In a healthy person the immune system is perfectly balanced to provide protection against invading harmful pathogens or cancerous cells, whilst maintaining a state of unresponsiveness (‘tolerance’) to our own body tissues and to harmless substances we eat or inhale. A breakdown in tolerance can lead to unwanted, inappropriate, immune reactions. These unwanted immune reactions are the cause of autoimmune diseases (AID; including rheumatoid arthritis (RA), type-1 diabetes (T1D) and multiple sclerosis (MS)) and allergies (including allergic asthma, food allergies).
The prevalence of AID and allergic diseases is increasing in developing countries. In Europe, nearly one percent of the adult population develops RA and it is estimated that 1 in 9 people have a recorded diagnosis for an allergy. Furthermore, tens of thousands of organ, tissue and stem-cell transplantations are performed in Europe each year. Transplanted patients need treatment to inhibit any immune attack to the graft or, in the case of stem-cell transplantation, to avoid Graft-versus-Host Disease (GvHD). Existing therapies to treat these pathological conditions include lifelong treatment with immune modulatory drugs leading to general immune suppression (average cost 10-20K €/patient/year or more).
Furthermore, these therapies have poor efficacy in up to 50% of cases, and are associated with severe adverse effects (e.g. infections, cancer) with a high healthcare and socioeconomic impact. More effective and safer therapies aimed at re-establishing tolerance and modifying the course of these pathologies permanently or for longer periods of time are strongly needed; such therapies would benefit hundreds of thousands patients in Europe and worldwide.
Immune tolerance is an active process that prevents the immune system from mounting a destructive response to a given protein or so-called antigen (i.e. self-antigen, inhaled or ingested environmental antigens or transplanted tissue antigen). In the last decade, much progress has been made in understanding the induction and maintenance of immune tolerance. The identification of regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic dendritic cells (tolDC) and regulatory macrophages (Mregs) as key regulators of immune tolerance has paved the way for novel forms of CTT which offer the prospect to induce tolerance to specific antigens, whilst preserving general protective immunity. CTT provide the possibility to develop personalised and long-lasting treatments, which would represent a breakthrough for healthcare in these chronic diseases.
Further development of these innovative therapies requires a close network between experts in the field of CTT that will facilitate exchange of knowledge and will build collaborative efforts.
This new network, for which COST is the ideal instrument, will be required to accelerate progress in the field.
Current State of Knowledge
Immune tolerance to autoantigens is achieved by the active silencing of destructive T-cell responses towards such antigens. Different cell types of the immune system have been shown to be crucial for the induction and maintenance of immune tolerance: antigen-presenting cells (APC), including certain dendritic cells (DC) subtypes and regulatory T cells (Tregs). Patients with a DC-deficiency syndrome, virtually lacking DC in their blood and interstitial tissues, have reduced numbers of Tregs and a quarter of these patients develop AID. Furthermore, patients lacking functional Tregs (through mutations in the transcription factor FOXP3, crucial for Treg function) also develop AID. There is a strong functional relationship between DC and Tregs; DC can induce the differentiation of Tregs and, vice versa, Tregs can enhance the tolerogenic function of DC. In addition to DC, other APC populations have been shown to exert tolerogenic function, including Mregs and Bregs.
Cell-based tolerance-inducing therapies (CTT)
The discovery that regulatory cells control/promote immune tolerance led to the idea that they could be developed as an immunotherapeutic cellular tool to restore tolerance in AID or allergy, or to induce tolerance to transplanted grafts. In order to achieve this, specific methods had to be developed. With respect to DC, protocols for the generation of DC with stable tolerogenic function (tolDC) were required. The ‘default’ function of DC is to induce tolerance, but in response to inflammation and infection, DC will lose this tolerogenic function and become ‘immunogenic’ i.e. they will acquire a proinflammatory phenotype with the ability to promote destructive T-cell responses in the context of AID or allergies. In the last 15 years, research groups around the world (including Europe) have developed a variety of current Good Manufacturing Practice (cGMP)- compatible methods to generate stable tolDC in vitro, and have provided important proof of principle evidence in animal models that these tolDC can reduce symptoms of established AID, or can prevent the rejection of transplanted tissues.
