Anti-α4ß7 integrin monoclonal antibody (vedolizumab) for the treatment of steroid-resistant severe intestinal acute graft-versus-host disease.

Steroid-resistant (SR) acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic stem cell transplantation. Vedolizumab is a monoclonal antibody that impairs homing of T cells to the gastrointestinal (GI) endothelium by blocking the α4ß7 integrin. We retrospectively analyzed outcomes following vedolizumab administration for treatment of SR GI GvHD. Overall, 29 patients from three transplantation centers were included. Histopathology was available in 24 (83%) patients. The overall response rate (ORR) was 23/29 (79%); 8 (28%) patients had a complete response and 15 (52%) a partial response. Vedolizumab was administered as a 2nd-line or ≥3rd-line treatment in 13 (45%) and 16 (55%) patients, respectively. ORR in the former groups was 13/13 (100%) versus 10/16 (63%) in the latter (p = 0.012); corresponding CR rates were 7/13 (54%) versus 1/16 (6%) (p = 0.005). Early administration of vedolizumab was also associated with a greater likelihood of patients being off immunosuppression ((9/13 (69%) versus 3/16 (19%), p = 0.007) and free from fatal infectious complications (5/13 versus 14/16, p = 0.006). Overall, our data suggest that vedolizumab, especially if administered early in the disease course, may ameliorate severe SR GI aGvHD. The timing, role, and safety of vedolizumab should be further explored in prospective clinical trials.

Manufacturing Mesenchymal Stromal Cells for the Treatment of Graft-versus-Host Disease: A Survey among Centers Affiliated with the European Society for Blood and Marrow Transplantation.

The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients' stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.