New research finds ‘Best Structure’ to enhance ‘anti-cancer vaccine’ effect!
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New research finds ‘Best Structure’ to enhance ‘anti-cancer vaccine’ effect!
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New research finds ‘Best Structure’ to enhance ‘anti-cancer vaccine’ effect!
Integrating antigen-encoding mRNA (messenger RNA) and immunostimulatory adjuvants into a single formulation is a promising approach to enhance the efficacy of mRNA vaccines.
A multi-institutional collaboration developed a novel mRNA derivative and demonstrated high cellular immunity-induced anticancer activity in a mouse model.
This novel mRNA, which has a comb-like structure and tooth-shaped double-stranded RNA, can activate immune cells and exhibit high anti-tumor effects in experiments using melanoma and lymphoma model mice.
The paper, “Comb-structured mRNA vaccine tethered with short double-stranded RNA adjuvants maximizes cellular immunity for cancer treatment,” was published online July 10, 2023 in Proceedings of the National Academy of Sciences.
https://www.pnas.org/doi/10.1073/pnas.2214320120
Research Background
The effectiveness and safety of mRNA vaccines against the novel coronavirus have been proven, and research is currently underway globally, targeting cancer cells as the next target.
This type of cancer mRNA vaccine provides cellular immunity to attack cancer cells by administering mRNA that produces proteins (cancer antigens) specifically expressed in cancer cells.
However, cancer cells are indistinguishable from normal cells and are immunosuppressive, making the development of cancer vaccines more challenging than infectious disease vaccines.
Therefore, strategies to improve the efficacy of cancer mRNA vaccines are necessary, and in this study, the researchers focused on immune-stimulating adjuvants.
If the adjuvant is too strong, it will cause adverse reactions, and if it is too weak, it will not provide enough vaccine effect.
Adjuvant functions have been empirically incorporated into previous mRNA vaccines, and to date there is a lack of rational and practical methods to obtain controlled adjuvant activity.
Research progress
In this study, the researchers developed a method to incorporate an adjuvant directly into the antigen-encoding mRNA strand without interfering with the ability of the antigenic protein to be produced using primitive RNA engineering techniques.
We designed a short double-stranded RNA (dsRNA) targeting the innate immune receptor retinoic acid-inducible gene I (RIG-I), and loaded it into the mRNA strand by hybridization, thereby obtaining an optimal comb-shaped RNA, by Altering the length and sequence of dsRNA effectively activated RIG-I.
The resulting comb mRNA efficiently activated dendritic cells, which play an important role in vaccine efficacy.
Furthermore, by varying the amount of dsRNA bound to the mRNA strand, the intensity of immune stimulation can be controlled.
This is important to prevent excessive immune activation and ensure safety while achieving sufficient vaccine efficacy.
Comb structure mRNA and its immune activity
Next, they assessed the efficacy of comb mRNA as a cancer vaccine using mice.
When comb-shaped mRNAs were loaded onto lipid nanoparticles used in clinical trials of cancer vaccines, the cellular immune activity necessary to attack cancer was significantly enhanced.
Another important practical aspect of this approach is that comb mRNAs can be loaded into various mRNA vaccine delivery systems to enhance their efficacy.
The researchers succeeded in improving vaccine efficacy by loading comb-like mRNA into lipid nanoparticles used in commercial novel coronavirus vaccines and our original polymer nanomicelles.
Therefore, this system is a simple and practical platform to safely enhance the efficacy of mRNA cancer vaccines in various formulations by freely controlling the adjuvant function of mRNA vaccines.
So far, there is no way to precisely control and rationally incorporate adjuvant functions (important for cancer mRNA vaccines) into vaccine design.
As a result, researchers have had to rely on an empirical approach, testing large numbers of candidate compounds in animal experiments to find the best one.
This approach complicates the development process. To address this issue, researchers have incorporated a reasonably necessary amount of adjuvant function into mRNA vaccines through mRNA engineering.
Using this approach, the adjuvant function can be easily integrated into various mRNA vaccine delivery systems to enhance the function of cancer vaccines.
Significance
Incorporation of immunostimulatory activity into mRNA (messenger RNA) packaging materials shows promise in designing mRNA vaccine nanoformulations that enable co-delivery of antigen-encoding mRNA and adjuvant into the same antigen-presenting cells in a simple formulation.
However, this orthodox approach requires careful optimization of packaging materials to achieve both mRNA delivery efficiency and adjuvant activity.
We developed a multifunctional adjuvant protocol that uses RNA engineering to incorporate immunostimulatory functions into mRNA strands.
This approach enhanced the adjuvant activity of three representative mRNA vaccine nanoformulations, namely, anionic lipoplexes, ionizable lipid-based lipid nanoparticles, and polycomplex micelles, without affecting their delivery functions.
Thus, this approach enhanced the vaccination efficacy of these three nanoformulations and the anticancer effects of anionic lipid compounds used in clinical trials.
In this study, comb mRNA is a multifunctional system that can enhance the efficacy of any mRNA vaccines already under development, and is expected to be put into practical use in the future by loading existing mRNA vaccine vectors.
Furthermore, its effectiveness could also be increased by combining it with independently developed vaccine technologies.
As the next generation of cancer immunotherapy, cancer mRNA vaccines are being rapidly developed around the world, and comb mRNA is expected to become the core basic technology to improve its efficacy.
References:
https://www.pnas.org/doi/10.1073/pnas.2214320120
New research finds ‘Best Structure’ to enhance ‘anti-cancer vaccine’ effect!
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