With respect to Tregs, a major challenge has been to culture these hard-to-grow cells to great purity and at large quantities. European groups have also greatly contributed to the development of methods to generate Tregs, including antigen-specific Tregs – this is even harder than culturing polyclonal (non-specific) Tregs, but it is believed that antigen-specific Tregs are more effective because they can act in a more targeted manner. Like tolDC, Tregs have been shown to have beneficial effects in animal models of AID and transplantation.
The development of Mregs is at least as advanced, as GMP quality Mregs have already been manufactured and used to treat two renal transplant recipients who showed a tolerogenic profile.
Also advances have been made using peripheral blood mononuclear cells (PBMC), chemically coupled with the target antigen as CTT. This strategy has proven excellent efficacy in several animal models of T cell mediated diseases, transplantation tolerance and allergy. Advantage of this approach is that the autologous cell product can be produced and injected in one day. For this CTT strategy a GMP manufacturing process has been established and has already been translated to the clinic.
Phase I trials with CTT
Several preparations of tolerance-inducing APC (tolAPC), Tregs and other cells with regulatory function have been tested in phase I clinical trials. Two trials with autologous tolDC have been completed for T1D (USA) and RA (Australia) and tolDC trials in RA and Crohn’s disease are ongoing (in the UK and Spain, respectively). A phase I trial with peptide-pulsed, fixed PBMC in MS was also carried out (Germany). Further trials with tolDC in MS (Spain) and allergic asthma (USA), or Mregs in kidney transplantation (Germany) are under way. Phase I trials with Tregs have been conducted in leukemia and lymphoma patients transplanted with cord blood or haematopoietic stem cells (USA, Germany, Italy, Poland), and trials with Tregs in T1D are ongoing (Poland, USA). In a coordinated effort, The ONE Study EU consortium (www.onestudy.org) is currently seeking licensing for the manufacture of Tregs, tolDCs and Mregs for the treatment of renal transplant recipients; these trials will take place in Europe and in the USA.Thus, together with the USA, Europe is at the forefront of bringing CTT to the clinic.
So far the results are highly encouraging in that none of the trials have found any safety concerns. Cell therapy was well-tolerated by the patients, and autoimmunity in the tolDC-treated patients was not enhanced. Furthermore, evidence of an antigen specific effect of the therapy was found in the peptide-pulsed, fixed PBMC trial.
Limitations of CTT
Limitations of CTT are related to both the production process and ‘read-outs’ of the clinical trials, which are supposed to provide confirmatory evidence for the postulated mechanism/s of action (MoA). Production methods for the generation of tol-APC -including tolDCs, Mregs and peptide-fixed PBMC- and Tregs vary from one laboratory to another and have not been standardised. Furthermore, there is no universal read-out system to measure the ‘tolerogenicity’ and suitability of the cellular products, rendering the comparison between products in terms of functionality and safety between different laboratories difficult. In addition, CTT require specialised facilities for production, are labour intensive, highly customised and therefore expensive (costing 30,000 to 40,000 € per patient per treatment). Although these costs are high, a single treatment with CTT will be more cost-efficient than conventional therapies that often require life-long administration. The trials conducted so far have recruited relatively small numbers of patients (between 10 and 30 patients). Although the safety trials have been encouraging, the clinical efficacy of CTT in various conditions remains to be determined. Furthermore, many questions relating to CTT remain unanswered, e.g. what cell type to use and how best to generate it; how many cells need to be transferred and how often; how long do their effects last; what is their MoA? In order to accelerate answering these questions, close collaboration between groups is required not only with the aim that the lessons learned from current trials can be transferred to other groups, but also to allow the systematic comparison of CTT products and outcomes of CTT trials, and to set up multi-centre
trials to conduct larger scale clinical trials.
Innovations in the CTT field through A FACTT
The A FACTT approach will be instrumental to improve the development and application of CTT at several levels including definition of the CTT products, a better understanding and validation of the MoA of specific CTT approaches, and demonstration of efficacy on either a surrogate- or clinical outcome in proof-of-concept clinical trials.
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