CAR-Treg transplantation (TX200)

CAR-Treg transplantation program with the University of British Columbia

In October 2016, TxCell entered into a strategic R&D collaboration agreement with the University of British Columbia (UBC) in Vancouver, Canada, a leading global center for multidisciplinary research and teaching.

This collaboration agreement covers the development of a CAR-Treg-based cellular immunotherapy for the prevention of graft rejection in the context of Solid Organ Transplantation (SOT).

Activities relating to this program are primarily conducted in the UBC laboratories and led by Professor Megan Levings.

In March 2016, her team published the first preclinical proof of concept with human HLA-A2-specific CAR-Treg cells in a preclinical transplantation model(1).

UBC will conduct non-clinical pharmacology studies with CAR-Treg cells with the aim of initiating a first-in-man study in transplantation patients as soon as possible.

Whilst the UBC team is focused on product development activities, it will in parallel perform research activities in the CAR-Treg field with the aim of optimizing and broadening the new product platform for transplantation.

(1) MacDonald KG, Hoeppli RE, Huang Q, Gillies J, Luciani DS, Orban PC, Broady R, Levings MK. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Invest. 2016, 126(4):1413-1424

About the UBC CAR-Treg proof of concept

The UBC team demonstrated that, in a preclinical xenogeneic Graft-vs-Host Disease (GvHD) model, human CAR engineered Treg cells that are specific for the molecule HLA-A2 were more effective than polyclonal Treg cells in reducing GvHD-related inflammation.

The model used by Dr. Levings’ team is based on xenogeneic GvHD induced in immunodeficient mice through the injection of human HLA A2+ white blood cells.

These human white blood cells (graft) attack the immunodeficient mice (host), resulting in an inflammatory reaction (Graft-vs-Host Disease, GvHD).

The CAR used in this experiment was designed to specifically recognize the HLA-A2 molecule found solely on graft cells.

These data will constitute the basis for the first product development under the new TxCell/UBC collaboration.

About Organ Transplantation

Solid Organ Transplantation (SOT) consists in moving an organ (graft) from one body (donor) to another body (recipient or host), to replace the recipient’s damaged or absent organ.

More than 30,000 organ transplants were performed in the US in 2015, and more than 31,000 in Europe in 2013. Transplant rejection is one of the key challenges of transplantation. In order to avoid such rejection, the most appropriate donor-recipient match is sought and immunosuppressant drugs can be used.

In 2014, the global market of immunosuppressant drugs used in transplantation was estimated to reach $5.1 billion. In the US alone, the cost of long term oral maintenance immunosuppression and other prescription drugs represents between $10,000 and $14,000 per patient per year on average, and can exceed $2,500 per month for certain patients.

Novel strategies aiming at inducing or restoring immune tolerance to a graft are expected to be less toxic and more efficient on the long-term than classical pharmacological immunosuppressive approaches.

CAR-Treg dermatology

CAR-Treg bullous pemphigoid program with the Lübeck Institute of Experimental Dermatology

In June 2016, TxCell entered into a strategic R&D collaboration agreement with the Lübeck Institute of Experimental Dermatology (LIED), a leading institution in the field of translational research on skin blistering diseases, part of the University of Lübeck in Germany.

This specific collaboration agreement covers the development of a CAR-Treg-based cellular immunotherapy for bullous pemphigoid, a rare, potentially fatal autoimmune disease characterized by tense inflammatory skin blisters and in some patients, erosions on mucous membranes.

TxCell scientists have already identified a relevant antigenic target for the development of a CAR-Treg product in bullous pemphigoid patients. The CAR construct is designed to ensure the activation of CAR-Treg cells specifically in the inflammatory skin lesions.

TxCell and LIED are conducting non-clinical pharmacology studies with CAR-Treg cells to prepare for a first in-man study in bullous pemphigoid patients.

About bullous pemphigoid

Bullous pemphigoid is a rare potentially fatal autoimmune skin condition that is characterized by large, fluid-filled blisters on the surface of the skin, called bullae.

Bullous pemphigoid occurs when the patient’s immune system attacks a thin layer of tissue below the outer layer of skin. The blisters usually develop on the abdomen, legs and arms and are accompanied by severe itching. Occasionally, the inner lining tissue of the mouth, nasal passages, or genitalia can be involved.

Bullous pemphigoid is most common in people aged 60 and older, with an estimated prevalence of 1/40,000.

If untreated, it will persist for years, with periods of spontaneous remissions and exacerbations. Current treatment is based on long-term use of corticosteroids such as prednisone.

Bullous pemphigoid can be life-threatening, especially for elderly people who are already in poor health.

CAR-Treg mutliple sclerosis

TxCell is exploring the development of a CAR-Treg-based cellular immunotherapy for the treatment of multiple sclerosis both internally and through a collaboration with the Center for Research in Transplantation and Immunology (CRTI) in Nantes, France.

Since June 2017, TxCell and the CRTI collaborate on the development of CAR engineered cells comprising a proprietary Treg cell population expressing the CD8 marker (CAR-CD8+Tregs). The collaboration concentrates on the treatment of transplant rejection and autoimmune diseases, specifically focusing on multiple sclerosis. In addition, TxCell and the CRTI will develop a manufacturing process to enable clinical proof-of-concept studies.

