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7. PLGA Nanoparticles Co-encapsulating NY-ESO-1 Peptides and IMM60 Induce Robust CD8 and CD4 T Cell and B Cell Responses

Author

Dolen, Y., Gileadi, U., Chen, J.L., Valente, M.C., Creemers, J.H.A., Dinther, E.A.W. van, Riessen, N.K. van, Jäger, E., Hruby, M., Cerundolo, V., Diken, M., Figdor, C.G., Vries, I.J.M. de, Dolen, Y., Gileadi, U., Chen, J.L., Valente, M.C., Creemers, J.H.A., Dinther, E.A.W. van, Riessen, N.K. van, Jäger, E., Hruby, M., Cerundolo, V., Diken, M., Figdor, C.G., and Vries, I.J.M. de

Abstract

Contains fulltext : 232076.pdf (Publisher’s version ) (Open Access), Tumor-specific neoantigens can be highly immunogenic, but their identification for each patient and the production of personalized cancer vaccines can be time-consuming and prohibitively expensive. In contrast, tumor-associated antigens are widely expressed and suitable as an off the shelf immunotherapy. Here, we developed a PLGA-based nanoparticle vaccine that contains both the immunogenic cancer germline antigen NY-ESO-1 and an α-GalCer analog IMM60, as a novel iNKT cell agonist and dendritic cell transactivator. Three peptide sequences (85-111, 117-143, and 157-165) derived from immunodominant regions of NY-ESO-1 were selected. These peptides have a wide HLA coverage and were efficiently processed and presented by dendritic cells via various HLA subtypes. Co-delivery of IMM60 enhanced CD4 and CD8 T cell responses and antibody levels against NY-ESO-1 in vivo. Moreover, the nanoparticles have negligible systemic toxicity in high doses, and they could be produced according to GMP guidelines. Together, we demonstrated the feasibility of producing a PLGA-based nanovaccine containing immunogenic peptides and an iNKT cell agonist, that is activating DCs to induce antigen-specific T cell responses.

Published
2021

8. Robust Antigen-Specific T Cell Activation within Injectable 3D Synthetic Nanovaccine Depots

Author

Weiden, J., Schluck, M., Ioannidis, M., Dinther, E.A.W. van, Rezaeeyazdi, M., Omar, F., Steuten, J., Voerman, D., Tel, J., Diken, M., Bencherif, S.A., Figdor, C.G., Verdoes, M., Weiden, J., Schluck, M., Ioannidis, M., Dinther, E.A.W. van, Rezaeeyazdi, M., Omar, F., Steuten, J., Voerman, D., Tel, J., Diken, M., Bencherif, S.A., Figdor, C.G., and Verdoes, M.

Abstract

Item does not contain fulltext, Synthetic cancer vaccines may boost anticancer immune responses by co-delivering tumor antigens and adjuvants to dendritic cells (DCs). The accessibility of cancer vaccines to DCs and thereby the delivery efficiency of antigenic material greatly depends on the vaccine platform that is used. Three-dimensional scaffolds have been developed to deliver antigens and adjuvants locally in an immunostimulatory environment to DCs to enable sustained availability. However, current systems have little control over the release profiles of the cargo that is incorporated and are often characterized by an initial high-burst release. Here, an alternative system is designed that co-delivers antigens and adjuvants to DCs through cargo-loaded nanoparticles (NPs) incorporated within biomaterial-based scaffolds. This creates a programmable system with the potential for controlled delivery of their cargo to DCs. Cargo-loaded poly(d,l-lactic-co-glycolic acid) NPs are entrapped within the polymer walls of alginate cryogels with high efficiency while retaining the favorable physical properties of cryogels, including syringe injection. DCs cultured within these NP-loaded scaffolds acquire strong antigen-specific T cell-activating capabilities. These findings demonstrate that introduction of NPs into the walls of macroporous alginate cryogels creates a fully synthetic immunostimulatory niche that stimulates DCs and evokes strong antigen-specific T cell responses.

