Ghosting the Cells, a cell therapy that bypasses the immune system – GTC

Regenerative medicine is coming of age and preclinical studies are currently leading worldwide –including in France- to clinical trials in a diversity of applications of substitutive cell/tissue therapies. Nevertheless, one major roadblock is hampering progress toward expansion of that new form of medicine to all patients who are in need: the immune rejection of allogeneic cell transplants. Massive use of immunosuppressant drugs is clearly precluded, at this moment, because of its high tumorigenic risk. There is, therefore, an open challenge, the success of which will open the path for a usage of cell therapy in a wide array of degenerative and injury indications. The overall ambition of the Ghosting the Cells (GTC) program is to fill that gap by designing an original way to make transplanted cells invisible to the recipient's immune system. We propose to do so through engineering cells with gene constructs that encode the immunosuppressive domain (ISD) that allows retroviruses to escape tracking and destruction after cell invasion.
The program is based on two engineered iPS lines that have already been produced and controlled for their capacity at differentiating into the three cell phenotypes of interest, namely keratinocytes, fibroblasts and endothelial cells , associated with a fibrin biomaterial in which the two latter cell populations are embedded, and the former seeded on top, in order to form a dermo-epidermic substitute.
On the path toward our overall objective, we have identified four intermediate steps. 1. The identification of biomarkers of efficacy of ISD in immune cells; this will be determined in vitro using classical cellular and molecular biology techniques. 2. The characterization of the protective effect of ISD as a function of the immune status of the transplanted cells as endothelial cells express HLA I and II, while keratinocytes and fibroblasts express HLA I only, and the latter is known to elicit some form of immune tolerance. 3. The identification of an efficient mean to eliminate an immune-invisible product comprising cells with different proliferative capacities, keratinocytes being continuusly cycling while fibroblasts are essentially post-mitotic and endothelial cells integrate into blood vessels as far as an angiogenetic process is triggerred. Such a post-grafting "safety switch" is a mandatory safety complement in case one faces an adverse effect of the transplanted cells, since by construction they evade normal immune defenses. 4. And, finally, the demonstration that our system provides a way to produce efficient and safe immune-invisible (“stealth”) products, even when comprising well organized tissues and a biomaterial.
Our consortium will collectively bring its expertise in all covered areas: 1. molecular and cellular analyses of T and NK lymphocyte populations challenged by ISD expressing cells (CNRS 9196, Viroxis); 2. In vitro and in vivo immunological tests for allo-identification and tolerance (Viroxis, CRTI INSERM 1064); 3. production of homogeneous cell populations (keratinocytes, fibroblasts, endothelial cells) from human iPS lines (CECS/I-Stem); 4. Production of composite dermo-epidermal grafts from these differentiated cells (CECS); 5. Humanized mice and experimental conditions of a challenge by PBMC (CRTI INSERM 1064); 6. Model of human dermo-epidermal tissue grafting in mice (CRTI INSERM 1064, CECS).
The success of the GTC program will therefore lift an important lock in the field of regenerative medicine while, in the same time, leading to strong patents and breakthrough publications. Interest from commercial entities and/or venture funds interested in the application and exploitation of iPS-derived regenerative medicine is anticipated, and will be exploited through licencing arrangements. Ultimately, successful strategies that address immunological barriers will lead to new forms of therapy, and should reduce waiting times and costs incurred by health services.