Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study

Kübler, Hubert; Scheel, Birgit; Gnad-Vogt, Ulrike; Miller, Kurt; Schultze-Seemann, Wolfgang; Dorp, F. vom; Parmiani, Giorgio; Hampel, Christian; Wedel, Steffen; Trojan, Lutz; Jocham, Dieter; Maurer, Tobias; Rippin, Gerd; Fotin‐Mleczek, Mariola; Mülbe, Florian von der; Probst, Jochen; Hoerr, Ingmar; Kallen, Karl-Josef; Lander, T.; Stenzl, Arnulf

doi:10.1186/s40425-015-0068-y

Cited by 231 publications

(167 citation statements)

References 48 publications

(52 reference statements)

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“…Active cancer immunotherapy based on CureVac's mRNA technology was previously shown to be safe and well tolerated and potently induced vaccine antigen-specific immune responses 26 . Similar observations were made in the clinical trial of CV9201 in NSCLC described here (manuscript in preparation).…”

Section: Discussionsupporting

confidence: 78%

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Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy

et al. 2016

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We recently completed a phase I/IIa trial of RNActive® CV9201, a novel mRNA-based therapeutic vaccine targeting five tumor-associated antigens in non-small cell lung cancer (NSCLC) patients. The aim of the study presented here was to comprehensively analyze changes in peripheral blood during the vaccination period and to generate hypotheses facilitating the identification of potential biomarkers correlating with differential clinical outcomes post RNActive® immunotherapy. We performed whole-genome expression profiling in a subgroup of 22 stage IV NSCLC patients before and after initiation of treatment with CV9201. Utilizing an analytic approach based on blood transcriptional modules (BTMs), a previously described, sensitive tool for blood transcriptome data analysis, patients segregated into two major clusters based on transcriptional changes post RNActive® treatment. The first group of patients was characterized by the upregulation of an expression signature associated with myeloid cells and inflammation, whereas the other group exhibited an expression signature associated with T and NK cells. Patients with an enrichment of T and NK cell modules after treatment compared to baseline exhibited significantly longer progression-free and overall survival compared to patients with an upregulation of myeloid cell and inflammatory modules. Notably, these gene expression signatures were mutually exclusive and inversely correlated. Furthermore, our findings correlated with phenotypic data derived by flow cytometry as well as the neutrophil-to-lymphocyte ratio. Our study thus demonstrates non-overlapping, distinct transcriptional profiles correlating with survival warranting further validation for the development of biomarker candidates for mRNA-based immunotherapy.

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Section: Discussionsupporting

confidence: 78%

“…This study showed that repeated immunizations with two-component mRNA vaccines, encoding prostate cancer-associated antigens, induced vaccine-specific immune responses and were well tolerated showing a favorable safety profile 26 . We have also successfully completed a phase I/IIa trial, conducted in patients with advanced NSCLC.…”

Section: Introductionmentioning

confidence: 83%

Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy

et al. 2016

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“…One such study demonstrated that mRNAs encoding survivin and various melanoma tumour antigens resulted in increased numbers of antigen-specific T cells in a subset of patients with melanoma 150 . In humans with castration-resistant prostate cancer, an RNActive vaccine expressing multiple prostate cancer-associated proteins elicited antigen-specific T cell responses in the majority of recipients 151 . Lipid-based carriers have also contributed to the efficacy of intra-dermally delivered mRNA cancer vaccines.…”

Section: Mrna Cancer Vaccinesmentioning

confidence: 99%

mRNA vaccines — a new era in vaccinology

Pardi

Hogan

Porter

et al. 2018

Nat Rev Drug Discov

3,132

3,330

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mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

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“…Nonetheless, there have been encouraging preliminary results of recent and ongoing clinical trials using mRNA, underscoring the rapidly emerging importance of mRNA therapeutics in the treatment or prevention of a range of diseases. To date, naked, chemically modified, or protamine-complexed mRNA have shown promise in phase I/II cancer trials (24)(25)(26). Recently, preclinical development of materials specific for mRNA delivery has resulted in cationic polymers such as polymethacrylates (27)(28)(29), poly(aspartamides) (30,31), and polypeptides (32), as well as multicomponent cationic lipid or lipid-like formulations (21,(33)(34)(35)(36).…”

mentioning

confidence: 99%

Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

McKinlay

Vargas

Blake

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

226

271

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Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here we report the stepeconomical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.

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Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study

Cited by 231 publications

References 48 publications

Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy

Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy

mRNA vaccines — a new era in vaccinology

Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

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