt, Gerty, Scharenborg, Nicole M, Brouwer, H Marylène H, Gerritsen, Marie-Jeanne P, Croockewit, Sandra, Coulie, Pierre, Torensma, Ruurd, Adema, Gosse J, Figdor, Carl G, de Vries, I Jolanda M, Punt, Cornelis J A, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands - Department of Medical Oncology, Lesterhuis, W Joost, Schreibelt, Gerty, Scharenborg, Nicole M, Brouwer, H Marylène H, Gerritsen, Marie-Jeanne P, Croockewit, Sandra, Coulie, Pierre, Torensma, Ruurd, Adema, Gosse J, Figdor, Carl G, de Vries, I Jolanda M, and Punt, Cornelis J A

Abstract

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients. Several strategies have been employed to load DC with antigen, including peptide loading. To increase immunogenicity of peptides, major histocompatibility complex (MHC) class I binding affinity and stability of peptide-MHC complexes at the cell surface may be improved by modification of the amino acid sequence. In this study, we compared the capacity of DC loaded with wild-type versus modified gp100 peptides with higher binding affinities to induce an immune and clinical response in advanced melanoma patients. Metastatic HLA-A2.1(+) melanoma patients were vaccinated intravenously (on average 25 × 10(6) DC) and intradermally (on average 11 × 10(6) DC) with mature DC loaded with keyhole limpet hemocyanin (KLH) together with tyrosinase peptide and either wild-type (15 patients) or modified (12 patients) gp100 peptides. All vaccinated patients showed a pronounced proliferative T cell or humoral response against KLH. Gp100-specific T cell responses were monitored in post-treatment delayed type hypersensitivity (DTH) skin biopsies by tetramer and functional analysis. Antigen-specific T cells were found in 2 of 15 patients vaccinated with wild-type gp100-loaded DC, versus 1 of 12 patients vaccinated with modified peptide-loaded DC. These three patients also had the best clinical response, with long-term (>8 years) complete responses in two patients, one in each group. We conclude that vaccination with peptide-loaded DC can result in long-term clinical responses in a minority of metastatic melanoma patients, and that the use of modified as compared to wild-type gp100 peptides for DC loading does not result in a relevant enhanced immune responses.

Published
2011

23. Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients

Author

Lesterhuis, W. Joost, primary, de Vries, I. Jolanda M., additional, Schreibelt, Gerty, additional, Lambeck, Annechien J.A., additional, Aarntzen, Erik H.J.G., additional, Jacobs, Joannes F.M., additional, Scharenborg, Nicole M., additional, van de Rakt, Mandy W.M.M., additional, de Boer, Annemiek J., additional, Croockewit, Sandra, additional, van Rossum, Michelle M., additional, Mus, Roel, additional, Oyen, Wim J.G., additional, Boerman, Otto C., additional, Lucas, Sophie, additional, Adema, Gosse J., additional, Punt, Cornelis J.A., additional, and Figdor, Carl G., additional

Published
2011
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24. Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used

Author

Lesterhuis, W. Joost, primary, Schreibelt, Gerty, additional, Scharenborg, Nicole M., additional, Brouwer, H. Mary-lène H., additional, Gerritsen, Marie-Jeanne P., additional, Croockewit, Sandra, additional, Coulie, Pierre G., additional, Torensma, Ruurd, additional, Adema, Gosse J., additional, Figdor, Carl G., additional, de Vries, I. Jolanda M., additional, and Punt, Cornelis J. A., additional

Published
2010
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25. Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

Author

Jacobs, Joannes F.M., primary, Punt, Cornelis J.A., additional, Lesterhuis, W. Joost, additional, Sutmuller, Roger P.M., additional, Brouwer, H. Mary-lène H., additional, Scharenborg, Nicole M., additional, Klasen, Ina S., additional, Hilbrands, Luuk B., additional, Figdor, Carl G., additional, de Vries, I. Jolanda M., additional, and Adema, Gosse J., additional

Published
2010
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26. Sensitivity of magnetic resonance imaging of dendritic cells for in vivo tracking of cellular cancer vaccines

Author

Verdijk, Pauline, primary, Scheenen, Tom W.J., additional, Lesterhuis, W. Joost, additional, Gambarota, Giulio, additional, Veltien, Andor A., additional, Walczak, Piotr, additional, Scharenborg, Nicole M., additional, Bulte, Jeff W.M., additional, Punt, Cornelis J.A., additional, Heerschap, Arend, additional, Figdor, Carl G., additional, and M. de Vries, I. Jolanda, additional

Published
2006
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33. Maturation of monocyte-derived dendritic cells with Toll-like receptor 3 and 7/8 ligands combined with prostaglandin E2 results in high interleukin-12 production and cell migration.

