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Axicabtagene ciloleucel (YESCARTA; Kite Pharma, a Gilead Company, Los Angeles CA) and tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp., Basel, Switzerland) are two CD19-directed chimeric antigen receptor (CAR) T cell products currently approved by the US Food and Drug Administration; the European Medicines Agency; Health Canada; Ministry of Health, Labor and Welfare (Japan); and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL). Although this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate use of this novel therapy and of short- and long-term toxicities. To address these issues, representatives of the American Society of Transplantation and Cellular Therapy convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts. The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the use of CD19 CAR T cell products for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Viral infections can be life threatening in patients with severe combined immunodeficiency (SCID) and other forms of profound primary immunodeficiency disorders both before and after hematopoietic stem cell transplantation (HSCT). Adoptive immunotherapy with virus-specific T cells (VSTs) has been utilized in many patients in the setting of HSCT, but has very rarely been attempted for treatment of viral infections before HSCT. Here we describe the use of VSTs in an infant with RAG1 SCID who had developed disseminated adenovirus which failed to improve on cidofovir. Adenovirus cleared following 2 doses of VSTs and marrow infusion from a matched unrelated donor, without incidence of graft versus host disease. T cell receptor-b sequencing demonstrated expansion of adenovirus-specific T cell fraction of the VSTs, suggesting that infusion facilitated viral clearance. This report suggests that VSTs are likely safe in the pre-HSCT period, and may be a useful bridge therapy for infants with SCID and persistent viral infections., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Virus infection remains an appreciable cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although pharmacotherapy and/or antibody therapy may help prevent or treat viral disease, these drugs are expensive, toxic, and often ineffective due to primary or secondary resistance. Further, effective treatments are limited for many infections (eg, adenovirus, BK virus), which are increasingly detected after alternative donor transplants. These deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders, leading to adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs), which can rapidly reconstitute antiviral immunity post-transplantation without causing graft-versus-host disease. This review will explore how the VST field has improved outcomes for many patients with life-threatening viral infections after HSCT, and how to broaden applicability beyond the "patient-specific" products, as well as extending to other viral diseases even outside the context of HSCT., (Copyright © 2018. Published by Elsevier Inc.)

Virus infection remains an appreciable cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although pharmacotherapy and/or antibody therapy may help prevent or treat viral disease, these drugs are expensive, toxic, and often ineffective due to primary or secondary resistance. Further, effective treatments are limited for many infections (eg, adenovirus, BK virus), which are increasingly detected after alternative donor transplants. These deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders, leading to adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs), which can rapidly reconstitute antiviral immunity post-transplantation without causing graft-versus-host disease. This review will explore how the VST field has improved outcomes for many patients with life-threatening viral infections after HSCT, and how to broaden applicability beyond the "patient-specific" products, as well as extending to other viral diseases even outside the context of HSCT., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (HSCT) can potentially cure human immunodeficiency virus (HIV) by eliminating infected recipient cells, particularly in the context of technologies that may confer HIV resistance to these stem cells. But, to date, the Berlin patient remains the only case of HIV cure despite multiple attempts to eradicate infection with HSCT. One approach to improve this is to administer virus-specific T cells, a strategy that has proven success in preventing other infections after transplantation. Although we have reported that broadly HIV-specific T cells can be expanded from HIV+ patients, allogeneic transplantations only contain virus-naïve T cells. Modifying this approach for the allogeneic setting requires a robust, reproducible platform that can expand HIV-specific cells from the naïve pool. Hence, we hypothesized that HIV-specific T cells could be primed ex vivo from seronegative individuals to effectively target HIV. Here, we show that ex vivo-primed and expanded HIV-specific T cells released IFNγ in response to HIV antigens and that these cells have enhanced ability to suppress replication in vitro. This is the first demonstration of ex vivo priming and expansion of functional, multi-HIV antigen-specific T cells from HIV-negative donors, which has implications for use of allogeneic HSCT as a functional HIV cure., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Cord blood transplantation (CBT) is curative for many patients with hematologic malignancies but is associated with delayed immune recovery and an increased risk of viral infections compared with HLA-matched bone marrow or peripheral blood progenitor cell transplantation. In this study we evaluated the significance of lymphocyte recovery in 125 consecutive patients with hematologic malignancies who underwent double-unit CBT (DUCBT) with an antithymocyte globulin-containing regimen at our institution. A subset of 65 patients was prospectively evaluated for recovery of T, natural killer (NK), and B cells, and in 46 patients we also examined viral-specific T cell recovery against adenovirus, Epstein-Barr virus, cytomegalovirus, BK virus, respiratory syncytial virus, and influenza antigen. Our results indicate that in recipients of DUCBT, the day 30 absolute lymphocyte count is highly predictive of nonrelapse mortality and overall survival. Immune recovery post-DUCBT was characterized by prolonged CD8+ and CD4+ T lymphopenia associated with preferential expansion of B and NK cells. We also observed profound delays in quantitative and functional recovery of viral-specific CD4+ and CD8+ T cell responses for the first year post-CBT. Taken together, our data support efforts aimed at optimizing viral-specific T cell recovery to improve outcomes post-CBT., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some nonmalignant disorders, some critical obstacles remain to be overcome, including relapse, engraftment failure, graft-versus-host disease (GVHD), and infection. Harnessing the immune system to induce a graft-versus-tumor effect or rapidly restore antiviral immunity through the use of donor lymphocyte infusion (DLI) has been remarkably successful in some settings. Unfortunately, however, the responses to DLI can be variable, and GVHD is common. Thus, manipulations to minimize GVHD while restoring antiviral immunity and enhancing the graft-versus-tumor effect are needed to improve outcomes after allogeneic HSCT. Cellular therapies, defined as treatment modalities in which hematopoietic or nonhematopoietic cells are used as therapeutic agents, offer this promise for improving outcomes post-HSCT. This review presents an overview of the field for pediatric cell therapies in the transplant setting and discusses how we can broaden applicability beyond phase I., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

