Actively personalized vaccination trial for newly diagnosed glioblastoma

Hilf, Norbert; Kuttruff-Coqui, Sabrina; Frenzel, Katrin; Bukur, Valesca; Stevanović, Stefan; Gouttefangeas, Cécile; Platten, Michael; Tabatabai, Ghazaleh; Dutoit, Valérie; Burg, Sjoerd H. van der; Straten, Per thor; Martínez‐Ricarte, Francisco; Ponsati, Berta; Okada, Hideho; Lassen, Ulrik; Admon, Arie; Ottensmeier, Christian; Ulges, Alexander; Kreiter, Sebastian; Deimling, Andreas von; Skardelly, Marco; Migliorini, Denis; Kroep, Judith R.; Idorn, Manja; Rodón, Jordi; Piró, Jordi; Poulsen, Hans Skovgaard; Shraibman, Bracha; McCann, Katy J.; 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 N.; Dorner, Sonja; Hoffgaard, Franziska; Rössler, Bernhard; Maurer, Dominik; Weinschenk, Toni; Reinhardt, Carsten; Huber, Christoph; Rammensee, Hans Georg; Singh‐Jasuja, Harpreet; Şahin, Uğur; Dietrich, Pierre Yves; Wick, Wolfgang

doi:10.1038/s41586-018-0810-y

Cited by 660 publications

(544 citation statements)

References 55 publications

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“…Patients immunized with neoantigen-based vaccines display expanded neoantigen-specific T cells, suggesting that this could be a promising therapeutic avenue (Hilf et al 2019;Sahin et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Neoantigens are currently predicted based on the detection of cancer-specific somatic mutations in annotated protein-coding regions by whole exome sequencing (WES) and RNA-seq (Hilf et al 2019; Sahin et al 2017). This approach often falls short for patients with few somatic mutations, generating few actionable neoantigens (Rajasagi et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer

Ouspenskaia

Law

Clauser

et al. 2020

Preprint

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Tumor epitopes -peptides that are presented on surface-bound MHC I proteins -provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples, developed a sensitive analytic approach for hierarchical ORF prediction, and constructed a high-confidence database of translated nuORFs across tissues. Peptides from 3,555 unique translated nuORFs were presented on MHC I, based on analysis of an extensive dataset of MHC I-bound peptides detected by mass spectrometry, with >20-fold more nuORF peptides detected in the MHC I immunopeptidomes compared to whole proteomes. We further detected somatic mutations in nuORFs of cancer samples and identified nuORFs with tumor-specific translation in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs thus expand the pool of MHC I-presented, tumorspecific peptides, targetable by immunotherapies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer

Ouspenskaia

Law

Clauser

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The correlation (albeit very imperfect) between mutation load and responses rates to immune checkpoint (CTLA-4 and PD-1) blockade reinforces the notion that the mutanome is immunologically relevant (6,(58)(59)(60). The discovery of TSA has provided new hopes for the field of cancer vaccines with several trials launched in the last decade (61)(62)(63)(64)(65)(66). It has also provided a rationale to explain the success of tumor infiltrating lymphocytes (TIL) infusions in certain cancers (67).…”