Author

Boullart, A. C. Inge, Aarntzen, Erik H. J., Verdijk, Pauline, Jacobs, Joannes F. M., Schuurhuis, Danita H., Benitez-Ribas, Daniel, Schreibelt, Gerty, van de Rakt, Mandy W. M. M., Scharenborg, Nicole M., de Boer, Annemiek, Kramer, Matthijs, Figdor, Carl G., Punt, Cornelis J. A., Adema, Gosse J., and de Vries, I. Jolanda M.

Subjects
DENDRITIC cells, IMMUNE system, T cells, CYTOKINES, MEDICAL research, LIGANDS (Biochemistry)
Abstract

Dendritic cells (DC) are professional antigen-presenting cells of the immune system that play a key role in regulating T cell-based immunity. In vivo, the capacity of DC to activate T cells depends on their ability to migrate to the T cell areas of lymph nodes as well as on their maturation state. Depending on their cytokine-secreting profile, DC are able to skew the immune response in a specific direction. In particular, IL-12p70 producing DC drive T cells towards a T helper 1 type response. A serious disadvantage of current clinical grade ex vivo generated monocyte-derived DC is the poor IL-12p70 production. We have investigated the effects of Toll-like receptor (TLR)-mediated maturation on ex vivo generated human monocyte-derived DC. We demonstrate that in contrast to cytokine-matured DC, DC matured with poly(I:C) (TLR3 ligand) and/or R848 (TLR7/8 ligand) are able to produce vast amounts of IL-12p70, but exhibit a reduced migratory capacity. The addition of prostaglandin E2 (PGE2) improved the migratory capacity of TLR-ligand matured DC while maintaining their IL-12p70 production upon T cell encounter. We propose a novel clinical grade maturation protocol in which TLR ligands poly(I:C) and R848 are combined with PGE2 to generate DC with both high migratory capacity and IL-12p70 production upon T cell encounter. [ABSTRACT FROM AUTHOR]

Published
2008
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34. Sensitivity of magnetic resonance imaging of dendritic cells for in vivo tracking of cellular cancer vaccines.

Author

Verdijk, Pauline, Scheenen, Tom W.J., Lesterhuis, W. Joost, Gambarota, Giulio, Veltien, Andor A., Walczak, Piotr, Scharenborg, Nicole M., Bulte, Jeff W.M., Punt, Cornelis J.A., Heerschap, Arend, Figdor, Carl G., and M. de Vries, I. Jolanda

Abstract

Success of immunotherapy with dendritic cells (DC) to treat cancer is highly dependent on their interaction with and activation of antigen specific T cells. To maximize DC-T cell contact accurate delivery of the therapeutic cells into the lymph node, or efficient trafficking of DC to the lymph nodes of the patient is essential. Since responses are seen in some patients but not in others, monitoring of the injected cells may be of major importance. Tracking of cells with magnetic resonance (MR) imaging is a non-invasive method that provides detailed anatomical information and is therefore more informative for the evaluation of the localization of therapeutic cells after injection than e. g. scintigraphic imaging. To challenge the sensitivity of this novel technique, we investigated the minimum amount of label and the number of cells required for MR imaging and the effect of labeling on DC function. DC were labeled with different concentrations of a clinically approved MR contrast agent consisting of superparamagnetic iron oxide particles and were imaged at both 3 and 7 T. Our results demonstrate the following: ( i) When loaded with 30 (±4) pg Fe/cell, cell numbers as low as 1,000 cells/mm [ABSTRACT FROM AUTHOR]

Published
2007
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35. Renal cell carcinoma–associated antigen G250 encodes a naturally processed epitope presented by human leukocyte antigen-dr molecules to CD4<SUP>+</SUP> T lymphocytes

Author

Vissers, Joost L.M., Vries, I. Jolanda M. de, Engelen, Linda P.H., Scharenborg, Nicole M., Molkenboer, Janneke, Figdor, Carl G., Oosterwijk, Egbert, and Adema, Gosse J.