In a retrospective study, we evaluated the cost and cost-effectiveness of allogeneic peripheral blood stem cell transplantation (PBSCT) (n = 30) compared with bone marrow transplantation (BMT) (n = 110) in children with acute leukemia after 1 year of follow-up. Treatment success was defined as disease-free survival at 1 year posttransplantation. For patients at standard risk for disease, the treatment success rate was 57.1% for PBSCT recipients and 80.3% for BMT recipients (P = not significant [NS]). The average total cost per treatment success at 1 year in the standard-risk disease group was $512,294 for PBSCT recipients and $352,885 for BMT recipients (P = NS). For patients with high-risk disease, the treatment success rate was 18.8% for PBSCT recipients and 23.5% for BMT recipients (P = NS). The cumulative average cost was $457,078 in BMT recipients and $377,316 in PBSCT recipients (P = NS). Point estimates of the incremental cost-effectiveness ratio (ICER) indicate that in patients with standard-risk disease, allogeneic BMT had lower costs and greater effectiveness than PBSCT (ICER, -$687,108; 95% confidence interval [CI], $2.4 million to dominated). For patients with high-risk disease, BMT was more effective and more costly, and it had an ICER of $1.69 million (95% CI, $29.7 million to dominated) per additional treatment success. The comparative economic evaluation provides support for BMT in standard-risk patients, but much uncertainty precludes a clear advantage of either treatment option in patients with high-risk disease. More studies using larger and randomized controlled trials are needed to confirm the long-term cost-effectiveness of each procedure., (Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Graft failure is a significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). We used a nonmyeloablative conditioning regimen consisting of the lympho-depleting humanized CD52-antibody Campath-1H and fludarabine to rescue 12 consecutive children age 9 months to 17 years with engraftment failure after initial myeloablative HSCT. Primary diagnoses included lymphohematologic malignancies (n=6), severe combined immunodeficiency syndrome (SCID) (n=4), and metabolic diseases (n=2). The same stem cell donor was used as for the primary graft: mismatched family member (n=7), matched unrelated donor (n=4), or matched related donor (n=1). The patients received doses of CD34+ cells that did not significantly differ from those used in the initial, failed transplant. At a median follow-up of 51 months (range, 4 to 84 months), 6 of 6 patients with nonmalignant diseases and 4 of 6 patients with malignancy were alive. Two patients died, 1 patient from pulmonary toxicity and 1 from relapse, at 51 days and 8 months posttransplantation, respectively. All 12 patients initially achieved sustained neutrophil engraftment and complete donor chimerism by day 28. Six patients received donor lymphocyte infusion (DLI) after "rescue" therapy to maintain donor chimerism. At 6 months, 4 patients had complete donor cell engraftment, 4 had 15% to 89% stable donor chimerism, and 3 had developed secondary graft failure. This conditioning regimen was generally well tolerated; 4 of the 12 patients never became neutropenic, and 9 never became thrombocytopenic. Only 1 patient developed graft-versus-host disease (GVHD; grade 1), and none had chronic GVHD. Thus, the regimen that we describe can be used with minimal toxicity to effectively overcome graft failure after myeloablative HSCT in children.

