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Personalized cancer vaccines

TriLink manufactures messenger RNA (mRNA) based personalized cancer vaccines, as well as the plasmids used to produce them. These are one-of-a-kind medicines designed to specifically target neoantigenes present in an individual patient’s unique tumors. In some cases, self-replicating mRNAs based on viruses, such as alphaviruses, are used as vectors for expressing neoantigens.

CAR T-cells

TriLink manufactures Cas9, zinc-finger nuclease, and Transcription activator-like effector nuclease (TALEN) mRNAs, which are used to produce Chimeric Antigen T-cell therapies. These nucleases cause a double stranded break at a specific genomic location. A donor template encoding the chimeric antigen receptor is then inserted at the cut site by homologous recombination.

Vaccine development

Messenger RNA (mRNA) based vaccines are a new emerging modality for vaccination, offering alternatives to live and subunit vaccines. mRNA vaccines encode one or more antigens, expressed by transfected cells. Because the antigen is expressed intracellularly, it elicits different MHC class responses than a subunit vaccine, and the mRNA itself acts as an adjuvant, boosting immunity. Researchers are currently developing mRNA vaccines for infectious diseases, and in contrast to traditional vaccines, mRNA vaccines can be mass produced at relatively lost cost and high turn-around times. Plasmid manufacturing processes have been developed that are optimized for therapeutic mRNA production, further increasing the viability of this method. For this reason, there is significant interest in these types of vaccines to counter pandemics or bioterrorism events.

Recently, there has been significant interest in use of mRNA vaccines for cancer, as they can be tailored to common cancer antigens, or personalized for individual cancer patients. In the individualized approach, a patient’s tumor is sequenced to identify neoantigens found in the tumor but not in somatic tissues. Then, a specialized vaccine expressing several patient specific neoantigens is produced.  

mRNAs can also be used to prime dendritic cells to present antigens. Dendritic cells can be transfected ex vivo or in vivo, later recruiting immune cells to target this antigen.

In addition, there is an emerging interest in vaccines based on self-replicating RNAs adapted from alpha viruses. The structural genes of the alpha virus are replaced with a payload to be expressed. Once transfected into cells, the self-replicating RNA expresses the viral polymerase and initiates several rounds of RNA replication. However, because the self-replicating RNA lacks capsid proteins, it cannot produce an infectious virus. As the self-replicating RNA replicates through a double stranded intermediate, it activates pattern recognition receptors that recognize double stranded RNA, inducing an adjuvant effect. Moreover, because it replicates, very low immunization doses are required.