We are thrilled to have been able to participate at this year’s Virtual 48th Annual Meeting of the EBMT, where scientists, physicians, and other cell therapy specialists meet to discuss important topics in HSCT and cellular therapy research.
Although we were unable to meet in person, our corporate symposium “Cell Therapy: revolutionary ideas improving today's practices” went ahead virtually. If you weren’t able to join the livestream, catch up now with our recorded sessions.
Scroll down for the agenda, abstracts, speaker information, and recordings.
The symposium is about the latest insights into clinical practice using ex vivo T cell depleted cell products in the context of allogeneic stem cell transplantation. It further includes new combination strategies of using CAR T cells and ex vivo T cell depleted stem cell grafts.
Chair and Speaker: Andrew Gennery
Perhaps the most difficult transplants are those of patients with inborn errors of immunity, with persistent viral infection and no matched donor. Although for many years, the outcomes of transplant for patients with inborn errors of immunity have been improving, the outcomes remain least favorable for patients with no matched family or unrelated donor1. With increasingly sophisticated approaches to graft engineering, T lymphocyte-depleted graft outcomes have been improving, particularly for patients with primary immunodeficiency2. However, good levels of myeloid chimerism are important for durable immune reconstitution, and the additional constituents of the inoculum, additional to the haematopoietic stem cell are important to achieve that3.
Historically, the main concern with outcomes of T lymphocyte-depleted grafts has been the increased risk of viral infection, due to the delayed T lymphocyte immune reconstitution4. For this reason, historically, T lymphocyte-depleted transplants have mainly been used in patients with severe combined immunodeficiencies1. The development and introduction of CD3+TCRαβ+/CD19+ depletion has transformed the use of mismatched donors for transplanting patients with inborn errors of immunity5, 6. Along with other developments in transplantation, including safer conditioning regimens, viral surveillance and pre-emptive treatment, survival outcomes for patients receiving T lymphocyte-depleted grafts are similar to those receiving replete HLA-matched grafts, particularly for patients with severe combined immunodeficiency, and younger patients with other inborn errors of immunity7,8. However, the most significant adverse event, and most common cause of mortality remains viral infection, particularly in older patients8,9. Further strategies are required to improve outcomes in this older group of patients.
1. Gennery, A. R. et al. (2010) J. Allergy Clin. Immunol. 126: 602–10 e1–11.
2. Lankester, A. C. et al. (2021) J. Allergy Clin. Immunol. (in press).
3. Slatter, M. A. et al. (2008) J. Allergy Clin. Immunol. 121: 361–7.
4. Haddad, E. et al. (1998) Blood 91: 3646–53.
5. Lum, S. H. et al. (2021) Bone Marrow Transplant 56: 1200–1204.
6. Balashov, D. et al. (2015) Biol. Blood Marrow Transplant 21: 1955–62.
7. Lum, S. H. et al. (2021) Blood Adv (in press).
8. Elfeky, R. et al. (2019) J. Allergy Clin. Immunol. 144: 280293.
9. Shah, R. M. et al. (2018) J. Allergy Clin Immunol. 141: 1417–1426.e1.
About Andrew Gennery
Professor Andrew Gennery, MBChB, MD, FRCPCH, MRCP, DCH, works at the Translational and Clinical Research Institute, Newcastle University, and is an honorary consultant at the Great North Children’s Hospital, Newcastle upon Tyne, UK, in Paediatric Immunology and Haematopoietic Stem Cell Therapies. His clinical training was in Newcastle and London, and he spent a year working in the laboratory at Necker Hospital, Paris, under Anne Durandy and Alain Fischer, where he was part of the team that discovered the first genetic cause of autosomal recessive hyper IgM, Activation-induced Cytidine Deaminase (AID) Deficiency. He has published widely, with over 360 articles on primary immunodeficiency, treatment and outcomes, as well as chapters in major text books. He has led or co-authored numerous disease-specific consensus statements and management guidelines. He is PID sub-section editor of the Orphanet Journal of Rare Diseases, Associate Editor for Frontiers in Immunology and Editorial Board member of Journal of Clinical Immunology. He is currently paediatric lead on the UKPID Registry Committee, CIBMTR Co-Chair of Primary Immune Deficiencies, Inborn Errors of Metabolism and other NMMD Working Committee, and is working with Public Health England to introduce Newborn Screening for Severe Combined Immunodeficiencies.
Speaker: Marie Bleakley
Allogeneic hematopoietic stem cell transplantation (HCT) represents the best available consolidation therapy for most types of high-risk or relapsed leukemia and is curative for many patients. However, current approaches to HCT are frequently complicated by leukemic relapse and/or by the development of severe or chronic graft-versus-host disease (GVHD). GVHD involves an immune-mediated attack on host tissues involving donor T cells, other immune cells and cytokines and results in a frequently debilitating, sometimes life-threatening, multi-system illness.
Furthermore, the development of GVHD generally necessitates treatment with pharmacological immunosuppression, which may preclude the effective implementation of adoptive T cell immunotherapy to prevent and treat relapse of leukemia. Complete depletion of T cells (TCD) from hematopoietic stem cell grafts is effective in preventing GVHD in animal and humans. However, recipients of TCD HCT are vulnerable to opportunistic infections and related complications. Development of new HCT strategies that involve selective depletion of T cells responsible for GVHD whilst preserving T cells specific for opportunistic infections may lead to improved HCT outcomes. In murine models of GVHD the infusion of bone marrow with naive T (Tn) cells or unseparated splenocytes leads to severe GVHD whilst the infusion of bone marrow with effector or central memory T cells result in no GVHD, or milder GVHD respectively. In in vitro experiments using human T cells we demonstrated that the naive CD8+ T cell population contains significantly more T cells that specifically respond to minor histocompatibility antigens, the molecular targets of alloreactive T cells in HLA-identical HCT.
