Virtual 46th Annual Meeting of the EBMT

Allogeneic hematopoietic cell transplantation provides a potential cure for a variety of hematological and nonhematological diseases. The use of this therapeutic strategy has been limited by the availability of a suitable matched related or unrelated donor, especially for ethnical minorities and if the aggressive course of the disease necessitates a successful donor search in a timely manner. Since virtually every patient has a potentially suitable haploidentical related donor in their family, a successful strategy for haploidentical allogeneic HCT eliminates the “lacking donor” problem. Initially, trials of haploidentical transplantation were complicated by a high incidence of engraftment failure, GVHD, and infectious complications resulting in an unacceptable treatment related morbidity and mortality. Compared to CD34+ selection and depletion of CD3+ cells, the ex vivo depletion of TCRα/β+ T lymphocytes is associated with a more rapid immune reconstitution after haploidentical transplantation. Furthermore, remaining TCRγ/δ+ T lymphocytes and NK cells in the graft may have important anti-infective and anti-tumor properties without causing GVHD. We report the final results of the first prospective, multicenter, open-label, single-arm phase l/ll clinical trial that assesses the safety and feasibility of stem cell transplantation with TCRα/β and CD19– depleted haploidentical grafts generated with the CliniMACS® Plus System in combination with a reduced intensity conditioning in adult patients suffering from various malignant and non-malignant diseases (www.clinicaltrialsregister.org; 2011-005562-38). All patients received single agent MMF as short-term GVHD prophylaxis (40 mg/kg/day for 30 days). 30 patients from six hospitals were treated. The conditioning regimen consisted of 15 or 30 mg ATG (Fresenius/Grafalon) or 7 Gy total nodal irradiation, 160 mg/m2 fludarabine, 10 mg/kg thiotepa, and 140 mg/m2 melphalan. Using TCRα/β depletion, a T cell reduction of 4.5-5 log can be achieved, which is comparable to CD34+ selection. However, this approach retains high numbers of NK cells as well as γ/δ+ T lymphocytes in the graft. We will present final data about engraftment, immune reconstitution, and clinical outcome including survival, non-relapse related mortality, GVHD, infections, and adverse events. Conclusions: The CliniMACS Plus System to deplete TCRα/β+ and CD19+ cells yielded a large number of CD34+ cells, NK cells, and TCRγ/δ+ cells, which could be infused safely into adult patients with minimal risk of severe GVHD. The immune reconstitution was rapid with a low incidence of serious viral or fungal infections. Coupled with a reduced-intensity regimen, the overall non-relapse mortality was low and the overall and disease-free survival was very promising although a high-risk patient was treated.

Haploidentical donor (haplo) hematopoietic cell transplantation (HCT) must include ex vivo or in vivo T cell depletion (TCD) to avoid high risk of severe graft-vs-host disease (GVHD). However, TCD has historically been associated with delayed immune recovery and increased 
risk of infection. Relapse of the underlying leukemia and infection remain the primary causes of death after TCD HCT. It is well known that naïve T cells are the primary driver of GVHD. Other T cell subsets, such as memory T cells, appear to be less alloreactive and hence are less likely to contribute to GVHD. We have previously shown that selective T cell depletion targeting CD45RA effectively removes naïve T cells from the donor graft and preserves diverse memory T cell populations for adoptive transfer to the recipient at the time of HCT. This leads to robust donor memory T cell reconstitution as early as day +30, with lymphocyte populations that are a direct recapitulation of the CD45RA-depleted donor graft. Critically, this rapid donor memory cell recovery was associated with a substantial reduction in viremia in the first six months following HCT. Recently published analyses of early clinical outcomes of the first 50 patients with hematologic malignancy who received 
haploHCT with CD45RA-depletion at our center demonstrates an improved three-year overall survival (78.9%) and event-free survival (77.7%) for patients in complete remission compared to recipients who received historic T cell–depleted haploHCT, which utilized CD3 depletion or CD34+ enrichment, over the prior ten years. This improvement was related primarily to a reduction in transplant-related mortality, though there was a trend towards a reduction in relapse as well. 
There was no significant difference in the rate of GVHD despite a median infused T cell dose approximately 2000-fold higher in the CD45RA-depleted recipients. These early clinical outcomes also compared favorably to a contemporaneous HLA-matched donor standard HCT cohort, which did not receive selective TCD but received identical clinical supportive care. 

CAR T cells are remarkably effective in treating certain types of leukaemia and lymphoma, unresponsive to conventional therapies. This has led to the FDA granting CAR T cells breakthrough status to accelerate patient access to these potentially life-saving therapies. The UCL CAR T-cell programme has evolved under the guidance of Dr. Martin Pule at the UCL Cancer Institute. 
A portfolio of clinical studies are now open and recruiting patients. With the aim of reducing manufacturing costs and scaling manufacture capability of our academic GMP facility, we have incorporated semiautomated, closed cell manufacturing processes into the UCL CAR T-cell programme in collaboration with Miltenyi Biotec. During this session, we will discuss the 
evolution of CAR T cell manufacturing at UCL from conventional, open processes to semi-automated, closed processes. We will additionally review recent UCL CAR T cell trial outcomes and will also look forward to the future of manufacturing and new directions for the UCL programme.