Targeting of products of genes to tumor sites using adoptively transferred A-NK and T-LAK cells

Abstract

Despite successes in animals, cytokine gene expression selectively in human tumors is difficult to achieve owing to lack of efficient delivery methods. Since interleukin (IL)-2-activated natural killer (A-NK) and phytohemagglutinin and IL-2 activated killer T (T-LAK) cells, as previously demonstrated, localize and accumulate in murine lung tumor metastases following adoptive transfer, we transduced them to test their ability to deliver products of genes selectively to tumors. Assessments of transduction efficiency in vitro demonstrated that adenoviral transduction consistently resulted in high (460%) transduction rates and substantial expression of transgenes such as GFP, Red2, luciferase, b-galactosidase and mIL-12 for at least 4 days. In vivo experiments illustrated that Ad-GFP transduced A-NK and Ad-Red2 (RFP) transduced T-LAK or mIL-12 transduced A-NK cells localized 10-50-fold more or survived significantly better than mock transduced cells, respectively, within lung metastases than in the surrounding normal lung tissue. Most importantly, mIL-12 transduced A-NK cells provided a significantly greater antitumor response than non-transduced A-NK cells. Thus, adoptive transfer of A-NK and T-LAK cells represents an efficient method for targeting products of genes to tumor sites.

Secretory TRAIL-Armed Natural Killer Cell–Based Therapy: In Vitro and In Vivo Colorectal Peritoneal Carcinomatosis Xenograft

“…5C and 5E). These results were consistent with previous observations: NK cells not only accumulate selectively at tumor sites independent of tumor antigen expression, but also penetrate deeply into tumor tissues (10–13). Upon activation, infiltrated NK cells proliferate and upregulate effector molecules such as perforin, granzymes, FasL, TNF-α, and TRAIL (24–27).…”

“…Several researchers have reported that NK cells possess tumor-infiltrating capability and accumulate selectively at tumor sites (10–13). First, we investigated whether NK-92MI or NK-92MI-FETZ cells can migrate to cancer cells in vitro .…”

“…In this study, we attempted to develop secretory TRAIL-natural killer (NK) cell-based therapy. Since NK cells possess tumor-infiltrating capabilities and accumulate selectively at tumor sites (10–13), we used NK cells as carriers to deliver secretory TRAIL.…”

NK Cells in the Tumor Microenvironment

“…A-NK cells pretreated with IL-12 or A-NK cells capable of IL-12–autostimulation via transgene IL-12 production need only 1/10–1/100 of the amount of IL-2 needed to maintain the same viability and functionality as A-NK cells that have not been stimulated with IL-12. 57 This is likely due to the IL-12–induced expression of the IL-2 receptor alpha chain by the A-NK cells, enabling them to express the complete IL-2α-β-γ, high-affinity IL-2 receptor. Thus, by adoptive transfer of IL-12 transduced A-NK cells supported by just two injections of Peg–IL-2 (each of 3 × 10 4 IU) given on the same day as the A-NK cells, a significant prolongation of survival was observed in both 3-day and well-established 7-day models of B16 and MCA205 lung metastases.…”

“…Thus, by adoptive transfer of IL-12 transduced A-NK cells supported by just two injections of Peg–IL-2 (each of 3 × 10 4 IU) given on the same day as the A-NK cells, a significant prolongation of survival was observed in both 3-day and well-established 7-day models of B16 and MCA205 lung metastases. 57,58 Although the A-NK-cell–produced IL-12 undoubtedly supported anti-tumor responses in addition to those generated by non–IL-12–producing A-NK cells, tumor homing by A-NK cells remained a very important and critical factor for the anti-tumor effect achieved by the IL-12 gene-transduced A-NK cells. 58 …”