CD40-Targeted Recombinant Adenovirus Significantly Enhances the Efficacy of Antitumor Vaccines Based on Dendritic Cells and B Cells

Abstract

Despite the advantages of using adenoviral vectors for specific antigenic gene delivery in the development of antigen-presenting cell (APC)-based vaccines, the lack of the coxsackievirus-adenovirus receptor (CAR) on APCs limits the use of adenoviral vectors for in vitro gene delivery. In this study, we used a recombinant adapter protein, CFm40L, which consists of the ectodomain of CAR genetically fused to the ectodomain of CD40 ligand (CD40L) via a trimerization motif, to target Her-2/neu- or human papillomavirus 16 (HPV16) E6/E7-encoding adenoviruses to CD40 on dendritic cells (DCs) and B cells. Targeting CD40 enabled the enhancement of tumor antigen delivery and simultaneous activation of APCs via the CD40-CD40L interaction. We found that these transduced DCs and B cells substantially enhanced the CTL response against human Her-2/neu- and HPV16 E6/E7-expressing tumors, resulting in significant inhibition of tumor growth in a murine tumor model. In addition, the use of the CFm40L adapter protein in combination with gemcitabine treatment allowed for a successful immune response against a self-tumor antigen, murine Her-2/neu. Our results suggest that targeting adenovirus to APCs via CD40, using CFm40L, represents a great improvement in anticancer cellular vaccines.

Tumor-Derived Osteopontin Suppresses Antitumor Immunity by Promoting Extramedullary Myelopoiesis

“…To this end, we employed a B-cell-based antitumor vaccine (31,32). We have convincingly showed that a NKT ligand-loaded, B-cell-based vaccine elicits tumor-specific immune responses (21,33,34). We subcutaneously inoculated Balb/c mice with CT26 tumor cells on day 0 and then intraperitoneally injected the mice with 0.5 mg of antiosteopontin (MPIIIB10) or mIgG as a control every other day for 10 days (Fig.…”

CD40 Ligand Preferentially Modulates Immune Response and Enhances Protection against Influenza Virus

“…Several groups have investigated the potential of CD40L as a molecular adjuvant by either codelivering CD40L with Ags (13)(14)(15)(16)(17)(18)(19)(20) or retargeting the Ag-delivery vector to CD40 on APCs (21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Although enhanced immune responses against various pathogens and tumors were observed, little is known about in vivo B cell responses, functional roles of CD4 + and CD8 + T cells during induction phase, or the contributions of Abs and CD8 + T cells in protection.…”

Potent Antitumor Immunity Generated by a CD40-Targeted Adenoviral Vaccine

“…The efficacy of ex vivo loaded DCs, which are often used as cancer vaccines (43), may be improved upon by transduction with CD40-Ad (17,44). This approach is however wrought with issues about logistics and consistency; in vivo targeting of antigens to DCs would instead allow for a more standardized vaccination method (5).…”