Redefining strategies to introduce tolerance-inducing cellular therapy in human beings to combat autoimmunity and transplantation reactions

Abstract

Clinical translation of tolerance-inducing cell therapies requires a novel approach focused on innovative networks, patient involvement, and, foremost, a fundamental paradigm shift in thinking from both Academia, and Industry and Regulatory Agencies. Tolerance-inducing cell products differ essentially from conventional drugs. They are personalized and target interactive immunological networks to shift the balance toward tolerance. The human cell products are often absent or fundamentally different in animals. This creates important limitations of pre-clinical animal testing for safety and efficacy of these products and calls for novel translational approaches, which require the combined efforts of the different parties involved. Dedicated international and multidisciplinary consortia that focus on clinical translation are of utmost importance. They can help in informing and educating regulatory policy makers on the unique requirements for these cell products, ranging from pre-clinical studies in animals to in vitro human studies. In addition, they can promote reliable immunomonitoring tools. The development of tolerance-inducing cell products requires not only bench-to-bedside but also reverse translation, from bedside back to the bench. Tolerance-inducing cellular therapies hold great promise for the treatment of patients with chronic inflammation, as seen in autoimmune diseases, and for the prevention of graft rejection and graft-versus-host-disease (GvHD) following transplantation (1, 2). Such treatments possess the key for a true restoration of the immune balance and thus may prevent or minimize the life-long use of immunosuppressive drugs and therewith associated adverse side-effects. Their potential is supported by a vast amount of data from in vitro human assays and experimental models (3-7). The first cautious steps to clinical translation have been undertaken by phase I and II studies with both regulatory T-cells (Tregs) and tolerogenic dendritic cells (tolDC) in GvHD, organ transplantation, type I diabetes, and RA (2, 8-11). It is becoming increasingly clear, however, that the intrinsic nature of tolerance-inducing cellular products leads to unique requirements for safe and efficient clinical translation. Here, we highlight some of the most notable hurdles in translation of tolerance-inducing cellular therapies and define some prerequisites that may substantially move the field forward. © 2014 ten Brinke, Joosten, van Ham, van Kooten and Prakken.