Abstract

We previously identified an HLA-A2.1-restricted epitope within the RCC-associated antigen G250 that is recognized by CTLs. Using DCs of healthy individuals, which were loaded with overlapping 20 mer G250-derived peptides, we here report the induction of CD4+ T cells that recognize the G250 peptide of amino acids 249–268. Moreover, naturally processed G250 protein is readily recognized by these G250-specific CD4+ T cells in the context of HLA-DR molecules. Interestingly, peptide G250:249–268 overlaps the previously identified HLA-A2.1-restricted G250 epitope recognized by CTLs. These data and the high prevalence of G250 in RCC patients make peptide G250:249–268 a potential target in peptide-based vaccines to induce both CD4+ and CD8+ T-cell responses in patients. © 2002 Wiley-Liss, Inc.

Published
2002
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37. Proliferation of endothelial cells on surfaceimmobilized albumin–heparin conjugate loaded with basic fibroblast growth factor

Author

Bos, Gert W., Scharenborg, Nicole M., Poot, André A., Engbers, Gerard H. M., Beugeling, Tom, van Aken, Willem G., and Feijen, Jan

Abstract

Seeding of endothelial cells ECs on the luminal surface of smalldiameter vascular grafts is a promising method to avoid occlusion of these prostheses. Immobilization of basic fibroblast growth factor bFGF to substrates used to coat or fill porous prostheses may enhance the formation of a confluent monolayer of ECs. Human umbilical vein endothelial cells HUVECs were grown on bFGFloaded albumin–heparin conjugate bound to CO2gasplasmatreated polystyrene. In the order of 2–3 ngcm2bFGF had to be immobilized to form a confluent monolayer of HUVECs. The most prominent effect of surfaceimmobilized bFGF was stimulation of the proliferation shortly after seeding, resulting within 3 days in confluent cell monolayers with high density. In contrast, in cultures with 0.3 ngmL bFGF in the medium instead of bFGF bound to the surface, it took almost a week before the cell layers reached confluency. Binding of bFGF to heparin and the biological activity of bFGF towards ECs were not influenced by the radiolabeling of bFGF with iodine. However, only a minor part of the bFGF used in this study displayed heparin affinity. Furthermore, degradation and multimerization of labeled bFGF in time occurred when the growth factor was stored at 20°–37°C. This limits the use of labeled bFGF to shortterm hours experiments. In conclusion, bFGF loading of vascular graft surfaces through complexation of bFGF with a heparincontaining matrix probably will lead to more rapid formation of a confluent monolayer of ECs on graft surfaces upon seeding of the cells. © 1999 John Wiley & Sons, Inc. J Biomed Mater Res, 44, 330–340, 1999.

Published
1999
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38. Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA mRNA for vaccination of colorectal cancer patients.

Author

Lesterhuis WJ, De Vries IJ, Schreibelt G, Schuurhuis DH, Aarntzen EH, De Boer A, Scharenborg NM, Van De Rakt M, Hesselink EJ, Figdor CG, Adema GJ, and Punt CJ

Subjects
Cancer Vaccines administration & dosage, Cancer Vaccines genetics, Carcinoembryonic Antigen genetics, Colorectal Neoplasms immunology, Dendritic Cells physiology, Epitopes, T-Lymphocyte immunology, HLA-A2 Antigen immunology, Hemocyanins immunology, Humans, RNA, Messenger administration & dosage, RNA, Messenger genetics, RNA, Messenger immunology, T-Lymphocytes immunology, Transfection, Cancer Vaccines immunology, Carcinoembryonic Antigen immunology, Colorectal Neoplasms therapy, Dendritic Cells immunology, Immunotherapy, Adoptive methods
Abstract

Background: Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. We have demonstrated that vaccination of autologous ex vivo cultured DCs results in the induction of tumor-specific immune responses in cancer patients, which correlates with clinical response. Optimization of antigen loading is one of the possibilities for further improving the efficacy of DC vaccination. Theoretically, transfection of DCs with RNA encoding a tumor-specific antigen may induce a broader immune response as compared to the most widely used technique of peptide pulsing., Patients and Methods: In this clinical study, RNA transfection was compared with peptide pulsing as an antigen loading strategy for DC vaccination. Patients with resectable liver metastases of colorectal cancer were vaccinated intravenously and intradermally 3 times weekly with either carcinoembryogenic antigen (CEA)-derived HLA-A2 binding peptide-loaded or CEA mRNA electroporated DCs prior to surgical resection of the metastases. All DCs were loaded with keyhole limpet hemocyanin (KLH) as a control protein. Evaluation of vaccine-induced immune reactivity consisted of T-cell proliferative responses and B-cell antibody responses against KLH in peripheral blood. CEA reactivity was determined in T-cell cultures of biopsies of post-treatment delayed type hypersensitivity skin tests., Results: Sixteen patients were included. All patients showed T-cell responses against KLH upon vaccination. CEA peptide-specific T-cells were detected in 8 out of 11 patients in the peptide group, but in none of the 5 patients in the RNA group., Conclusion: In our study, DC CEA mRNA transfection was not superior to DC CEA peptide pulsing in the induction of a tumor-specific immune response in colorectal cancer patients.

