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1. Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma

Author

Naghavian, Reza, primary, Faigle, Wolfgang, additional, Oldrati, Pietro, additional, Wang, Jian, additional, Toussaint, Nora C., additional, Qiu, Yuhan, additional, Medici, Gioele, additional, Wacker, Marcel, additional, Freudenmann, Lena K., additional, Bonté, Pierre-Emmanuel, additional, Weller, Michael, additional, Regli, Luca, additional, Amigorena, Sebastian, additional, Rammensee, Hans-Georg, additional, Walz, Juliane S., additional, Brugger, Silvio D., additional, Mohme, Malte, additional, Zhao, Yingdong, additional, Sospedra, Mireia, additional, Neidert, Marian C., additional, and Martin, Roland, additional

Published
2023
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2. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens

Author

Gubin, Matthew M., Zhang, Xiuli, Schuster, Heiko, Caron, Etienne, Ward, Jeffrey P., Noguchi, Takuro, Ivanova, Yulia, Hundal, Jasreet, Arthur, Cora D., Krebber, Willem-Jan, Mulder, Gwenn E., Toebes, Mireille, Vesely, Matthew D., Lam, Samuel S.K., Korman, Alan J., Allison, James P., Freeman, Gordon J., Sharpe, Arlene H., Pearce, Erika L., Schumacher, Ton N., Aebersold, Ruedi, Rammensee, Hans-Georg, Melief, Cornelis J.M., Mardis, Elaine R., Gillanders, William E., Artyomov, Maxim N., and Schreiber, Robert D.

Subjects
Sarcoma -- Drug therapy -- Development and progression, Antigenic determinants -- Health aspects, Immunotherapy -- Analysis, Cancer -- Care and treatment, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity (1-6), but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion (1,2,7). Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cell (s8,9). Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits--including durable responses--to patients with different malignancies (10-13). However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments., In this study, we used two distinct progresser 3-methylcholanthrene-induced (MCA) sarcoma cell lines (d42m1-T3 and F244) and asked whether they expressed sufficient immunogenicity to be controlled by checkpoint blockade immunotherapy. [...]

Published
2014

3. A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity

Author

Heitmann, Jonas S., primary, Bilich, Tatjana, additional, Tandler, Claudia, additional, Nelde, Annika, additional, Maringer, Yacine, additional, Marconato, Maddalena, additional, Reusch, Julia, additional, Jäger, Simon, additional, Denk, Monika, additional, Richter, Marion, additional, Anton, Leonard, additional, Weber, Lisa Marie, additional, Roerden, Malte, additional, Bauer, Jens, additional, Rieth, Jonas, additional, Wacker, Marcel, additional, Hörber, Sebastian, additional, Peter, Andreas, additional, Meisner, Christoph, additional, Fischer, Imma, additional, Löffler, Markus W., additional, Karbach, Julia, additional, Jäger, Elke, additional, Klein, Reinhild, additional, Rammensee, Hans-Georg, additional, Salih, Helmut R., additional, and Walz, Juliane S., additional

Published
2021
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9. Identification of classical minor histocompatibility antigen as cell-derived peptide

Author

Wallny, Hans-Joachim and Rammensee, Hans-Georg

Subjects
Histocompatibility antigens -- Identification and classification, Peptides -- Physiological aspects, Graft rejection -- Physiological aspects, Cell-mediated cytotoxicity -- Physiological aspects, T cells -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Published
1990

10. Publisher Correction: Actively personalized vaccination trial for newly diagnosed glioblastoma

Author

Hilf, Norbert, primary, Kuttruff-Coqui, Sabrina, additional, Frenzel, Katrin, additional, Bukur, Valesca, additional, Stevanović, Stefan, additional, Gouttefangeas, Cecile, additional, Platten, Michael, additional, Tabatabai, Ghazaleh, additional, Dutoit, Valerie, additional, van der Burg, Sjoerd H., additional, Straten, Per thor, additional, Martinez-Ricarte, Francisco, additional, Ponsati, Berta, additional, Okada, Hideho, additional, Lassen, Ulrik, additional, Admon, Arie, additional, Ottensmeier, Christian H., additional, Ulges, Alexander, additional, Kreiter, Sebastian, additional, von Deimling, Andreas, additional, Skardelly, Marco, additional, Migliorini, Denis, additional, Kroep, Judith R., additional, Idorn, Manja, additional, Rodon, Jordi, additional, Piro, Jordi, additional, Poulsen, Hans S., additional, Shraibman, Bracha, additional, McCann, Katy, additional, Mendrzyk, Regina, additional, Lower, Martin, additional, Stieglbauer, Monika, additional, Britten, Cedrik M., additional, Capper, David, additional, Welters, Marij J. P., additional, Sahuquillo, Juan, additional, Kiesel, Katharina, additional, Derhovanessian, Evelyna, additional, Rusch, Elisa, additional, Bunse, Lukas, additional, Song, Colette, additional, Heesch, Sandra, additional, Wagner, Claudia, additional, Kemmer-Bruck, Alexandra, additional, Ludwig, Jorg, additional, Castle, John C., additional, Schoor, Oliver, additional, Tadmor, Arbel D., additional, Green, Edward, additional, Fritsche, Jens, additional, Meyer, Miriam, additional, Pawlowski, Nina, additional, Dorner, Sonja, additional, Hoffgaard, Franziska, additional, Rossler, Bernhard, additional, Maurer, Dominik, additional, Weinschenk, Toni, additional, Reinhardt, Carsten, additional, Huber, Christoph, additional, Rammensee, Hans-Georg, additional, Singh-Jasuja, Harpreet, additional, Sahin, Ugur, additional, Dietrich, Pierre-Yves, additional, and Wick, Wolfgang, additional