The collaboration expands TxCell’s research efforts, which were focusing previously on engineered CD4+ Treg cells, to explore the therapeutic potential of engineered CD8+ Treg cells in parallel. These CD8+ Tregs are non-cytotoxic and display a unique and highly immunosuppressive mechanism of action, mediated through the release of cytokines with anti-inflammatory and tolerogenic properties1,2.

In December 2016, TxCell gained exclusive worldwide rights to two patent families covering the new type of CD8+ Tregs for all autoimmune diseases and transplantation-related disorders. The CRTI team has already demonstrated the efficacy of these CD8+ Tregs in a number of preclinical models of inflammation3.

(1) Bézie S, Picarda E, Ossart J, Tesson L, Usal C, Renaudin K, Anegon I, Guillonneau C. IL-34 is a Treg-specific cytokine and mediates transplant tolerance. J Clin Invest. 2015 Oct 1;125(10):3952-64.

(2) Picarda E, Bézie S, Venturi V, Echasserieau K, Mérieau E, Delhumeau A, Renaudin K, Brouard S, Bernardeau K, Anegon I, Guillonneau C. MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection. J Clin Invest. 2014 Jun;124(6):2497-512.

(3) Guillonneau C, Hill M, Hubert FX, Chiffoleau E, Hervé C, Li XL, Heslan M, Usal C, Tesson L, Ménoret S, Saoudi A, Le Mauff B, Josien R, Cuturi MC, Anegon I.  CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase. J Clin Invest. 2007 Apr;117(4):1096-106.

About Multiple Sclerosis

Multiple sclerosis is an inflammatory disease of the Central Nervous System (CNS).

The target of the pathological process is myelin, a protective sheath that surrounds the nerve fibers (axons). Multiple sclerosis is an autoimmune disease as the individual’s immune system becomes disrupted and treats the myelin sheath as a foreign body.

The inflammatory reaction will degrade the myelin sheath, which is called demyelination. The transmission of nerve impulses is then altered, which can show up as extremely variable symptoms: numbness of a limb, vision problems, sensations of electric shock in a limb or in the back, movement disorders, etc. At the same time, this demyelination will lead to neurodegeneration.

Most commonly, multiple sclerosis evolves with relapses, during which symptoms recur or new symptoms occur. After a few years, permanent sequelae can affect many functions (motion control, sensory perception, memory, speech etc.) and become very debilitating.

The Multiple Sclerosis Research Foundation (arsep foundation) estimates that 2.3 million people are affected by multiple sclerosis worldwide, including 400,000 in Europe. The disease generally manifests between the age of 25 and 35 years, and three out of four patients are women. To this day there is no curative treatment for this disease. Patient management is usually symptomatic and involves corticosteroids to reduce inflammation and decrease the intensity and duration of the symptoms.


Ovasave, TxCell’s former lead drug-candidate from the ASTrIA platform (naturally antigen-specific Tregs), is composed of autologous ovalbumin-specific regulatory T lymphocytes.

In 2016, TxCell identified a new isolation method for its non-engineered Treg cells (ASTrIA). In September 2017, TxCell confirmed it had fully completed the optimization of the ASTrIA manufacturing process. As expected, the reduction of production costs and of the overall manufacturing leadtime allowed by the new process identified by TxCell in 2016 can reach 50%. The new ASTrIA process is simple, robust and scalable.

However, TxCell now intends to lower its investment on the ASTrIA platform and to focus on continuing promising developments on the ENTrIA platform. This includes utilizing know-how and intellectual property from the ASTrIA platform to work on new engineered Tregs. As a result, the ASTrIA and ENTrIA denominations will ultimately be replaced by a single platform of engineered Treg products.

CATS1 Phase I/IIa clinical study

The first-in-man phase I/IIa study, CATS1, was an open label, 12 weeks multicenter clinical trial, assessing the tolerability and exploring the efficacy of escalating and multiple doses of Ovasave in patients with active moderate-to-severe refractory Crohn’s disease. Several eligible patients in CATS1 also received additional injections at the best responding dose.

CATS1 study has been completed on Q3 2011 and final results have been presented at major international medical conferences, published in Gastroenterology and reviewed in Nature.

Key findings

  • Ovasave is well tolerated.
  • The positive effect of Ovasave was particularly relevant in the best dose group with 75% of patients responding and 38% remitting five weeks after treatment.

About Crohn's disease

Crohn’s Disease is an inflammatory bowel disease that can affect the gastrointestinal tract from mouth to anus as well as present some extra-intestinal manifestations. Generally begins during adolescence and often affects young adults.

The cause of Crohn’s Disease is still unknown even though an interaction between a genetic predisposition and environmental factors is believed to be in the origin of the pathology. The incidence is about 6 to 15 cases per 100.000 and the prevalence of 50 to 200 cases per 100.000.

It is a chronic relapsing and remitting disease manifested mainly by abdominal pain, diarrhea and weight loss, together with systemic symptoms.

Patient’s quality of life may be significantly impaired with Crohn’s Disease.

There is currently no curative therapy and treatments aim at reducing the inflammation and manage the symptoms.

Medications used include immuno-suppressors and biologics (anti-TNF), which frequently show limited efficacy, tolerability issues and development of resistance.

It is estimated that about 160.000 patients live with severe Crohn’s Disease in Europe and the United States and about half of them have primary, secondary or tolerance failure to existing treatments.

There is a high unmet medical need for new treatment options to treat patients with Crohn’s disease.