HLA-matched sibling donor (MSD) stem cell transplantation can cure>60% of pediatric patients with acute lymphoblastic leukemia (ALL), but <30% of patients will have a sibling donor. Alternative donor (AD) transplantation can be curative but has a higher risk of graft-versus-host disease (GVHD). The addition of alemtuzumab (Campath 1-H) to AD transplants produces in vivo T cell depletion, which may reduce the risk for GVHD. We now report the outcome for 83 children with ALL (41 MSD, 42 AD) undergoing stem cell transplantation in first or second complete remission. All patients received myeloablative conditioning, including cyclophosphamide, cytarabine arabinoside, and total-body irradiation, with alemtuzumab administered to AD recipients. GVHD prophylaxis consisted of a calcineurin inhibitor with either short-course methotrexate or prednisone. Disease-free survival (DFS) for MSD recipients was 72.3% (95% confidence interval [CI], 55.4%-83.6%) versus 62.4% (95% CI, 45.2%-75.4%) for AD recipients. The 100-day mortality was 7.1% in the AD group and 2.4% in the MSD group. Relapse rates were identical (24%). Treatment-related mortality, principally viral infection, explained the difference in survival. For children undergoing stem cell transplantation (SCT) from alternative donors, alemtuzumab with a myeloablative conditioning regimen resulted in DFS comparable to MSD.

Matched sibling donor (MSD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia (SAA); however, only about 33% of patients will have an HLA-identical sibling. Alternative donor (AD) transplants may be an option for these patients, but such therapies have been associated with greater incidence of graft failure and graft-versus-host disease (GVHD). We retrospectively analyzed 36 pediatric patients who received 38 bone marrow or peripheral blood stem cell transplants (15 MSD and 23 AD) for SAA at our institution from April 1997 to October 2005. Nineteen AD recipients received reduced intensity conditioning with cyclophosphamide, low-dose total body irradiation, and antithymocyte globulin (ATG) or Campath. The 4-year overall survival for MSD recipients was 93% versus 89% for AD recipients treated with reduced intensity conditioning regimens at a median follow-up of 52 months (range, 6-99 months). No patient receiving Campath, compared with 3 of 9 patients receiving ATG, developed extensive, chronic GVHD. We conclude that, for children with SAA, AD transplantation is as effective as MSD transplantation. Further, compared with ATG, preparatory regimens containing Campath may be associated with a lower incidence of extensive, chronic GHVD.

Adenoviruses are lytic DNA viruses that are ubiquitous in human communities. In total, 51 different serotypes with varying tissue tropisms have been identified. Adenovirus infections, although frequent, are rarely fatal in immunocompetent individuals who have potent innate and adaptive immunity. But in immunosuppressed individuals, adenoviruses are a significant cause of morbidity and mortality, with limited treatment options. In particular, pediatric recipients of allogeneic hematopoietic stem cell transplantation frequently develop infections early in the posttransplantation period. Because the endogenous recovery of adenovirus-specific T cells has proven important in controlling infection, we explore the potential of adoptive T-cell immunotherapy as a therapeutic strategy. We discuss the advantages and limitations of T-cell therapy for the prophylaxis and treatment of adenovirus infection posttransplantation.

Viral diseases are a major cause of morbidity and mortality after hemopoietic stem cell transplantation. Because viral complications in these patients are clearly associated with the lack of recovery of virus-specific cellular immune responses, reconstitution of the host with in vitro expanded cytotoxic T lymphocytes is a potential approach to prevent and treat these diseases. Initial clinical studies of cytomegalovirus and Epstein-Barr virus in human stem cell transplant patients have shown that adoptively transferred donor-derived virus-specific T cells may restore protective immunity and control established infections. Preclinical studies are evaluating this approach for other viruses while strategies for generating T cells specific for multiple viruses to provide broader protection are being evaluated in clinical trials. The use of genetically modified T cells or the use of newer suicide genes may result in improved safety and efficacy.