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
Basic Principles in the Management and Treatment (of cancer)
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.