TLR4 modulator program

In this study, we used an in vitro system to compare the priming of human MSCs by two inflammatory inducers TNF-α and CRX-527 (a highly potent synthetic TLR4 agonist that can be used as a vaccine adjuvant or to induce anti-tumor immunity) on exosome molecular cargo, as well as on an in vivo rat ligament injury model to validate exosome potency...Additionally, a link was identified between altered exosomal microRNA levels and expression changes in microRNA targets in ligaments. These findings elucidate the nuanced interplay between MSCs, their exosomes, and tissue regeneration.

CRX-exosomes are superior to exosomes from unstimulated MSCs at preventing xenogeneic GVHD. Interestingly, CRX-exosome treatment does not prevent GVL activity despite the induction of Tregs. CRX-exosome treatment does not directly alter T cell biology but does cause dramatic differences in the transcriptome of monocytes, increasing IL-6 and IL-10 expression which may impact T cell activation.

This translates into enhanced tumor protection upon prophylactic and therapeutic vaccination via intradermal injection against B16-OVA melanoma and HPV-related TC1 tumors. These results highlight the potential of CRX-527 as an adjuvant for molecularly defined cancer vaccines, and support the design of adjuvant-peptide conjugates as a strategy to optimize vaccine formulation.