Published
2021

13. Abstract OT2-06-01: Highly innovative personalized RNA-immunotherapy for patients with triple negative breast cancer

Author

Schmidt, M, primary, Bolte, S, additional, Frenzel, K, additional, Heesen, L, additional, Derhovanessian, E, additional, Bukur, V, additional, Diken, M, additional, Gruetzner, J, additional, Kreiter, S, additional, Klein, A, additional, Kuhn, A, additional, Langer, D, additional, Loewer, M, additional, Lindman, H, additional, Schneeweiss, A, additional, Tuereci, O, additional, and Sahin, U, additional

Published
2019
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14. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma

Author

Jabulowsky, R.A., primary, Loquai, C., additional, Derhovanessian, E., additional, Mitzel-Rink, H., additional, Utikal, J., additional, Hassel, J., additional, Kaufmann, R., additional, Pinter, A., additional, Diken, M., additional, Gold, M., additional, Heesen, L., additional, Schreeb, K.H., additional, Schwarck-Kokarakis, D., additional, Kreiter, S., additional, Gaiser, M.R., additional, Jäger, D., additional, Grabbe, S., additional, Türeci, Ö, additional, and Sahin, U., additional

Published
2018
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15. Mutanome engineered RNA immuno-therapy (MERIT) for patients with triple negative breast cancer (TNBC)

Author

Heesen, L., primary, Frenzel, K., additional, Bolte, S., additional, Bukur, V., additional, Diken, M., additional, Derhovanessian, E., additional, Kreiter, S., additional, Kuhn, A., additional, Kühlcke, K., additional, Löwer, M., additional, Lindman, H., additional, Pascolo, S., additional, Schmidt, M., additional, Schneeweiss, A., additional, Sjöblom, T., additional, Thielemans, K., additional, Zitvogel, L., additional, Türeci, Ö, additional, and Sahin, U., additional

Published
2018
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19. In vitro effects of some pesticides on glutathione-s transferase activity

Author

Diken, M. E., Dogan, S., Dogan, M., Turhan, Y., and Bilim Tek. Araş.Uygulama Merkezi

Subjects
Glutathione S-transferase, Pesticides, Environmental Toxicity, Inhibition
Abstract

Human populations have been constantly exposed to pesticides due to their extensive use and presence in food and drinking water. Therefore, the aim of this study is to compare the inhibitory effect of three commonly used pesticides such as glyphosate (herbicide) and lambda-cyhalothrin and deltamethrin (insecticides) on glutathione S-transferase (GST) activity in vitro in human blood. GST enzyme activity was spectrophotometrically determined with observation of the formation of 1-chloro-2,4-dinitrobenzene-glutathione (CDNB-GSH) conjugate. GST activities were suppressed by all the pesticides tested; the deltamethrin was the most potent inhibitor, reducing GST activity in vitro in a dosage-dependent manner. The inhibition mechanism of pesticides on GST was different from each other. The inhibition types of glyphosate, lambda-cyhalothrin and deltamethrin pesticides were uncompetitive, mixed and competitive, respectively.

Published
2017

21. Mutanome engineered RNA immuno-therapy (MERIT) for patients with triple negative breast cancer

Author

Frenzel, K., primary, Heesen, L., additional, Bolte, S., additional, Bukur, V., additional, Diken, M., additional, Derhovanessian, E., additional, Kreiter, S., additional, Kuhn, A., additional, Kuehlcke, K., additional, Löwer, M., additional, De Greve, J., additional, Lindman, H., additional, Pascolo, S., additional, Schmidt, M., additional, Schneeweiss, A., additional, Sjöblom, T., additional, Thielemans, K., additional, Zitvogel, L., additional, Türeci, Ö, additional, and Sahin, U., additional

Published
2017
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22. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for potent melanoma immunotherapy

Author

Heesen, L., primary, Jabulowsky, R., additional, Loquai, C., additional, Utikal, J., additional, Gebhardt, C., additional, Hassel, J., additional, Kaufmann, R., additional, Pinter, A., additional, Derhovanessian, E., additional, Diken, M., additional, Kranz, L., additional, Haas, H., additional, Attig, S., additional, Kuhn, A., additional, Langguth, P., additional, Schwarck-Kokarakis, D., additional, Jäger, D., additional, Grabbe, S., additional, Türeci, Ö, additional, and Sahin, U., additional