Section: Tumor-specific Antigens (Tsa)mentioning

confidence: 68%

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

et al. 2020

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Over the last decades, T-cell immunotherapy has revealed itself as a powerful, and often curative, strategy to treat blood cancers. In hematopoietic cell transplantation, most of the so-called graft-vs.-leukemia (GVL) effect hinges on the recognition of histocompatibility antigens that reflect immunologically relevant genetic variants between donors and recipients. Whether other variants acquired during the neoplastic transformation, or the aberrant expression of gene products can yield antigenic targets of similar relevance as the minor histocompatibility antigens is actively being pursued. Modern genomics and proteomics have enabled the high throughput identification of candidate antigens for immunotherapy in both autologous and allogeneic settings. As such, these major histocompatibility complex-associated tumor-specific (TSA) and tumor-associated antigens (TAA) can allow for the targeting of multiple blood neoplasms, which is a limitation for other immunotherapeutic approaches, such as chimeric antigen receptor (CAR)-modified T cells. We review the current strategies taken to translate these discoveries into T-cell therapies and propose how these could be introduced in clinical practice. Specifically, we discuss the criteria that are used to select the antigens with the greatest therapeutic value and we review the various T-cell manufacturing approaches in place to either expand antigen-specific T cells from the native repertoire or genetically engineer T cells with minor histocompatibility antigen or TSA/TAA-specific recombinant T-cell receptors. Finally, we elaborate on the current and future incorporation of these therapeutic T-cell products into the treatment of hematological malignancies.

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“…Frameshift peptide microarrays as an antigen discovery technology, while an indirect measure of the presence of neoantigen in the tumor, are a direct measure of the immunogenicity of the neoantigens in the patient. This is in contrast to PCV approaches which identify the neoantigen and then predict immunogenicity with mixed success at best [2][3][4][5]. It should be noted that neoantigens can evolve over time as was recently noted in colorectal cancers [25] and in pancreatic cancers which have different FSP neoantigen profiles in early stage and late stage [10,11].…”

Section: Discussionmentioning

confidence: 99%

“…The patient is then administered the unique vaccine, often in combination with another immunotherapeutic. Early reports on clinical trials applying such a system are encouraging in that the vaccines appear safe and may have signs of efficacy [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Personal and Shared Frameshift Neoantigen Vaccines in a Mouse Mammary Cancer Model.

Batista

Murphy

Lainson

et al. 2020

Preprint

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Background: It is widely hoped that personal cancer vaccines will extend the number of patients benefiting from checkpoint and other immunotherapies. However, it is clear creating such vaccines will be challenging. It requires obtaining and sequencing tumor DNA/RNA, predicting potentially immunogenic neoepitopes and manufacturing one-use vaccine. This process takes time and considerable cost. Importantly, most mutations will not produce an immunogenic peptide and many patient's tumors do not contain enough DNA mutations to make a vaccine. We have discovered that Frameshift peptides (FSP) created from errors in the production of RNA rather than from DNA mutation are potentially a rich source of neoantigens for cancer vaccines. These errors are predictable, enabling the production of a FSP microarray. Previously we found that these microarrays can identify both personal and shared neoantigens.Methods: Here, we compared the performance of personal cancer vaccines (PCVs) with that of a shared antigen vaccine, termed Frameshift Antigen Shared Therapeutic (FAST) vaccine , using the 4T1 breast cancer model. Sera from 4T1-tumor bearing mice were assayed on the peptide microarray containing 200 FS neoantigens and for the PCV, the top 10 candidates were select and personal vaccines constructed and administrated to the respective mice. For the FAST, we selected the top 10 candidates with higher prevalence among all the mice challenged. Seven to 12-days challenged mice were immunized, combined or not with checkpoint inhibitor (CPI) (αPD-L1 and αCTLA-4). Primary and secondary tumor clearance and growth were evaluated as well as both cellular and humoral immune response against the vaccines targets by IFN-γ ELISPOT and ELISA. Lastly, we analyzed the immune response of the FAST-vaccinated mice by flow cytometry in comparison to control group.Results: We found that PCVs and FAST vaccines both reduced primary tumor incidence and growth as well as lung metastases when delivered as monotherapies or in combination with checkpoint inhibitor antibodies. Additionally, the FAST vaccine induces a robust and effective T-cell response.Conclusions: These results suggest that FSPs produced from RNA-based errors are potent neoantigens that could enable production of off-the-shelf shared antigen vaccines for solid tumors with efficacy comparable to that of PCVs.

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Actively personalized vaccination trial for newly diagnosed glioblastoma

Cited by 660 publications

References 55 publications

Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer

Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

Comparison of Personal and Shared Frameshift Neoantigen Vaccines in a Mouse Mammary Cancer Model.

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