Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.

Polymer-Functionalised Nanograins of Mg-Doped Amorphous Calcium Carbonate via a Flow-Chemistry Approach.

Calcareous biominerals typically feature a hybrid nanogranular structure consisting of calcium carbonate nanograins coated with organic matrices. This nanogranular organisation has a beneficial effect on the functionality of these bioceramics. In this feasibility study, we successfully employed a flow-chemistry approach to precipitate Mg-doped amorphous calcium carbonate particles functionalized by negatively charged polyelectrolytes-either polyacrylates (PAA) or polystyrene sulfonate (PSS). We demonstrate that the rate of Mg incorporation and, thus, the ratio of the Mg dopant to calcium in the precipitated amorphous calcium carbonate (ACC), is flow rate dependent. In the case of the PAA-functionalized Mg-doped ACC, we further observed a weak flow rate dependence concerning the hydration state of the precipitate, which we attribute to incorporated PAA acting as a water sorbent; a behaviour which is not present in experiments with PSS and without a polymer. Thus, polymer-dependent phenomena can affect flow-chemistry approaches, that is, in syntheses of functionally graded materials by layer-deposition processes.

Phase-specific bioactivity and altered Ostwald ripening pathways of calcium carbonate polymorphs in simulated body fluid.

Calcium carbonate is an abundant biomineral, and already archeological records demonstrate its bioactivity and applicability for osseo-integrative implants. Its solubility, which is generally higher than those of calcium phosphates, depends on its polymorph turning calcium carbonate into a promising biomaterial with tunable bioresorption rate. However, the phase-dependent bioactivity of calcium carbonate, i.e., its osteoconductivity, is still insufficiently characterized. In this study, we address this issue by monitoring the behavior of the four most important calcium carbonate phases, i.e., calcite, aragonite, vaterite, and amorphous calcium carbonate, in simulated body fluid solution at 37 °C. Our results demonstrate that the thermodynamically stable calcite phase is essentially inert. In contrast, the metastable phases aragonite and vaterite are bioactive, thus promoting the formation of calcium phosphate. Amorphous calcium carbonate (ACC) shows prominent bioactivity accompanied by pronounced redissolution processes. Mg-stabilized ACC was additionally tested since its increased stability eases formulation and handling in future applications. It is highly bioactive and, moreover, the additional release of Mg promotes cell viability. Overall, our results demonstrate that bioactivity of calcium carbonate is phase-dependent, allowing tailored response and bioactivity of future calcareous biomaterials. Our results also reveal that phosphate ions strongly interfere with Ostwald-Lussac step ripening of calcium carbonate, kinetically stabilizing metastable polymorphs such as vaterite and aragonite; this is a distinctive feature of the calcium carbonate mineral system which clearly has to be considered in future applications of calcium carbonate as a bioceramic.

The Human Genome Editing Race: Loosening Regulatory Standards for Commercial Advantage?

Medicinal products based on genome editing must undergo rigorous preclinical testing and are subject to regulatory oversight for proper risk assessment prior to first evaluation in humans. We give a European perspective on the regulatory expectations to translate genome editing to the clinic to ensure their timely progress to market.

Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts.

Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B-cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti-tumor activities, and related toxicities. More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients using CD19-specific CARs. An increasing number of studies address solid tumors as well. Notably, not all clinical trials conducted so far have shown promising results. Indeed, in a few patients CAR T cell therapy resulted in severe adverse events with fatal outcome. Of note, less than 10% of the ongoing CAR T cell clinical trials are performed in Europe. Taking lead from our analysis, we discuss the problems and general hurdles preventing efficient clinical development of CAR T cells as well as opportunities, with a special focus on the European stage.

Advanced Therapy Medicinal Products: How to Bring Cell-Based Medicinal Products Successfully to the Market - Report from the CAT-DGTI-GSCN Workshop at the DGTI Annual Meeting 2014.

On September 11, 2014, a workshop entitled 'Advanced Therapy Medicinal Products: How to Bring Cell-Based Medicinal Product Successfully to the Market' was held at the 47th annual meeting of the German Society for Transfusion Medicine and Immunohematology (DGTI), co-organised by the European Medicines Agency (EMA) and the DGTI in collaboration with the German Stem Cell Network (GSCN). The workshop brought together over 160 participants from academia, hospitals, small- or medium-sized enterprise developers and regulators. At the workshop, speakers from EMA, the Committee for Advanced Therapies (CAT), industry and academia addressed the regulatory aspects of development and authorisation of advanced therapy medicinal products (ATMPs), classification of ATMPs and considerations on cell-based therapies for cardiac repair. The open forum discussion session allowed for a direct interaction between ATMP developers and the speakers from EMA and CAT.