VAX014: A multi-faceted mechanism of Action
VAX014 is first-in-class
VAX014's multi-faceted MoA
VAX014's multi-faceted MoA
VAX014 is a first-in-class tumor targeted oncolytic immunotherapy based on recombinant bacterial minicells (rBMCs). VAX014 contains four major components. The first is the rBMC vector, the surface of which contains a tumor-specific integrin targeting protein (invasin). The second is a pre-formed oncolytic protein (perfringolysin O; PFO) which rapidly forms pores in cholesterol containing cell membranes. The third and fourth are bacterial di-cyclic nucleotides (di-cGMP) and short hairpin tRNAs, which are well-characterized agonists of the STING and RIG-I pathways, respectively. Recent nonclinical data demonstrate this unique combination of components provides optimal activity of VAX014 in STING- and RIG-I positive solid tumors, a known limitation of oncolytic virus-based therapies. Also unlike oncolytic virus-based agents, VAX014 is replication incompetent, thereby eliminating the need for complicated biocontainment procedures for manufacturing, clinical preparation and administration, and the need for at-home biocontainment/isolation for patients.
VAX014's multi-faceted MoA
VAX014's multi-faceted MoA
VAX014's multi-faceted MoA
VAX014 works by specifically targeting and delivering a novel fast-acting pre-formed oncolytic protein toxin directly to tumor cells that express either α3β1 or α5β1 integrin(s) (selectively expressed in many solid tumor types). Invasin-mediated engagement of either integrin subtype leads to rapid internalization of VAX014 into the endosomal/lysosomal pathway. The subsequent degradation of the rBMC carrier in endosomes leads to immediate release of the pre-formed oncolytic protein PFO along with STING and RIG-I agonists. PFO first degrades the endosomal membrane, which allows the STING and RIG-I agonists to enter the cytosol to acutely activate STING and/or RIG-I prior to PFO-mediated tumor cell lysis. These overlapping primary oncolytic and innate activation mechanisms occur within a matter of hours following administration of VAX014 and coordinate to activate and mobilize the immune system. The secondary immunotherapeutic effect mediated by these primary events results in protective in situ immunization through the priming of robust polyclonal antitumor T cell effector and memory response.
VAX014: robust antitumor immunotherapeutic effects
Exciting preclinical data
Preclinical studies of VAX014 following local administration have demonstrated remarkable results in multiple in vivo tumor models conducted in immune competent mice. Treatment of established immunologically cold tumors (devoid of immune cells) with VAX014 quickly leads to local tumor inflammation followed by immune infiltration and complete immune-mediated tumor clearance. Tumor clearance(s) is durable, tumor specific, and leads to protective systemic antitumor immunologic memory. In experimental models where mice bearing multiple tumors are treated locally by intratumoral injection of one tumor with VAX014, immune-mediated clearance of both treated and untreated tumors is observed, indicating VAX014 facilitates in situ immunization against the treated tumor type. When combined with systemic immune checkpoint blockade therapy, protective systemic antitumor effects improve to a point where nearly all study subjects demonstrate complete response.