SA-4-1BBL as an immune modulator and vehicle to deliver antigens into dendritic cells for effective cancer immunotherapy (144.25)

Abstract The success of TAAs-based vaccines may depend on the nature of adjuvants used. We recently generated a chimeric 4-1BBL with streptavidin (SA-4-1BBL) that exists as tetramers/oligomers with potent activity and can be used as a vehicle to deliver TAAs into dendritic cells constitutively expressing 4-1BB receptor. We demonstrated that SA-4-1BBL can be effectively conjugated to biotinylated ovalbumin (Ova) as a model antigen. Immunization with Ova conjugated to SA-4-1BBL resulted in increased Ova uptake and cross-presentation by DCs, that resulted in potent Ova specific proliferation of CD4+ (OT-II) and CD8+ (OT-I) T cells. The conjugate vaccine also generated significantly higher in vivo specific CTL responses to Ova and HPV E7 oncoprotein than nonconjugate vaccine. Importantly, a single vaccination with HPV E7 oncoprotein or survivin conjugated to SA-4-1BBL resulted in robust and superior efficacy than nonconjugate vaccine in the eradication of established E7 expressing TC-1 and survivin expressing 3LL tumors, respectively. Therapeutic efficacy was achieved in the absence of detectable toxicity and associated with increased CD4+ T and CD8+ T cell effector and memory responses and higher intratumoral CD8+ Teff/CD4+CD25+Foxp3+Treg ratio. In conclusion, potent immunomodulatory activities of SA-4-1BBL combined with its ability to serve as a vehicle to deliver TAAs to DCs further rationalizes the extensive evaluation for the development of therapeutic vaccines against cancer.