Published
2010

39. Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients.

Author

de Vries IJ, Lesterhuis WJ, Scharenborg NM, Engelen LP, Ruiter DJ, Gerritsen MJ, Croockewit S, Britten CM, Torensma R, Adema GJ, Figdor CG, and Punt CJ

Subjects
Adjuvants, Immunologic pharmacology, Adult, Aged, Antigens, Neoplasm immunology, Cell Division, Female, HLA-A2 Antigen metabolism, Hemocyanins pharmacology, Humans, Hypersensitivity, Delayed immunology, Interferon-gamma metabolism, Male, Melanoma metabolism, Melanoma secondary, Membrane Glycoproteins immunology, Middle Aged, Monocytes immunology, Monocytes metabolism, Monophenol Monooxygenase immunology, Neoplasm Proteins immunology, Vaccination, gp100 Melanoma Antigen, Cancer Vaccines therapeutic use, Cytotoxicity, Immunologic immunology, Dendritic Cells immunology, Melanoma immunology, Peptide Fragments immunology, T-Lymphocytes, Cytotoxic immunology
Abstract

Purpose: We have investigated the capacity of immature and mature monocyte-derived DCs pulsed with melanoma-associated peptides (gp100 and tyrosinase) to induce a primary cytotoxic T-lymphocyte response in vivo., Experimental Design: Advanced HLA-A2.1(+) melanoma patients were vaccinated with peptide- and keyhole limpet hemocyanin (KLH)-pulsed DCs, either immature (9 patients) or matured by monocyte-conditioned medium/tumor necrosis factor alpha/prostaglandin E(2) (10 patients)., Results: All patients vaccinated with mature DCs showed a pronounced proliferative T-cell and humoral response against KLH. By contrast, KLH responses were absent in most of the patients vaccinated with immature DCs. Delayed-type hypersensitivity (DTH) reactions against antigen-pulsed DCs were only observed in patients vaccinated with mature DCs and not in patients vaccinated with immature DCs. MHC-peptide tetramer staining of DTH-derived T cells revealed the presence of specific T cells recognizing the melanoma-associated peptides in 1 patient. In a second patient, DTH-derived T cells showed specific lysis of tumor cells expressing the antigens used for DC pulsing. Only patients vaccinated with mature DCs showed objective clinical responses. Interestingly, both patients with long-term progression-free survival (22 and >40 months) were both vaccinated with mature DCs and demonstrated antigen-specific T-cell reactivity of DTH-derived T cells., Conclusions: We conclude that mature DC are superior to immature DC in the induction of immunological responses in melanoma patients, which may translate into improved clinical results.

Published
2003

40. Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state.

Author

De Vries IJ, Krooshoop DJ, Scharenborg NM, Lesterhuis WJ, Diepstra JH, Van Muijen GN, Strijk SP, Ruers TJ, Boerman OC, Oyen WJ, Adema GJ, Punt CJ, and Figdor CG

Subjects
Antibodies, Monoclonal, Antigens, CD analysis, Autoradiography, Humans, Indium Radioisotopes, Lymph Nodes pathology, Major Histocompatibility Complex, Melanoma pathology, T-Lymphocytes immunology, Dendritic Cells immunology, Lymph Nodes immunology, Melanoma immunology
Abstract

Dendritic cells are the professional antigen-presenting cells of the immune system. To induce an effective immune response, these cells should not only express high levels of MHC and costimulatory molecules but also migrate into the lymph nodes to interact with naïve T cells. Here, we demonstrate that in vitro-generated mature, but not immature dendritic cells, efficiently migrate into the T-cell areas of lymph nodes of melanoma patients. This difference is confirmed by in vitro studies, in which immature dendritic cells are strongly adherent, whereas mature dendritic cells remain highly motile. Our present findings demonstrate that the ability of dendritic cells to mount a proper immune response correlates with their ability to migrate both in vitro and in vivo.

Published
2003

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