Published
2017
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23. Mutanome engineered RNA immuno-therapy (MERIT) for patients with triple negative breast cancer

Author

Frenzel, K., Heesen, L., Bolte, S., Bukur, V., Diken, M., Derhovanessian, E., Kreiter, S., Kuhn, A., Kuehlcke, K., Löwer, M., De Greve, J., Lindman, Henrik, Pascolo, S., Schmidt, M., Schneeweiss, A., Sjöblom, Tobias, Thielemans, K., Zitvogel, L., Tuereci, Ö., Sahin, U., Frenzel, K., Heesen, L., Bolte, S., Bukur, V., Diken, M., Derhovanessian, E., Kreiter, S., Kuhn, A., Kuehlcke, K., Löwer, M., De Greve, J., Lindman, Henrik, Pascolo, S., Schmidt, M., Schneeweiss, A., Sjöblom, Tobias, Thielemans, K., Zitvogel, L., Tuereci, Ö., and Sahin, U.

Published
2017
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36. Exploiting the mutanome for tumor vaccination.

Author

Castle, J.C., Kreiter, S., Diekmann, J., Lower, M., Roemer, N. van de, Graaf, J. de, Selmi, A., Diken, M., Boegel, S., Paret, C., Koslowski, M., Kuhn, A.N., Britten, C.M., Huber, C., Tureci, O., Sahin, U., Castle, J.C., Kreiter, S., Diekmann, J., Lower, M., Roemer, N. van de, Graaf, J. de, Selmi, A., Diken, M., Boegel, S., Paret, C., Koslowski, M., Kuhn, A.N., Britten, C.M., Huber, C., Tureci, O., and Sahin, U.

Abstract

Item does not contain fulltext, Multiple genetic events and subsequent clonal evolution drive carcinogenesis, making disease elimination with single-targeted drugs difficult. The multiplicity of gene mutations derived from clonal heterogeneity therefore represents an ideal setting for multiepitope tumor vaccination. Here, we used next generation sequencing exome resequencing to identify 962 nonsynonymous somatic point mutations in B16F10 murine melanoma cells, with 563 of those mutations in expressed genes. Potential driver mutations occurred in classical tumor suppressor genes and genes involved in proto-oncogenic signaling pathways that control cell proliferation, adhesion, migration, and apoptosis. Aim1 and Trrap mutations known to be altered in human melanoma were included among those found. The immunogenicity and specificity of 50 validated mutations was determined by immunizing mice with long peptides encoding the mutated epitopes. One-third of these peptides were found to be immunogenic, with 60% in this group eliciting immune responses directed preferentially against the mutated sequence as compared with the wild-type sequence. In tumor transplant models, peptide immunization conferred in vivo tumor control in protective and therapeutic settings, thereby qualifying mutated epitopes that include single amino acid substitutions as effective vaccines. Together, our findings provide a comprehensive picture of the mutanome of B16F10 melanoma which is used widely in immunotherapy studies. In addition, they offer insight into the extent of the immunogenicity of nonsynonymous base substitution mutations. Lastly, they argue that the use of deep sequencing to systematically analyze immunogenicity mutations may pave the way for individualized immunotherapy of cancer patients.

Published
2012

37. Confidence-based Somatic Mutation Evaluation and Prioritization

Author

Lower, M., Renard, B.Y., Graaf, J. de, Wagner, M., Paret, C., Kneip, C., Tureci, O., Diken, M., Britten, C., Kreiter, S., Koslowski, M., Castle, J.C., Sahin, U., Lower, M., Renard, B.Y., Graaf, J. de, Wagner, M., Paret, C., Kneip, C., Tureci, O., Diken, M., Britten, C., Kreiter, S., Koslowski, M., Castle, J.C., and Sahin, U.

Abstract

Contains fulltext : 110677.pdf (publisher's version ) (Open Access), Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set.