Published
2019
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11. A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity

Author

Heitmann, Jonas S., Bilich, Tatjana, Tandler, Claudia, Nelde, Annika, Maringer, Yacine, Marconato, Maddalena, Reusch, Julia, Jäger, Simon, Denk, Monika, Richter, Marion, Anton, Leonard, Weber, Lisa Marie, Roerden, Malte, Bauer, Jens, Rieth, Jonas, Wacker, Marcel, Hörber, Sebastian, Peter, Andreas, Meisner, Christoph, Fischer, Imma, Löffler, Markus W., Karbach, Julia, Jäger, Elke, Klein, Reinhild, Rammensee, Hans-Georg, Salih, Helmut R., and Walz, Juliane S.

Abstract

T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18–80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+and CD8+T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency.

Published
2022
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12. Actively personalized vaccination trial for newly diagnosed glioblastoma

Author

Hilf, Norbert, primary, Kuttruff-Coqui, Sabrina, additional, Frenzel, Katrin, additional, Bukur, Valesca, additional, Stevanović, Stefan, additional, Gouttefangeas, Cécile, additional, Platten, Michael, additional, Tabatabai, Ghazaleh, additional, Dutoit, Valerie, additional, van der Burg, Sjoerd H., additional, thor Straten, Per, additional, Martínez-Ricarte, Francisco, additional, Ponsati, Berta, additional, Okada, Hideho, additional, Lassen, Ulrik, additional, Admon, Arie, additional, Ottensmeier, Christian H., additional, Ulges, Alexander, additional, Kreiter, Sebastian, additional, von Deimling, Andreas, additional, Skardelly, Marco, additional, Migliorini, Denis, additional, Kroep, Judith R., additional, Idorn, Manja, additional, Rodon, Jordi, additional, Piró, Jordi, additional, Poulsen, Hans S., additional, Shraibman, Bracha, additional, McCann, Katy, additional, Mendrzyk, Regina, additional, Löwer, Martin, additional, Stieglbauer, Monika, additional, Britten, Cedrik M., additional, Capper, David, additional, Welters, Marij J. P., additional, Sahuquillo, Juan, additional, Kiesel, Katharina, additional, Derhovanessian, Evelyna, additional, Rusch, Elisa, additional, Bunse, Lukas, additional, Song, Colette, additional, Heesch, Sandra, additional, Wagner, Claudia, additional, Kemmer-Brück, Alexandra, additional, Ludwig, Jörg, additional, Castle, John C., additional, Schoor, Oliver, additional, Tadmor, Arbel D., additional, Green, Edward, additional, Fritsche, Jens, additional, Meyer, Miriam, additional, Pawlowski, Nina, additional, Dorner, Sonja, additional, Hoffgaard, Franziska, additional, Rössler, Bernhard, additional, Maurer, Dominik, additional, Weinschenk, Toni, additional, Reinhardt, Carsten, additional, Huber, Christoph, additional, Rammensee, Hans-Georg, additional, Singh-Jasuja, Harpreet, additional, Sahin, Ugur, additional, Dietrich, Pierre-Yves, additional, and Wick, Wolfgang, additional

Published
2018
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14. Qa-2 molecules are peptide receptors of higher stringency than ordinary class I molecules

Author

Rotzschke, Olaf, Falk, Kirsten, Stevanovic, Stefan, Grahovac, Blazenka, Soloski, Mark J., Jung, Gunther, and Rammensee, Hans-Georg

Subjects
Ligand binding (Biochemistry) -- Research, Major histocompatibility complex -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Natural ligands of glycophosphatidyl-anchored mouse class I major histocompatibility complex molecules are distinctly specialized peptide receptors whose purpose remains unknown. They have similar ligand specificity and peptide binding grooves to the traditional class I molecules and yet, of their nine binding sites, two are anchors and four are limited binders. This pool sequencing suggests a very specific function for the molecules which is possibly the presentation of epithelial-pathogen derived antigens to gamma upsilon T cells.

