1579P - TRAIL-engineered umbilical cord mesenchymal stem cells (UC-MSC) as anti-multiple myeloma (MM) cytotherapy approach

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Presenter Paola Cafforio
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors P. Cafforio, C. Felici, F. Mannavola, E. Pellè, F. Silvestris
  • Department Of Biomedical Sciences And Human Oncology, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, 70124 - Bari/IT

Abstract

Background

MSCs are recently under intensive investigation for cell-based anti-cancer therapies and we have shown that UC-MSCs inhibit the MM cell growth in vitro. Also, UC-MSCs express chemotactic molecules that drive their migration to tumor sites and ultimately promote apoptosis by cell-to-cell cross-talk. Thus, we reasoned that UC-MSCs are suitable for gene engineering to express TRAIL in a cytotherapy approach against MM in vitro and in vivo.

Methods

UC-MSCs were transduced by a retroviral vector expressing GFP, and TRAIL under the control of IL6 promoter to induce TRAIL only in presence of IL-1α and IL-1ß secreted within the MM microenvironment. Transduced cells (92% GFP+) were assayed for TRAIL expression by q-PCR, flow cytometry, Western blot and ELISA. TRAIL+-UC-MSC apoptotic potential was tested by Annexin-V in co-cultures with MM cells or in presence of IL-1α and IL-1ß. To evaluate their in vivo anti-MM activity, we generated bone disease by intratibial injections of luminescent U266 cells in 6 week old NOD-SCID mice followed one week later by intracardiac inoculation of TRAIL+-UC-MSCs, and the tumor burden was evaluated weekly.

Results

In transduced cells, TRAIL mRNA levels were 40.000 fold higher with a concurrent 5 fold higher protein expression. TRAIL mRNA and protein levels increased when the cells were co-cultured with U266 cells, or in presence of IL-1α and IL-1ß, whereas the MM cell apoptosis after 48 hrs was 70,3 ± 3,5% compared to 20,5 ± 2,3% of control UC-MSCs. Significant reduction of MM tumor masses were detected in mice injected with TRAIL+-UC-MSCs, as compared to control mice (p 

Conclusions

Our data support the TRAIL+-UC-MSCs approach to treat MM in NOD-SCID mice. Besides their migratory property to the MM microenvironment, TRAIL+-UC-MSCs reinforce their constitutive anti-MM activity by TRAIL over-expression.

Clinical trial identification

Legal entity responsible for the study

Prof. Franco Silvestris

Funding

AIRC (Associazione Italiana per la Ricerca sul Cancro)

Disclosure

All authors have declared no conflicts of interest.