Vaccination with nanoparticles combined with micro-adjuvants protects against cancer

Abstract

Background Induction of strong T cell responses, in particular cytotoxic T cells, is a key for the generation of efficacious therapeutic cancer vaccines which yet, remains a major challenge for the vaccine developing world. Here we demonstrate that it is possible to harness the physiological properties of the lymphatic system to optimize the induction of a protective T cell response. Indeed, the lymphatic system sharply distinguishes between nanoscale and microscale particles. The former reaches the fenestrated lymphatic system via diffusion, while the latter either need to be transported by dendritic cells or form a local depot. Methods Our previously developed cucumber-mosaic virus-derived nanoparticles termed (CuMV TT -VLPs) incorporating a universal Tetanus toxoid epitope TT830–843 were assessed for their draining kinetics using stereomicroscopic imaging. A nano-vaccine has been generated by coupling p33 epitope as a model antigen to CuMV TT -VLPs using bio-orthogonal Cu-free click chemistry. The CuMV TT -p33 nano-sized vaccine has been next formulated with the micron-sized microcrystalline tyrosine (MCT) adjuvant and the formed depot effect was studied using confocal microscopy and trafficking experiments. The immunogenicity of the nanoparticles combined with the micron-sized adjuvant was next assessed in an aggressive transplanted murine melanoma model. The obtained results were compared to other commonly used adjuvants such as B type CpGs and Alum. Results Our results showed that CuMV TT -VLPs can efficiently and rapidly drain into the lymphatic system due to their nano-size of ~ 30 nm. However, formulating the nanoparticles with the micron-sized MCT adjuvant of ~ 5 μM resulted in a local depot for the nanoparticles and a longer exposure time for the immune system. The preclinical nano-vaccine CuMV TT -p33 formulated with the micron-sized MCT adjuvant has enhanced the specific T cell response in the stringent B16F10p33 murine melanoma model. Furthermore, the micron-sized MCT adjuvant was as potent as B type CpGs and clearly superior to the commonly used Alum adjuvant when total CD8 + , specific p33 T cell response or tumour protection were assessed. Conclusion The combination of nano- and micro-particles may optimally harness the physiological properties of the lymphatic system. Since the nanoparticles are well defined virus-like particles and the micron-sized adjuvant MCT has been used for decades in allergen-specific desensitization, this approach may readily be translated to the clinic. Electronic supplementary material The online version of this article (10.1186/s40425-019-0587-z) contains supplementary material, which is available to authorized users.

Virus‐like particles for vaccination against cancer

“…(b) Mix multi‐target VLP‐based vaccine consisting of germline and mutated CTL epitopes coupled to Qβ‐VLPs by Cu‐free click chemistry and loaded with B‐type CpGs (Mohsen, Vogel, et al, ). (c) A microcrystalline tyrosine crystal decorated with CuMV TT ‐p33 nanoparticles labeled with AF488 (Mohsen, Heath, et al, )…”

“…(b) Mix multi-target VLP-based vaccine consisting of germline and mutated CTL epitopes coupled to Qβ-VLPs by Cu-free click chemistry and loaded with B-type CpGs (Mohsen, Vogel, et al, 2019). (c) A microcrystalline tyrosine crystal decorated with CuMV TT -p33 nanoparticles labeled with AF488 (Mohsen, Heath, et al, 2019) inhalation of eCPMV triggered the activation and accumulation of neutrophils in the lungs accompanied with an increase in neutrophil-associated chemokines and cytokines. The study concluded that the anti-tumor effects induced by eCPMV required neutrophils.…”

Recent Advances in the Use of Plant Virus-Like Particles as Vaccines

“…VLPs adjuvanted with MCT effectively retarded the development of the tumor. The effect was comparable when CpG DNA was used as the adjuvant, whereas alum was ineffective in slowing down tumor growth [69].…”

Nanoparticles to Improve the Efficacy of Peptide-Based Cancer Vaccines

“…The addition of the micron-sized MCT adjuvant of ~ 5 μM resulted in a local depot for the nanoparticles and a longer exposure to the immune system, eliciting an enhanced specific T cell response in the stringent B16F10p33 murine melanoma model. The study showed that the micron-sized MCT adjuvant was as potent as B type CpGs and superior to the alum adjuvant [72].…”