An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma

Şahin, Uğur; Oehm, Petra; Derhovanessian, Evelyna; Jabulowsky, Robert A.; Vormehr, Mathias; Gold, Maike; Maurus, Daniel; Schwarck-Kokarakis, Doreen; Kuhn, Andreas N.; Omokoko, Tana; Kranz, Lena M.; Diken, Mustafa; Kreiter, Sebastian; Haas, Heinrich; Attig, Sebastian; Rae, Richard; Ćuk, Katarina; Kemmer-Brück, Alexandra; Breitkreuz, Andrea; Tolliver, Claudia; Caspar, Janina; Quinkhardt, Juliane; Hebich, Lisa; Stein, Malte; Hohberger, Alexander; Vogler, Isabel; Liebig, Inga; Renken, Stephanie; Sikorski, Julian; Leierer, Melanie; Müller, Verena; Mitzel-Rink, Heidrun; Miederer, Matthias; Huber, Christoph; Grabbe, Stephan; Utikal, Jochen; Pinter, Andreas; Kaufmann, Roland; Hassel, Jessica C.; Loquai, Carmen; Türeci, Özlem

doi:10.1038/s41586-020-2537-9

Cited by 668 publications

(502 citation statements)

References 36 publications

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“…We, therefore, consider that these three antigens are probably, but not certainly, aeTSAs. Notably, objective anti-tumor response correlated more closely with the expansion of T cells recognizing MAGEA3 and CTAG1B [98]. This study, therefore, (i) supports the immunogenicity of aeTSAs in humans and (ii) suggests that direct aeTSA presentation by DCs activates and expands a pool of complementary aeTSA-specific T cells that were insensitive to immune checkpoint therapy and likely tumor-naïve.…”

Section: Vaccination-induced T-cell Primingsupporting

confidence: 68%

“…In these conditions, since the DC-targeted RNAs drive synthesis of antigenic peptides inside DCs, their processing follows the rule of direct presentation as opposed to cross-presentation. A phase I trial evaluating a nanoparticulate liposomal RNA vaccine in immune checkpoint therapy-experienced melanoma patients (stage III B, C and stage IV) recently provided suggestive evidence that, when presented by DCs, aeTSAs can elicit anti-tumor responses [98]. This vaccine contained four antigens that were originally labeled as TAAs.…”

Section: Vaccination-induced T-cell Primingmentioning

confidence: 99%

“…This suggests that immune checkpoint therapy works at least in part by invigorating T cells responding to cross-presented TSAs. Likewise, preliminary evidence suggests that immune checkpoint therapy may potentiate T-cell response to aeTSAs directly presented by DCs [98]. The idea of combining vaccines and immune checkpoint therapy, therefore, appears very attractive.…”

Section: Combining Vaccines and Immune Checkpoint Therapymentioning

confidence: 99%

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The Origin and Immune Recognition of Tumor-Specific Antigens

Apavaloaei

Hardy

Thibault

et al. 2020

Cancers

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The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and reverse immunology studies cannot provide this type of conclusive evidence. Most TSAs are coded by unmutated non-canonical transcripts that arise from cancer-specific epigenetic and splicing aberrations. When searching for TSAs, it is therefore important to perform mass spectrometry analyses that interrogate not only the canonical reading frame of annotated exome but all reading frames of the entire translatome. The majority of aberrantly expressed TSAs (aeTSAs) derive from unstable short-lived proteins that are good substrates for direct major histocompatibility complex (MHC) I presentation but poor substrates for cross-presentation. This is an important caveat, because cancer cells are poor antigen-presenting cells, and the immune system, therefore, depends on cross-presentation by dendritic cells (DCs) to detect the presence of TSAs. We, therefore, postulate that, in the untreated host, most aeTSAs are undetected by the immune system. We present evidence suggesting that vaccines inducing direct aeTSA presentation by DCs may represent an attractive strategy for cancer treatment.

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Section: Vaccination-induced T-cell Primingsupporting

confidence: 68%

Section: Vaccination-induced T-cell Primingmentioning

confidence: 99%

Section: Combining Vaccines and Immune Checkpoint Therapymentioning

confidence: 99%

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The Origin and Immune Recognition of Tumor-Specific Antigens

Apavaloaei

Hardy

Thibault

et al. 2020

Cancers

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“…Nucleic acid drugs encoding immune responses can be delivered through many non‐viral gene vectors, [44] thereby enhancing the role of nucleotides in inhibiting the blocking effect of immune checkpoint pathways [45,46] . Huang et al.…”

Section: The Application Of Nanotechnology In Immune Checkpointsmentioning

confidence: 99%

“…Nucleic acid drugs encoding immune responses can be delivered through many non-viral gene vectors, [44] thereby enhancing the role of nucleotides in inhibiting the blocking effect of immune checkpoint pathways. [45,46] Huang et al constructed a plasmid encoding inflammatory cytokines (PLIGHT) to promote tumor-specific expression. To achieve the simultaneous delivery of PLICT and the anti-fibrotic drug MP, they introduced calcium phosphate liposome (CAP) technology that can effectively transfect in vivo and deliver small phosphate-based molecules.…”

Section: Nanotechnology Based On Nucleic Acidsmentioning

confidence: 99%

Combined Application of Nanotechnology and Multiple Therapies with Tumor Immune Checkpoints

Sun

et al. 2020

ChemistrySelect

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Tumor immunotherapy has received worldwide attention in cancer treatment owing to its apparent advantages, such as strong specificity and long curative effect. Among them, significant progress has been made on the immune checkpoint therapy in recent years. FDA approved PD‐L1/PD‐1 and CTLA‐4 immune checkpoint inhibitors have been broadly used in a variety of malignant tumors. However, because of the low response rate of immune checkpoint drugs, its clinical application has been greatly hindered. With the prominence of nanotechnology in bio‐medicine, the application of nanotechnology in immune checkpoints has also gained more and more attention. The combination of radiotherapy, chemotherapy, phototherapy, magnetic therapy and other methods in nanotechnology makes an excellent promoting effect in the treatment of immune checkpoint drugs. This article reviews the recent breakthroughs of nanotechnology in immune checkpoint blocking therapy, mainly focusing on the significant advantages of the combination of nanotechnology‐based immune checkpoint blocking therapy with other treatment methods. In addition, we also discussed the challenges in this area and pointed out some potential directions for future development.

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