Messenger RNA vaccination in NSCLC: Findings from a phase I/IIa clinical trial.

Sebastian, Michael; Boehmer, Lotta von; Zippelius, Alfred; Mayer, F.; Reck, M.; Atanackovic, D.; Thomas, Melissa; Schneller, Folker; Stoehlmacher, Jan; Goekkurt, Eray; Bernhard, Helga; Groeschel, Andreas; Bals, Robert; Schmidt, Sarah; Scheel, Birgit; Koch, Sven D.; Lander, T.; Kallen, Karl-Josef; Knuth, Alexander

doi:10.1200/jco.2011.29.15_suppl.2584

Cited by 21 publications

(13 citation statements)

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“…The first clinical data demonstrate their safety, tolerability and strong immunogenicity in humans [68,69]. The data reported in the present study demonstrate how this innovative technology can be effectively transferred into the clinic by optimizing the vaccination schedule, as well as how it can provide a platform for different combination therapies.…”

Section: Discussionmentioning

confidence: 81%

Highly potent mRNA based cancer vaccines represent an attractive platform for combination therapies supporting an improved therapeutic effect

Fotin‐Mleczek

Zanzinger

Heidenreich

et al. 2012

The Journal of Gene Medicine

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Direct vaccination with mRNA encoding tumor antigens is a novel and promising approach in cancer immunotherapy. CureVac's mRNA vaccines contain free and protamine-complexed mRNA. Such two-component mRNA vaccines support both antigen expression and immune stimulation. These self-adjuvanting RNA vaccines, administered intradermally without any additional adjuvant, induce a comprehensive balanced immune response, comprising antigen specific CD4+ T cells, CD8+ T cells and B cells. The balanced immune response results in a strong anti-tumor effect and complete protection against antigen positive tumor cells. This tumor inhibition elicited by mRNA vaccines is a result of the concerted action of different players. After just two intradermal vaccinations, we observe multiple changes at the tumor site, including the up-regulation of many genes connected to T and natural killer cell activation, as well as genes responsible for improved infiltration of immune cells into the tumor via chemotaxis. The two-component mRNA vaccines induce a very fast and boostable immune response. Therefore, the vaccination schedules can be adjusted to suit the clinical situation. Moreover, by combining the mRNA vaccines with therapies in clinical use (chemotherapy or anti-CTLA-4 antibody therapy), an even more effective anti-tumor response can be elicited. The first clinical data obtained from two separate Phase I/IIa trials conducted in PCA (prostate cancer) and NSCLC (non-small cell lung carcinoma) patients have shown that the twocomponent mRNA vaccines are safe, well tolerated and highly immunogenic in humans.

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Section: Discussionmentioning

confidence: 81%

Highly potent mRNA based cancer vaccines represent an attractive platform for combination therapies supporting an improved therapeutic effect

Fotin‐Mleczek

Zanzinger

Heidenreich

et al. 2012

The Journal of Gene Medicine

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“…They have demonstrated excellent safety as well as high levels of cellular immunity with T and B cell responses in several clinical trials. 55–59 Moderna is another company that has been investigating mRNA as a vaccine and therapeutic technology, with two ventures Onkaido Therapeutics and Valera actively exploring the discovery and development of mRNA-based treatments in oncology and infectious diseases, respectively. Some representative studies using modified naked mRNA are summarized in Table 1.…”

Section: Mrna Modification For Clinical Translationmentioning

confidence: 99%

Biomaterials for mRNA delivery

et al. 2015

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Messenger RNA (mRNA) has recently emerged with remarkable potential as an effective alternative to DNA-based therapies because of several unique advantages. mRNA does not require nuclear entry for transfection activity and has a negligible chance of integrating into the host genome which excludes the possibility of potentially detrimental genomic alternations. Chemical modification of mRNA has further enhanced its stability and decreased its activation of innate immune responses. Additionally, mRNA has been found to have rapid expression and predictable kinetics. Nevertheless, the ubiquitous application of mRNA remains challenging given its unfavorable attributes, such as large size, negative charge and susceptibility to enzymatic degradation. Further refinement of mRNA delivery modalities is therefore essential for its development as a therapeutic tool. This review provides an exclusive overview of current state-of-the-art biomaterials and nanotechnology platforms for mRNA delivery, and discusses future prospects to bring these exciting technologies into clinical practice.

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“…A cocktail of the four tumor associated antigens PSA (prostate specific antigen), PSCA (prostate stem cell antigen), PSMA (prostate specific membrane antigen) and STEAP1 (six transmembrane epithelial antigen of the prostate 1) was selected for the first-in-man phase I/ IIa study in prostate cancer patients and designated CV9103. For the NSCLC cocktail CV9201, five tumor-associated antigens were chosen: MAGE-C1, MAGE-C2, NY-ESO-1, survivin, and 5T4 32 , 33 …”

Section: Clinical Experiences With Rnactive® Vaccinesmentioning

confidence: 99%

A novel, disruptive vaccination technology

Kallen

Heidenreich

Schnee

et al. 2013

Human Vaccines & Immunotherapeutics

194

101

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Nucleotide based vaccines represent an enticing, novel approach to vaccination. We have developed a novel immunization technology, RNActive® vaccines, that have two important characteristics: mRNA molecules are used whose protein expression capacity has been enhanced by 4 to 5 orders of magnitude by modifications of the nucleotide sequence with the naturally occurring nucleotides A (adenosine), G (guanosine), C (cytosine), U (uridine) that do not affect the primary amino acid sequence. Second, they are complexed with protamine and thus activate the immune system by involvement of toll-like receptor (TLR) 7. Essentially, this bestows self-adjuvant activity on RNActive® vaccines. RNActive® vaccines induce strong, balanced immune responses comprising humoral and cellular responses, effector and memory responses as well as activation of important subpopulations of immune cells, such as Th1 and Th2 cells. Pre-germinal center and germinal center B cells were detected in human patients upon vaccination. RNActive® vaccines successfully protect against lethal challenges with a variety of different influenza strains in preclinical models. Anti-tumor activity was observed preclinically under therapeutic as well as prophylactic conditions. Initial clinical experiences suggest that the preclinical immunogenicity of RNActive® could be successfully translated to humans.

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Messenger RNA vaccination in NSCLC: Findings from a phase I/IIa clinical trial.

Cited by 21 publications

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Highly potent mRNA based cancer vaccines represent an attractive platform for combination therapies supporting an improved therapeutic effect

Highly potent mRNA based cancer vaccines represent an attractive platform for combination therapies supporting an improved therapeutic effect

Biomaterials for mRNA delivery

A novel, disruptive vaccination technology

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