Last update on March 2012

The new program on cell therapy in experimental radiopathology program, launched in 2009 for a five-year duration, is continuing the research conducted in this field by the IRSN for several years. The aim of this new period is to define the optimum conditions of clinical use of adult stem cells in the context of the treatment of severe tissue lesions following radiotherapy or accidental exposure to ionizing radiation.

Recently, the introduction of cell therapy has opened new therapeutic hopes in the field of treating radiation-induced tissue lesions. Starting with animal experiments conducted by the IRSN, the first graft of mesenchymal stem cells (MSC) was carried out on compassionate grounds in 2006, on a patient accidentally irradiated by a radioactive source [Lataillade et al. 2007]. Since then, eight more patients have benefited from this innovative treatment for severe tissue lesions after irradiation  [Benderitter et al. 2010, Bey et al. 2010]. The results obtained were very promising, since the patients observed had no more pain within 48 hours following the MSC injections. In addition, their clinical evolution very quickly became favorable and graft compatibility turned out to be of excellent quality. With several years’ feedback no necrosis recurency has been observed in these patients. These patients all currently display very good healing of their lesions.

Why cell therapy?
 

Cell therapy is a recent technique that consists of sampling, isolating, amplifying ex vivo and reinjecting stem cells for therapeutic purposes. Stem cells are undifferentiated cells, qualified as ‘pluripotent’ because they are capable of self-renewal and evolution towards mature cells with a variety of morphologies and functions. The choice of adult stem cells depends on the pathology targeted as well as the accessibility to those cells, their capacity for culture, and their therapeutic potential. Historically, bone marrow was the primary source of adult stem cells because of the relative accessibility.

Mesenchymal stem cells (MSC) of therapy has proven its clinical effectiveness in the treatment of radiological burns. The side effects arising from radiotherapy, in their most severe forms, are currently still beyond the capacity of classic pharmacological therapeutic schemes. Cell therapy at the service of regenerative medicine could therefore be a therapeutic alternative to the radiotherapy adverse effects. The cell  treatment protocols concerning the medical management of radiological burns must now be optimized for this innovative therapeutic approach to become the benchmark in the treatment of severe radiation- induced lesions.

Recent successes obtained for cutaneous lesions lead us to extend the scope of application of MSC-cell therapy into other organs, such as organs at risk that are present in the field of abdominopelvic radiotherapies. Moreover, the effectiveness of other types of adult stem cell must be tested MSCs being now our ‘reference cell model’.

Other adult stem cells have interesting therapeutic potential, including adipose stem cells and endothelial progenitor cells, for examples. The demonstration of the therapeutic effectiveness of adult stem cells will rely on a precise understanding of their modes of action, and the control of all the parameters required for their clinical use: injection, systemic and/or local, injection delay after the appearance of lesions, quantity of stem cells injected and rate of administration, and finally, the choice: cell therapy alone, or combined with surgery.

The three main objective of the program are to:

• Increase our knowledge of the modes of action of adult stem cells;
• Evaluate the potential risks of the treatments;
• Optimize the clinical transfer of cell therapy in the treatment of severely irradiated tissues.

The clinical end point of this R&D program are to:

• Determine the injection for adult stem cells in order to obtain optimum therapeutic efficacy in the treatment of severe damages after radiation exposure. Based on clinical knowledge obtained with MSCs, the criteria for use, modes of action, and possible toxicity of adult stem cells will be established, whether injected separately, co-injected, or injected after specific conditioning.
• Test the use of other types of stem cell (induced pluripotent stem cells, embryonic stem cells, etc.) or other injection procedures (co-therapy, activation of stem cells before injection, etc.) and demonstrate their potential with respect to MSCs.

