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Allogeneic Hematopoietic Stem Cell Transplantation for Autoimmune Diseases
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Shimon Slavin, Alberto Marmont, Richard K. Burt
In addition to replacement of host stem cells which may be genetically resistant to development of a particular autoimmune disorder, an unselected allogeneic graft may provide additional potential immunotherapy against self-reactive lymphocytes that may survive the chemoradiotherapy conditioning regimen. This has been termed a graft versus autoimmune (GVA) effect, theoretically mediated by donor lymphocytes. It is therefore important to understand the principles of immunotherapy of leukemia, including elimination of malignant lymphocytes by donor T-cells through a process termed graft versus leukemia (GVL), as a model for the feasibility of GVA by alloreactive donor T cells.10 We and others have established the feasibility of inducing remission of a relapsed malignancy following allogeneic HSCT by donor lymphocyte infusion (DLI).11,12 The data suggests that the major therapeutic component of allogeneic HSCT can be attributed to immunocompetent donor T lymphocytes recognizing and eliminating tumor cells of host origin. Closely similar effects have been observed following allogeneic HSCT in coincident autoimmune diseases.8,13 In addition, a parallism between the insurgence of GVHD and the achievement of complete remission was reported after allogeneic SCT for refractory Evans syndrome.14 In a similar case, the reinduction of complete clinical and immune remission was achieved following a series of DLI.15,16
Active Specific Immunization by the Use of Leukemic Dendritic Cell Vaccines
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Ilse Houtenbos, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht
Although intensive chemotherapy-based approaches induce complete remission (CR) in 80% of patients with acute myeloid leukemia (AML), still a lot of patients ultimately relapse because of persistence of minimal residual disease (MRD) cells, resulting in survival percentages of 30% to 40% (2). Immunotherapy for leukemia patients, aiming at the generation of antileukemic T-cell responses could provide a new therapeutic approach in eliminating MRD cells in leukemia (3,4). Considerable data point out the critical role played by T-cell immunity in the control of leukemia. Most well known is the reinduction of CR after donor lymphocyte infusion (DLI) for patients with relapsed leukemia after allogeneic stem cell transplantation (5,6). T cells present in DLI are held responsible for this graft-versus-leukemia effect. Already in the early 1970s, it was shown that a combination of chemotherapy and immunotherapy, consisting of vaccination with irradiated autologous AML blasts, resulted in an increased survival of patients as compared with treatment with chemotherapy alone (7). More recent data emphasize a possible role for immunotherapy in the eradication of MRD cells, by exploring vaccination strategies (8–11).
Graft versus host disease
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Sandeep Arora, Sandeep Lal, Manasa Shettisara Janney
Graft versus host disease (GVHD) is a multisystem disorder that occurs most commonly after allogenic hematopoietic stem cell transplantation (ASCT). It is also observed in transfusion of nonirradiated blood to an immunocompromised host (Wiskott-Aldrich syndrome, ataxia telangiectasia) [1], in donor lymphocyte infusion, solid organ transplant [2], umbilical cord blood transplant, and maternofetal transfusion (Table 53.1). GVHD mirrors allograft rejection caused by the immunocompetent alloreactive donor T lymphocytes that recognize the minor or major histocompatibility antigens on the target tissue of the host, leading to multiorgan involvement. In short, GVHD is a host rejection by the graft. Skin is the earliest and the most common organ to be affected in GVHD. Recognition and treatment of various manifestations of GVHD remain a challenge in transplant medicine, a field that is now being practiced routinely in all major centers across the country.
Chimeric antigen receptor T cell therapy for pediatric and young adult B cell acute lymphoblastic leukemia
Published in Expert Review of Clinical Immunology, 2020
Regina M. Myers, Joseph Dolan, David T. Teachey
Treatment of tumors using directed T cells began in the 1980s with the application of autologous tumor-infiltrating lymphocytes (TILs) infused to treat melanoma and allogenic T cells to treat relapsed leukemia. Early experiments attempted to identify and select T cells with maximal anti-tumor effect. Rosenberg and colleagues used a selection process to collect TILs with improved in vitro anti-tumor effect [24]. In conjunction with cyclophosphamide and Interleukin-2 (IL-2), TILs were able to demonstrate anti-tumor effect in 50% of patients with melanoma [25]. In the 1990s, donor lymphocyte infusion in the absence of additional chemotherapy was shown to have an anti-tumor effect in patients who had received a bone marrow transplant for CML [26]. Donor lymphocyte infusion has since been described by numerous studies and is commonly utilized in bone marrow transplant. These early studies demonstrated proof of concept that immune surveillance could be improved using select allogeneic lymphocytes.
Advancing treatment of acute myeloid leukemia: the future of FLT3 inhibitors
Published in Expert Review of Anticancer Therapy, 2019
Amro Elshoury, Amanda Przespolewski, Jeffrey Baron, Eunice S. Wang
Because RR-AML is usually considered a monoclonal disease, combinations of highly selective second-generation FLT3 inhibitors with HMA may also be efficacious in this setting. Moreover, combination FLT3 TKI and HMA therapy following alloSCT offers the potential for both agents to synergize with post-transplant allo-immune effects. FLT3 mutant AML patients experiencing disease relapse after alloSCT typically have limited therapeutic options as their disease is usually rapidly proliferating, and patients often are intolerant of intensive chemotherapy. Rautenberg et al. treated eight patients with relapsed FLT3 mutant AML following alloSCT with Aza and sorafenib (doses ranging from 400 to 800 mg) for a median of 129 days (range 61–221 days) [47]. Six patients subsequently received donor lymphocyte infusion (DLI) with a median of 2 DLI per patient. Combining FLT3 inhibitors with Aza and DLI resulted in CR in four patients (3 molecular CR) with a median OS of 322 days. A phase III study of gilteritinib (120 mg) in FLT3 mutant RR-AML after frontline therapy with or without prior alloSCT is currently accruing (NCT02421939).
Hematopoietic stem cell transplant with HLA-mismatched grafts: impact of donor, source, conditioning, and graft versus host disease prophylaxis
Published in Expert Review of Hematology, 2019
Leland Metheny, Marcos de Lima
Haplo-identical grafts are obtained from related donors that are identically matched at one haplotype of the recipient; examples of which include parents, children, and siblings. By allowing for greater HLA disparity, they increase the pool of potential donors for patients without an MSD or MUD. Initially, haplo-identical transplants using cyclosporine and methotrexate (MTX) GVHD prophylaxis were associated with unacceptable rates of GVHD, graft rejection, and TRM [42]. Modern haplo-identical transplants utilize either post-transplant cyclophosphamide (Post-Cy) [43], intensive immune-suppression [44], or T-cell depletion [45–47], which have resulted in acceptable GVHD rates, TRM, and OS. In fact, retrospective analyses have demonstrated that haplo-identical transplant has similar OS when compared to MUD transplant [43,48–50]. Haplo-identical donors are attractive options for a number of reasons including ease of search, selection, and control of cellular dose [1], which is a major limitation of CBT. In addition, donors are usually available for post-transplant cellular interventions such as donor lymphocyte infusion, as opposed to when transplanted cells were obtained from CB.