Modified mesenchymal stem/stromal cells as next generation cellular immunotherapy: manufacturing, safety, efficacy and mechanisms of action

Mesenchymal stem/stromal cells (MSCs) are one of the most investigated biological tools for cellular therapy, thanks to their capacity to exert strong regenerative and immunomodulatory effects. Their widespread use in the past two decades has offered an extraordinary amount of scientific data showing clinical benefits in certain scenarios. However, in the vast majority of cases, the use of this Advanced Therapy Medicinal Product (ATMP) has been based on direct formulation of expanded, “physiological” state-MSCs. Such approach can be useful in some therapeutic contexts, but not in all where MSCs may exert their therapeutic effects. In addition, we now know that MSCs possess functional plasticity. Indeed, similarly to immune cells, according to environmental cues, they can exist in different activation states, whereby certain aspects of their functionality can be substantially amplified or guided. Furthermore, MSCs can be genetically modified in many ways to increase/direct their therapeutic efficacy. Next generation of MSC-based ATMPs can therefore benefit from us exploiting their full biological potential, mostly by using ex vivo modification, to steer and optimize their therapeutic function prior to application, in order to amplify those characteristics that better match with the pathology at hand.

The aim of this Research Topic is to highlight the most recent advances and developments in MSC basic science, manufacturing using either genetic or non-genetic modifications, and therapeutic application to optimize their immunomodulatory potential for immune-mediated diseases. This topic includes different kinds of approaches to MSC licensing/activation with biomolecules, synthetic small molecules and genetic modifications to introduce genes coding for cytokines, chemokines and their receptors, enzymes, surface immunomodulatory molecules and others, such as apoptosis-inducing ligands for cancer immunotherapy. Reports on newly discovered signalling pathways and mechanisms of action (MoA) related to their immunological network are also included. The goal is to discuss the most suitable manufacturing approaches in view of defining critical therapeutic attributes. Finally, we welcome discussions on the aspect of safety and efficacy of translating such ATMP into the clinic.

Main topic subjects include but are not limited to:
• Novel approaches in genetic modification of MSCs with improved immunomodulatory function
• Bioengineering approaches aimed to optimize GMP manufacturing protocols and efficient genetic modification of MSCs
• Non-genetic, ex vivo licensing of MSCs to achieve optimization of immunomodulatory function
• The role of chemokines and MSC migratory capacity
• MSCs as carriers of biomolecules with anti-tumour efficacy
• The importance of surface inhibitory molecules and their induction in MSC-based immunotherapy
• Novel discoveries in signalling pathways and MoA associated with MSC's immunomodulatory function
• The influence of cancer environment on MSCs
• Defining critical quality attributes for next generation, MSC-based therapeutics (e.g., future role of in vitro/in vivo potency assays)

Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.

Topic Editor Dr. Rachele Ciccocioppo is member of the Takeda Italian Advisory Board for the use of Mesenchymal stem/stromal cells in perianal Crohn's disease. The other Topic Editors declare no competing interests with regard to the Research Topic subject.