A DNA Vaccine Encoding SA-4-1BBL Fused to HPV-16 E7 Antigen Has Prophylactic and Therapeutic Efficacy in a Cervical Cancer Mouse Model

Abstract

The SA-4-1BBL, an oligomeric novel form of the natural ligand for the 4-1BB co-stimulatory receptor of the tumor necrosis factor (TNF) superfamily, as a recombinant protein has potent pleiotropic effects on cells of innate, adaptive, and regulatory immunity with demonstrated therapeutic efficacy in several tumor models. However, the production of soluble form of SA-4-1BBL protein and quality control is time and resource intensive and face various issues pertinent to clinical development of biologics. The present study sought to take advantage of the simplicity and translatability of DNA-based vaccines for the production and delivery of SA-4-1BBL for cancer immune prevention and therapy. A chimeric HPV-16 E7 DNA vaccine (SP-SA-E7-4-1BBL) was constructed that contains the signal peptide (SP) of calreticulin (CRT), streptavidin (SA) domain of SA-4-1BBL, HPV-16 E7 double mutant gene, and the extracellular domain of mouse 4-1BBL. Immunization by gene gun with SP-SA-E7-4-1BBL induced greater prophylactic as well as therapeutic effects in C57BL/6 mice against TC-1 tumor model compared with immunization with E7wt, SP-SA-4-1BBL or reference-positive control CRT-E7wt. The therapeutic efficacy of the DNA vaccine was associated with increased frequency of E7-specific T cells producing interferon (IFN)-γ. Overall, our data suggest that this DNA-based vaccine strategy might represent a translational approach because it provides a simpler and versatile alternative to a subunit vaccine based on SA-4-1BBL and E7 proteins.

<p>Therapeutic Vaccines for HPV-Associated Malignancies</p>

“…Another DNA vaccine (SP-SA-E7-1BBL) encoding SA-4-1BBL fused to HPV16 E7 antigen has shown promising results in preclinical studies. 122 SA-4-1BBL is an oligomeric form of the ligand 4-1BB receptor of the TNF superfamily, which has been shown to have proinflammatory effects when it is engaged. The fusion of SA-4-1BBL to HPV16 E7, administered via gene gun, showed increased anti-tumor efficacy in the TC-1 model compared to controls, and also increased IFNγ-producing E7-specific T cells.…”

Targeted Gene Delivery Therapies for Cervical Cancer

“…This vaccine induced higher prophylactic and therapeutic effects in TC-1 tumor model in vivo compared to mice treated with SP-SA-4-1BLL or E7 only, in relation to an increase in E7-specific T cells producing IFN-γ. Furthermore, this vaccine established long-term immunologic memory that prevents recurrence [115]. The use of co-stimulatory molecules of the TNF superfamily seems to enhance the immune response achieved with vaccines.…”

“…Another field of future research is chimeric antigen receptor (CAR)-T cells, genetically modified T cells that could be used to target the specific E6 and E7 oncoproteins. They have been developed against a wide variety of tumor antigens, mainly hematologic malignancies [114,115].…”

An Oncolytic Adenovirus Encoding SA-4-1BBL Adjuvant Fused to HPV-16 E7 Antigen Produces a Specific Antitumor Effect in a Cancer Mouse Model

“…Several reports have demonstrated that specific antitumor immune responses can be elicited using naked DNA vaccines encoding 4-1BBL in conjunction with TAAs [ 9 , 10 , 11 ]. These types of vaccines are cheap to produce, easy to construct, and have a long shelf life, plus they can be quickly manufactured for preclinical trials.…”