Inhaltszusammenfassung

Target specific induction of adaptive immune responses against tumor-associated antigens (TAAs) is an already established strategy to fight cancer diseases. Furthermore, chimeric TAA-presenting virus-like particle (VLP)-based vaccines have been shown to be an attractive modality for inducing target specific immune responses after active immunization. However, the therapeutically successful application of such type of vaccines often depends on co-administration of adjuvants, enhancing the ...Target specific induction of adaptive immune responses against tumor-associated antigens (TAAs) is an already established strategy to fight cancer diseases. Furthermore, chimeric TAA-presenting virus-like particle (VLP)-based vaccines have been shown to be an attractive modality for inducing target specific immune responses after active immunization. However, the therapeutically successful application of such type of vaccines often depends on co-administration of adjuvants, enhancing the vaccine induced adaptive immune responses. Toll-like receptor (TLR) agonists have been shown to improve the quality and quantity of host adaptive immune responses when used in vaccine formulations against infectious diseases or cancer. Based on an iterative fragmentation strategy in combination with in silico predictions, we were able to identify novel, small immunostimulatory RNA sequences (isRNAs) derived from Influenza A virus nucleoprotein (NP) with high specificity for TLR7 and/or TLR8. The identified isRNAs could be in vitro transcribed and purified in large scale and were potent IFN type I, but only very weak TNF-α inducers. Liposomally formulated isRNAs in particular NP71-Seq45 co-administered with chimeric HBcAg-VLP based anti-cancer vaccines profoundly increased the immunogenicity of the VLP-based vaccine and elicited high-titer antibody responses against the target molecule, characterized by a balanced Th1/Th2 profile. Furthermore, the co-administration of formulated isRNAs with chimeric HBcAg-VLPs elicited antibodies recognizing the target molecule in its native conformation and exerting potent cytocidal effector functions like complement dependent cytotoxicity (CDC). A direct comparison of the identified isRNAs with CpG-ODN1826 and more than seven other classes of adjuvants (e.g. MPLA, poly(I:C), R848, CFA/IFA, Addavax, and aluminum hydroxide) revealed a superior efficacy of the novel isRNA-based adjuvants to enhance a strong target molecule specific B cell response. Moreover, only the immunization of liposomally formulated isRNAs in combination with HBcAg-CLDN6 VLPs was capable to elicit significant target-epitope specific CD4+ T cell responses as determined by ex vivo IFN-γ ELISpot. Preclinical data shown for three different, syngeneic mouse tumor models demonstrated that the isRNA adjuvant can significantly increase the anti-tumoral potency of HBcAg-CLDN6 VLPs as a prophylactic and also therapeutic cancer vaccine. Complete immune protection against s.c. or i.v. challenge with syngeneic tumor cells could be achieved only by prophylactic vaccination with isRNA adjuvanted HBcAg-#A79 VLPs in Balb/c mice indicating the strong effects of the induced CLDN6-specific B responses. This work revealed for the first time that the combination of HBcAg-CLDN6 VLP vaccines with a liposomally formulated TLR7 agonist based on small isRNAs induced therapeutically active anti-tumoral immune responses and may result in the development of a novel vaccine format for active cancer immunotherapy.» weiterlesen» einklappen

Autoren

Klassifikation

DDC Sachgruppe:
Biowissenschaften, Biologie