4-1BB Ligand as an Effective Multifunctional Immunomodulator and Antigen Delivery Vehicle for the Development of Therapeutic Cancer Vaccines

Abstract

Therapeutic subunit vaccines based on tumor-associated antigens (TAA) represent an attractive approach for the treatment of cancer. However, poor immunogenicity of TAAs requires potent adjuvants for therapeutic efficacy. We recently proposed the tumor necrosis factor family costimulatory ligands as potential adjuvants for therapeutic vaccines and, hence, generated a soluble form of 4-1BBL chimeric with streptavidin (SA-4-1BBL) that has pleiotropic effects on cells of innate, adaptive, and regulatory immunity. We herein tested whether these effects can translate into effective cancer immunotherapy when SA-4-1BBL was also used as a vehicle to deliver TAAs in vivo to dendritic cells (DCs) constitutively expressing the 4-1BB receptor. SA-4-1BBL was internalized by DCs upon receptor binding and immunization with biotinylated antigens conjugated to SA-4-1BBL resulted in increased antigen uptake and cross-presentation by DCs, leading to the generation of effective T-cell immune responses. Conjugate vaccines containing human papillomavirus 16 E7 oncoprotein or survivin as a self-TAA had potent therapeutic efficacy against TC-1 cervical and 3LL lung carcinoma tumors, respectively. Therapeutic efficacy of the vaccines was associated with increased CD4 + T and CD8 + T-cell effector and memory responses and

Targeting CD137 enhances the efficacy of cetuximab

“…In further support by the Winn assay (47), we observed that anti-CD137 mAb following cetuximab treatment enhanced adaptive immunity with a significantly higher rate of CD8 + T cell-mediated protection to EGFR-expressing and nonexpressing tumors. The role of adaptive immunity and CD8 + T cells may be an on-target effect of anti-CD137 mAbs in vivo influencing the function of multiple cell types including hematopoietic cells such as granulocytes, T cells, B cells, DCs, and monocytes in addition to NK cells, as well as nonhematopoietic cells (31,(48)(49)(50)(51). Recently, Lee et al reported that tumor-targeting mAbs such as cetuximab induce an adaptive tumor antigen-specific T cell response that is primed by NK cell activation and subsequent NK cell-DC crosstalk (20).…”

Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer

“…The nu/nu and SCID mice are both competent in NK cells and macrophages and complement but lack a functional adaptive immune response. However, mAbs targeting CD137 in vivo likely influence the function of multiple cell types, including hematopoietic cells such as granulocytes, T cells, B cells, dendritic cells, and monocytes, in addition to NK cells, as well as nonhematopoietic cells (25,(40)(41)(42)(43). In particular, our partially immunodeficient mouse models do not explore the impact of trastuzumab and anti-CD137 combination therapy on the adaptive immune response.…”

Anti-prostate cancer effects of CTL cell induction in vitro by recombinant adenovirus mediated PSMA/4-1BBL dendritic cells: an immunotherapy study

“…4-1BBL is a newly discovered costimulatory molecule expressed on the surface of antigen-presenting cells. 4-1BBL belongs to the TNF ligand superfamily, and can bind to 4-1BB molecules on the surface of T cells, generating costimulatory signals for late immune response, which is critical for survival and response of the CD8 + T cell mass (Sharma et al, 2010). This pair of co-stimulatory molecules play an important role in the immune response, immunomodulation, and anti-tumor and viral infection defense, in transplant rejection, etc., and have become an important area of modern immunological research.…”