Pancreatic carcinoma-specific immunotherapy using novel tumor specific cytotoxic T cells

Abstract

Pancreatic cancer represents one of the most lethal human cancers. Investigation of the effective targeting to the tumor cells is essential for both primary tumors and metastases. Tumor specific cytotoxic T lymphocytes (CTLs) have recently been considered to be the attractive vehicles for delivering therapeutic agents toward various tumor diseases. This study was to explore the distribution pattern of CTL carrying the lentiviral vectors with the characteristic of adenoviral E1 gene under the control of the cell activation-dependent CD40 ligand promoter (Lenti/hCD40L/E1AB). Following transduction with adenoviral particles containing chimeric type 5 and type 35 fiber proteins (Ad5/35-TRAIL), these CTLs produced infectious virus when exposed to SW1990 cells. We found that the novel CTL harboring Lenti/hCD40L/E1AB and Ad5/35-TRAIL inhibited pancreatic cancer cell growth and angiogenesis in vitro and in vivo. Furthermore, Ad5/35-TRAIL transduced CTL induced significant apoptosis in pancreatic carcinoma cell lines and upregulated IFN-gamma (IFN-γ) secretion of CTLs. Importantly, Ad5/35-TRAIL transduced CTLs had no inhibitory effect on normal cells. Thus, the novel CTLs may be safe and feasible for the development of gene therapy approaches to pancreatic carcinoma.

The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma

“…As described above, the reduction of hyaluronan in the tumor tissue reduces the IFP and promotes drug perfusion via the release of compressed microvessels. Several studies have reported that an immunological approach, such as the administration of peptides [74], tumor-specific cytotoxic T cells [75], and immune checkpoint inhibitors [76], showed efficacy in PDAC treatment. The alteration of the cancer microenvironment by the control of hyaluronan may also increase the sensitivity of these immune targeting agents (Figure 2).…”

TAMing pancreatic cancer: combat with a double edged sword

“…This revealed that the mechanism is similar to that of paclitaxel, which stimulates M1 polarization by acting as an LPS mimetic [106]. CD40, a member of the tumor necrosis factor receptor (TNFR) family, and its ligation have been shown to have anti-tumor effect via agonistic anti-CD40 mAbs to either directly kill CD40-positive tumor cells or activate T-cell immune responses [107, 108]. Beatty et al demonstrated the efficacy of using CD40 agonists in combination with gemcitabine therapy by altering the tumor stroma in PDAC, effecting a T cell anti-tumor activity and recalibration of TAMs to become tumoricidal [109].…”