Published
2012

40. Therapeutics

Author

Azimi, A., primary, Kuznecovs, S., additional, Kuznecovs, J., additional, Blazejczyk, A., additional, Switalska, M., additional, Chlopicki, S., additional, Marcinek, A., additional, Gebicki, J., additional, Wietrzyk, J., additional, Egyhazi, S., additional, Azimi, A., additional, Ghasghgaei, S., additional, Frostvik Stolt, M., additional, Hertzman Johansson, C., additional, Hansson, J., additional, Delage, J. D., additional, Li, H., additional, Lu, H., additional, Cazin, L. H., additional, Vannier, J. P., additional, Drouet, L., additional, Dupuy, E., additional, Soria, J., additional, Varin, R., additional, Soria, C., additional, Castle, J., additional, Kreiter, S., additional, Diekmann, J., additional, Lower, M., additional, van der Roemer, N., additional, de Graaf, J., additional, Selmi, S., additional, Diken, M., additional, Boegel, S., additional, Paret, C., additional, Koslowski, M., additional, Kuhn, A. N., additional, Britten, C. M., additional, Huber, C., additional, Tureci, O., additional, Sahin, U., additional, Procopio, G., additional, Verzoni, E., additional, Testa, I., additional, de Braud, F., additional, Misale, S., additional, Yaeger, R., additional, Hobor, S., additional, Scala, E., additional, Janakiraman, M., additional, Liska, D., additional, Valtorta, E., additional, Schiavo, R., additional, Buscarino, M., additional, Siravergna, G., additional, Bencardino, K., additional, Cercek, A., additional, Chen, C., additional, Veronese, S., additional, Zanon, C., additional, Sartore-Bianchi, A., additional, Gambacorta, M., additional, Gallicchio, M., additional, Vakiani, E., additional, Boscaro, V., additional, Medico, E., additional, Weiser, M., additional, Siena, S., additional, di Nicolantonio, F., additional, Solit, D., additional, Bardelli, A., additional, Burbridge, M. F., additional, Dovat, S. P., additional, Song, C., additional, Payne, K. J., additional, Yang, L., additional, Cree, A., additional, Glaysher, M., additional, Bolton, L., additional, Johnson, P., additional, Atkey, N., additional, Torrance, C., additional, Bogush, T. A., additional, Dudko, E. A., additional, Shaturova, A. S., additional, Tikhomirov, M. V., additional, Bogush, E. A., additional, Polotsky, B. E., additional, Tjulandin, S. A., additional, Davydov, M. I., additional, Pernemalm, M., additional, Pawitan, Y., additional, Lazar, V., additional, Lundeberg, J., additional, Lehtio, J., additional, Rasul, A., additional, Ma, T., additional, Dyshlovoy, S. A., additional, Naeth, I., additional, Venz, S., additional, Fedorov, S. N., additional, Shubina, L. K., additional, Stonik, V. A., additional, Balabanov, S., additional, Honecker, F., additional, Kongpracha, P., additional, Tohtong, R., additional, Demidkina, V., additional, Kudryavtsev, V. A., additional, Kabakov, A. E., additional, Golan, T., additional, Atias, D., additional, Barshack, I., additional, Avivi, C., additional, Goldstein, R. S., additional, Berger, R., additional, Ben-Arieh, S., additional, Urban, D., additional, Maimon, N., additional, Leibowitz-Amit, R., additional, Keizman, D., additional, Biran, H., additional, Mishaeli, M., additional, Onn, A., additional, Gottfried, M., additional, Saraswati, S., additional, Agrawal, S. S., additional, Raval, P., additional, Patel, M., additional, Ganure, L., additional, Hanen, J. H., additional, Sonia, B. H. K., additional, Aya, M., additional, Zohra, H., additional, Touhami, M., additional, Cheng, X., additional, Shi, T. Y., additional, Yang, G., additional, Tu, X. Y., additional, Wu, X. H., additional, Wei, Q. Y., additional, Benboubker, H., additional, Zheng, B. Q., additional, Shi, Y. Q., additional, He, X. H., additional, Liang, L. H., additional, and Saied, G. M., additional

Published
2012
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41. P2.06 Exploiting The Mutanome for Tumor Vaccination