About Marie Bleakley
Marie Bleakley, MD, PhD, received her medical degree, master’s degree and PhD in Australia and completed post-graduate training in pediatric oncology and bone marrow transplantation (BMT) in Australia and Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, USA. She is currently an Associate Professor of Pediatrics at the University of Washington and Associate Member of FHCRC where she conducts translational research in the Program in Immunology and attends on the pediatric BMT service. Dr. Bleakley’s major research interests include the development of new immunotherapies and transplant strategies to prevent leukemic relapse and graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (HCT).
Speaker: Luca Castagna
Allogeneic stem cell transplantation from haploidentical donor using post-transplantation
cyclophosphamide has been employed to cure hematological diseases. Due to slow immunological reconstitution, there is an increased incidence of viral infection. The aim of our study was to prospectively evaluate the efficacy and the feasibility of a CD45RA+ depleted donor lymphocytes infusion (DLI) in terms of reduction of viral infection early after haploidentical transplantation.
This was a prospective single center study. We enrolled 23 patients, of whom 19 were evaluable. GVHD prophylaxis were the same for all patients, consisting of post-transplantation cyclophosphamide, cyclosporine A, and MMF. The primary end point was 100-day cumulative incidence of viral infections. The primary endpoint was met, since the 100-day cumulative incidence of viral infection was 32%. The median time from transplantation to first CD45RA+ depleted DLI was 55 days (range 46–63). 28% of patients had CMV reactivation, no patients reactivated HHV6; 1 patient developed BK virus related hemorrhagic cystitis. Most of the patients received the planned 3 infusions. Only 1 patient developed grade 2 acute GVHD and 2 patients moderate chronic GVHD. All evaluable patients were off immunosuppressive therapy at last follow-up.
With a median follow-up was 12 months (range 3–23), the 1-y OS and PFS was 79% and 75%, respectively; the 100-day and 1-y NRM were 5% and 12%, respectively. CD45RA+ depleted DLI are feasible in patients treated with haploidentical transplantation. The toxic profile is good with a low risk to develop GVHD, both acute and chronic.
About Luca Castagna
Dr. Luca Castagna is Chief of the Transplantation program in the Ospedale Cervello, Palermo, Italy. Graduate of the University of L’Aquila, he has a postgraduate degree in Oncology at University of Chieti, Italy, and in Hematology at Milan University, Italy. Dr. Castagna spent many years in the Hematology Department of Institut Gustave Roussy, Paris, France, as a senior assistant. More recently, he co-worked actively with the Bone Marrow Unit of Institut Paoli Calmettes, Marseille, France, on the development of a new and more adapted conditioning regimen. In recent years, his research has been focused on haploidentical transplantation using T-replete bone marrow and post-infusion cyclophosphamide in patients with advanced Hodgkin and non-Hodgkin lymphoma.
Speaker: Michael Maschan
Graft-versus-host disease (GVHD) remains the major obstacle to the success of HSCT. The negative impact of GVHD increases significantly with less compatible grafts, derived from matched unrelated donors (MUD) and haploidentical donors. Profound ex vivo T cell depletion of the graft was developed as the most reliable method of GVHD prevention, but this approach also holds significant risks, of which poor engraftment and severe infections are the most notable ones. Since 2012, our group has been using TCRα/β+ T cell and CD19 depletion as a principal GVHD prophylaxis method in haploidentical and MUD transplantation.
At the time of this report, more than 900 transplantations have been performed in pediatric patients suffering from malignant and non-malignant diseases. We were able to show that outcomes of HSCT from haploidentical related donors are not different and, under certain circumstances, may even exceed the results of HSCT from unrelated donors. Further improvement of the platform was based on the use of donor-derived memory T cells (CD45RA–depleted) in an attempt to boost the recovery of pathogen-specific immunity. We have shown that use of low-dose memory DLI is safe after engraftment and may provide functional virus-specific immune responses. Optimization of the pharmacological component of the GVHD prophylaxis resulted in a steady improvement of GVHD control, with a 10% cumulative incidence of clinically significant GVHD and <3% incidence of non-relapse mortality. Since 2018 an investigator-initiated clinical trial of CD19 CAR T cells, manufactured at the point-of-care, was run in a cohort of children with relapsed/refractory B-ALL. Clinical application of CD19 CAR-T cells was refined based on locally generated data on toxicity, immediate efficacy and long-term outcome.
About Michael Maschan
Michael Maschan, MD, PhD, is the Scientific Director of the Hematopoietic Stem Cell Transplantation Department of the Dmitry Rogachev National Medical Center for Pediatric Hematology, Oncology, and Immunology in Moscow, Russia. He received his training in Pediatrics and Pediatric Hematology at the Russian State Medical University. In 2011, he was awarded a doctoral degree for his thesis on histiocytic proliferative disorders in children. He is a member of the Histiocyte Society, the EBMT, and the American Society of Hematology. Currently, his transplant-related research is focused on the clinical study of graft manipulation in pediatric hematopoietic stem cell transplantation (HSCT), novel therapeutic approaches to leukemia control after transplantation, and cancer therapy based on gene-modified T cells.
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