Published
1993

15. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells

Author

Rotzschke, Olaf, Falk, Kirsten, Deres, Karl, Schild, Hansjorg, Norda, Maria, Metzger, Jorg, Jung, Gunther, and Rammensee, Hans-Georg

Subjects
Peptides -- Physiological aspects, T cells -- Physiological aspects, Cell-mediated cytotoxicity -- Research, Viruses -- Physiological aspects, Major histocompatibility complex -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Published
1990

16. Actively personalized vaccination trial for newly diagnosed glioblastoma

Author

Hilf, Norbert, Kuttruff-Coqui, Sabrina, Frenzel, Katrin, Bukur, Valesca, Stevanović, Stefan, Gouttefangeas, Cécile, Platten, Michael, Tabatabai, Ghazaleh, Dutoit, Valerie, van der Burg, Sjoerd H., thor Straten, Per, Martínez-Ricarte, Francisco, Ponsati, Berta, Okada, Hideho, Lassen, Ulrik, Admon, Arie, Ottensmeier, Christian H., Ulges, Alexander, Kreiter, Sebastian, von Deimling, Andreas, Skardelly, Marco, Migliorini, Denis, Kroep, Judith R., Idorn, Manja, Rodon, Jordi, Piró, Jordi, Poulsen, Hans S., Shraibman, Bracha, McCann, Katy, Mendrzyk, Regina, Löwer, Martin, Stieglbauer, Monika, Britten, Cedrik M., Capper, David, Welters, Marij J. P., Sahuquillo, Juan, Kiesel, Katharina, Derhovanessian, Evelyna, Rusch, Elisa, Bunse, Lukas, Song, Colette, Heesch, Sandra, Wagner, Claudia, Kemmer-Brück, Alexandra, Ludwig, Jörg, Castle, John C., Schoor, Oliver, Tadmor, Arbel D., Green, Edward, Fritsche, Jens, Meyer, Miriam, Pawlowski, Nina, Dorner, Sonja, Hoffgaard, Franziska, Rössler, Bernhard, Maurer, Dominik, Weinschenk, Toni, Reinhardt, Carsten, Huber, Christoph, Rammensee, Hans-Georg, Singh-Jasuja, Harpreet, Sahin, Ugur, Dietrich, Pierre-Yves, and Wick, Wolfgang

Abstract

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+T cells. APVAC2 induced predominantly CD4+T cell responses of T helper 1 type against predicted neoepitopes.

Published
2019
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17. Immunology: Protein surgery

Author

Rammensee, Hans-Georg

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Hans-Georg Rammensee [1] Question: how many different peptides composed of nine amino acids can a cell produce from a protein made up of 500 amino acids? Answer: 482 -- [...]

Published
2004
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18. In vivo priming of virus-specific cytotoxic T lymphocytes with synthetic lipopeptide vaccine

Author

Deres, Karl, Schild, Hansjorg, Wiesmuller, Karl-Heinz, Jung, Gunther, and Rammensee, Hans-Georg

Subjects
Immune system -- Research, T cells -- Research, Lipoproteins -- Research, Peptides -- Research, Vaccines -- Research, Immunization -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Immunity to an organism that causes disease is a complex phenomenon involving many types of cells of the immune system. Cytotoxic T cells, a subset of lymphocytes, can recognize a cell containing a foreign molecule and destroy the cell. The T cells recognize a portion of the foreign molecule along with host molecules known as major histocompatibility antigens. Since T cells recognize only a portion of the foreign molecule, it was hoped that peptides that are identical to that segment and are synthesized in the laboratory could be used to stimulate the immune system to respond. Although this artificial stimulation works in helper T cells, which are T cells involved in the production of antibodies, synthetic peptides do not stimulate cytotoxic, or killer, T cells. A peptide present in a structural protein of a virus that causes influenza was shown to stimulate and activate cytotoxic T cells when it was attached to a lipoprotein, a molecule consisting of fatty acids and protein. The mechanism of activation may involve the ability of the peptide to enter the cytoplasm of the cell, or to associate with certain major histocompatibility antigens, of which there are many, or for the complex to be inserted into the cell membrane. Peptides are being developed for vaccines. However, many different peptides from the immunogenic proteins of infectious organisms may have to be used in any given vaccine to ensure that the peptides will combine with certain host major histocompatibility antigens and will activate the immune response of cytotoxic T cells.

Published
1989

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