• Christelle Durand: Role of mesenchymal stem cells in the modulation of visceral pain associated with a model of radiation-induced colorectal ulceration
• Jean-Victor Lacavé-Lapalun: Role of Toll-like Receptors (TLR) in immune orientations induced by abdominal irradiation : potentialization of TLRs in the treatment of radiation-induced lesions by mesenchymal stem cells
• Raphaëlle Bessout: Therapeutic benefit of an injection of mesenchymal stem cells (MSC) on the repair of radiation-induced colorectal lesions – Role of the inflammatory process
• Sabine François: Study of the plastic capacity of human mesenchymal stem cells (MSC) after irradiation of the receptor tissue: therapeutic approach to radiation-induced effects on multiple organs 
  

• Haydée Lugo-Martinez: "Implementation of a treatment for radio-induced musculocutaneous burns by administering adipose adult stem cells"

   
  

• Health Phys. 2010; 98(6):851-7. "New emerging concepts in the medical management of local radiation injury." Benderitter M, Gourmelon P, Bey E, Chapel A, Clairand I, Prat M, Lataillade JJ.
• Wound Repair Regen. 2010;18(1):50-8. "Emerging therapy for improving wound repair of severe radiation burns using local bone marrow-derived stem cell administrations." Bey E, Prat M, Duhamel P, Benderitter M, Brachet M, Trompier F, Battaglini P, Ernou I, Boutin L, Gourven M, Tissedre F, Créa S, Mansour CA, de Revel T, Carsin H, Gourmelon P, Lataillade JJ.
• Blood. 2010; 115(8):1549-53. "Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation." Tarte K, Gaillard J, Lataillade JJ, Fouillard L, Becker M, Mossafa H, Tchirkov A, Rouard H, Henry C, Splingard M, Dulong J, Monnier D, Gourmelon P, Gorin NC, Sensebé L
• Cell Death Differ. 2010; 17(6):952-61. "Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis." Sémont A, Mouiseddine M, François A, Demarquay C, Mathieu N, Chapel A, Saché A, Thierry D, Laloi P, Gourmelon P
• Arterioscler Thromb Vasc Biol. 2009. "Cell Therapy Based on Adipose Tissue-Derived Stromal Cells Promotes Physiological and Pathological Wound Healing." Ebrahimian TG, Pouzoulet F, Squiban C, Buard V, André M, Cousin B, Gourmelon P, Benderitter M, Casteilla L, Tamarat R.
• Regen Med. 2007; 2(5):785-94. "New approach to radiation burn treatment by dosimetry-guided surgery combined with autologous mesenchymal stem cell therapy." Lataillade JJ, Doucet C, Bey E, Carsin H, Huet C, Clairand I, Bottollier-Depois JF, Chapel A, Ernou I, Gourven M, Boutin L, Hayden A, Carcamo C, Buglova E, Joussemet M, de Revel T, Gourmelon P.
• Ann Hematol. 2007; 86(1):1-8. "Human mesenchymal stem cells favour healing of the cutaneous radiation syndrome in a xenogenic transplant model." François S, Mouiseddine M, Mathieu N, Semont A, Monti P, Dudoignon N, Saché A, Boutarfa A, Thierry D, Gourmelon P, Chapel A.
• Stem Cells. 2006 Apr;24(4):1020-9. "Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage.” François S, Bensidhoum M, Mouiseddine M, Mazurier C, Allenet B, Semont A, Frick J, Saché A, Bouchet S, Thierry D, Gourmelon P, Gorin NC, Chapel A.
• Adv Exp Med Biol. 2006; 585:19-30. "Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury." Sémont A, François S, Mouiseddine M, François A, Saché A, Frick J, Thierry D, Chapel A.
•  J Gene Med. 2003; 5(12):1028-38. "Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome." Chapel A, Bertho JM, Bensidhoum M, Fouillard L, Young RG, Frick J, Demarquay C, Cuvelier F, Mathieu E, Trompier F, Dudoignon N, Germain C, Mazurier C, Aigueperse J, Borneman J, Gorin NC, Gourmelon P, Thierry D.
• Cell Immunol. 2008;253(1-2):16-22. "Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression." Nasef A, Mazurier C, Bouchet S, François S, Chapel A, Thierry D, Gorin NC, Fouillard L
• Gene Expr. 2007;13(4-5):217-26. "Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells." Nasef A, Chapel A, Mazurier C, Bouchet S, Lopez M, Mathieu N, Sensebé L, Zhang Y, Gorin NC, Thierry D, Fouillard L.