Author

Castle, J., primary, Kreiter, S., additional, Diekmann, J., additional, Löwer, M., additional, van der Roemer, N., additional, de Graaf, J., additional, Selmi, S., additional, Diken, M., additional, Boegel, S., additional, Paret, C., additional, Koslowski, M., additional, Kuhn, A.N., additional, Britten, C.M., additional, Huber, C., additional, Türeci, Ö., additional, and Sahin, U., additional

Published
2012
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45. Phenolic content, antioxidant activities and stimulatory roles of citrus fruits on some lactic acid bacteria

Author

Irkin Reyhan, Dogan Serap, Degirmencioglu Nurcan, Diken Mehmet Emin, and Guldas Metin

Subjects
Citrus fruits, flavonoid content, phenolic compounds, antioxidant, lactic acid bacteria, Biology (General), QH301-705.5
Abstract

In this study, phenolic compounds and antioxidant activities in citrus fruits and their peels were determined, and their stimulatory roles on some lactic acid bacteria were investigated. Phenolic compounds in citrus fruits such as mandarin, lemon, orange and grapefruit were determined either in the juices or in the peel extracts. Total phenolic content was determined in a spectrophotometer at 685 nm using the adapted Folin-Ciocalteu method. Total flavonoid content was measured using LC/MS (liquid chromatography-mass spectrometry). The effects of the fruit juices and peel extracts on the selected lactic acid bacteria (Lactobacillus delbrueckii NRRL B5448, Lb. casei NRRL B1922, Lb. acidophilus NRRL B4495) were investigated. The tested lactic acid bacteria were significantly affected by chlorogenic acid, hesperidin, naringin and caffeic acid compared to the control samples (P≤0.05). Antioxidant properties of fruit samples were also measured using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method. The phenolics positively affected the metabolism of bacteria, with the stimulatory effects of the assayed samples being influenced by the phenolic profile.

Published
2015
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46. Actively personalized cancer vaccines--the step into clinical application

Author

Bp, Kloke, Kreiter S, Mathias Vormehr, Diken M, An, Kuhn, and Sahin U

Subjects
Neoplasms, Animals, Humans, RNA, Neoplasm, Cancer Vaccines
Abstract

Cancer vaccine development enters a new phase of innovation based on the development of modern sequencing technologies and novel RNA-based synthetic drug formats which enable the analysis and therapeutic targeting of every patient's tumor genome. By applying and combining these innovations, we have brought the concept of "actively personalized cancer vaccines" to clinical testing. Synthetic RNA is used as the drug format, allowing affordable, individual "on demand" manufacturing of tumor-optimized vaccines.

48. A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing.

Author

Benderski K, Schneider P, Kordeves P, Fichter M, Schunke J, De Lorenzi F, Durak F, Schrörs B, Akilli Ö, Kiessling F, Bros M, Diken M, Grabbe S, Schattenberg JM, Lammers T, Sofias AM, and Kaps L

Subjects
Animals, Cell Line, Tumor, Liver pathology, Mice, Disease Models, Animal, Male, Liver Cirrhosis pathology, Humans, Carbon Tetrachloride, Carcinoma, Hepatocellular pathology, Mice, Inbred C57BL, Liver Neoplasms pathology
Abstract

Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, which, due to cellular tropism, invade the liver and allow for a controllable disease progression. Specifically, C57BL/6JRj mice were intrasplenically inoculated with Dt81Hepa1-6 HCC cells, with a subgroup pre-treated with CCl 4 to induce cirrhosis (C-HCC). At four weeks post-inoculation, mice were sacrificed, and diseased livers were analyzed via histology, flow cytometry, and RT-qPCR to profile the extracellular matrix (ECM), angiogenesis, and immune cells. In addition, tumor-bearing mice were treated with the first-line therapy, AtezoBev, to assess therapeutic responsiveness of the model. Dt81Hepa1-6 cells displayed similar gene expression as human HCC. After intrasplenic injection, all mice developed multifocal disease. C-HCC mice had a significantly higher tumor load than non-cirrhotic HCC mice. Both HCC and C-HCC models displayed extensive ECM formation, increased levels of vascularization, and immune cell infiltration compared to healthy and non-cancerous cirrhotic livers. AtezoBev treatment produced robust antitumor efficacy, validating the model's suitability for therapy testing. In conclusion, we established a rapidly developing and high-yield HCC model through a simple intrasplenic injection, with or without cirrhotic damage. The model overexpressed key human HCC genes and showed high responsiveness to first-line treatment. Our model uniquely combines all the above-mentioned features, promoting its use towards HCC therapy testing., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LK declares receiving travel expenses and speaker honoraria from Gilead science (Foster city, USA) and Takeda (Doshomachi, Japan). JMS declares consultant honorary from Alentis, Alexion, Altimmune, Astra Zeneca, 89Bio, Bionorica, Boehringer Ingelheim, Gilead Sciences, GSK, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, Lilly, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Siemens Healthineers. JMS declares speaker honorarium from AbbVie, Academic Medical Education (AME), Boehringer Ingelheim, Echosens, Forum für Medizinische Fortbildung (FOMF), Gilead Sciences, MedicalTribune, MedPublico GmbH, MedScape, Novo Nordisk, Madrigal Pharmaceuticals, Stockholder options: AGED diagnostics, and Hepta Bio. The other authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2025
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49. RNA-encoded Interleukin 2 with Extended Bioavailability Amplifies RNA Vaccine-Induced Antitumor T-cell Immunity.

Author

Peters D, Kranz LM, Eisel D, Diken M, Kreiter S, Türeci Ö, Sahin U, and Vormehr M

Subjects
Animals, Mice, Female, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes immunology, mRNA Vaccines, Cell Line, Tumor, Biological Availability, T-Lymphocytes immunology, Humans, RNA genetics, Cancer Vaccines immunology, Interleukin-2
Abstract

Interleukin 2 (IL-2) is a crucial cytokine in T-cell immunity, with a promising potential in cancer vaccines. However, therapeutic application of IL-2 is hampered by its short half-life and substantial toxicity. This study reports preclinical characterization of a mouse serum albumin-IL-2 fusion protein (Alb-IL2) encoded on nucleoside-modified RNA that is delivered via a nanoparticle formulation (Alb-IL2 RNA-NP) mediating prolonged cytokine availability. Alb-IL2 RNA-NP was combined with RNA-lipoplex (RNA-LPX) vaccines to evaluate its effect on the expansion of vaccine-induced antigen specific T-cell immunity. In mice dosed with Alb-IL2 RNA-NP, translated protein was shown to be systemically available up to 2 days, with an albumin-dependent preferred presence in the tumor and tumor-draining lymph node. Alb-IL2 RNA-NP administration prolonged serum availability of the cytokine compared with murine recombinant IL-2. In combination with RNA-LPX vaccines, Alb-IL2 RNA-NP administration highly increased the expansion of RNA-LPX vaccine-induced CD8+ T cells in the spleen and blood. The combination enhanced and sustained the fraction of IL-2 receptor (IL-2R) α-positive antigen-specific CD8+ T cells and ameliorated the functional capacity of the CD8+ T-cell population. Alb-IL2 RNA-NP strongly improved the antitumor activity and survival of concomitant RNA-LPX vaccination and PD-L1 blockade in a subcutaneous mouse tumor model. The favorable pharmacokinetic properties of Alb-IL2 RNA-NP render it an attractive modality for rationally designed combination immunotherapy. RNA vaccines that induce tumor-specific T-cell immunity for Alb-IL2 RNA-NP to further amplify are particularly attractive combination partners., (©2024 American Association for Cancer Research.)

Published
2024
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50. Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.

Author

Schneider P, Zhang H, Simic L, Dai Z, Schrörs B, Akilli-Öztürk Ö, Lin J, Durak F, Schunke J, Bolduan V, Bogaert B, Schwiertz D, Schäfer G, Bros M, Grabbe S, Schattenberg JM, Raemdonck K, Koynov K, Diken M, Kaps L, and Barz M

Subjects
Animals, Mice, Humans, Cell Line, Tumor, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular metabolism, RNA, Small Interfering chemistry, Liver Neoplasms drug therapy, Liver Neoplasms pathology, Liver Neoplasms metabolism, Micelles, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts drug effects
Abstract

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-π interaction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Published
2024
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