In:
Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 1_Supplement ( 2016-01-01), p. B041-B041
Abstract:
Immunotherapeutic approaches have evolved as promising and valid alternatives to available conventional cancer treatments. Amongst others, vaccination with tumor antigen-encoding RNAs by local administration is currently successfully employed in various clinical trials. To allow for a more efficient targeting of antigen-presenting cells (APCs) we have developed a novel RNA immunotherapeutic for systemic application based on a fixed set of four liposome complexed RNA drug products (RNA(LIP)) each encoding one shared melanoma-associated antigen. Similar to other liposomal drugs, the four injectable RNA(LIP) products constituting the investigational medicinal product will be prepared individually in a straight-forward manner directly prior to use from three components, namely solutions containing RNA drug product, NaCl diluent, and liposome excipient, that are provided as a kit. The novel lipoplex formulation was engineered (i) to protect RNA from degradation by plasma RNases and (ii) to enable directed in vivo targeting of APCs in lymphoid compartments, thus (iii) allowing for intravenous administration of multiple RNA products advancing from local to systemic targeting of APCs. The improved selective delivery of the RNA(LIP) products into APCs has further been shown to lead to an enhanced induction of vaccine-induced T-cell responses. Extensive pharmacological characterization of the RNA(LIP) platform revealed that upon cellular uptake the encoded antigens will be translated into proteins that will be rapidly processed into peptide fragments, which after presentation by MHC class I and II molecules on the surface of APCs induce tumor antigen-specific CD8+ and CD4+ T-cell responses that spread systemically. These vaccine-induced T cells have been shown to specifically recognize and kill antigen-positive tumor cells eliciting potent anti-tumoral activity in vivo. The potent vaccination effects are additionally enhanced by further immunomodulatory effects based on the transient release of pro-inflammatory cytokines such as IFN-α, IP-10, and IL-6 due to binding of the administered RNA drug products to Toll-like receptors (TLRs). The clinical translation of this pioneering therapeutic concept is currently being realized in a multi-center, first-in-human phase I trial in patients with malignant melanoma. Main objectives of the clinical trial are to study safety, tolerability, and immunogenicity of this innovative immunotherapy approach. The novel lipoplex formulation, RNA(LIP) mechanism of action, study design and clinical workflow, as well as recruitment and treatment status of the ongoing clinical trial will be presented. Citation Format: Robert A. Jabulowsky, Carmen Loquai, Mustafa Diken, Lena M. Kranz, Heinrich Haas, Sebastian Attig, Cedrik M. Britten, Janina Buck, Evelyna Derhovanessian, Jan Diekmann, Isaac Esparza, Daniel Fritz, Yves Huesemann, Veronika Jahndel, Klaus Kuehlcke, Andreas N. Kuhn, Peter Langguth, Ulrich Luxemburger, Martin Meng, Felicitas Mueller, Kerstin C. Reuter, Doreen Schwarck, Kristina Spiess, Meike Witt, Jessica C. Hassel, Jochen Utikal, Roland Kaufmann, Marc Schrott, Sebastian Kreiter, Oezlem Tuereci, Christoph Huber, Ugur Sahin. A novel nanoparticular formulated tetravalent RNA cancer vaccine for treatment of patients with malignant melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B041.
Type of Medium:
Online Resource
ISSN:
2326-6066
,
2326-6074
DOI:
10.1158/2326-6074.CRICIMTEATIAACR15-B041
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2732517-9
