The Graft-Versus-Leukemia Effect in AML

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the most established and commonly used cellular immunotherapy in cancer care. It is the most potent anti-leukemic therapy in patients with acute myeloid leukemia (AML) and is routinely used with curative intent in patients with intermediate and poor risk disease. Donor T cells, and possibly other immune cells, eliminate residual leukemia cells after prior (radio)chemotherapy. This immune-mediated response is known as graft-versus-leukemia (GvL). Donor alloimmune responses can also be directed against healthy tissues, which is known as graft-versus-host disease (GvHD). GvHD and GvL often co-occur and, therefore, a major barrier to exploiting the full immunotherapeutic benefit of donor immune cells against patient leukemia is the immunosuppression required to treat GvHD. However, curative responses to allo-SCT and GvHD do not always occur together, suggesting that these two immune responses could be de-coupled in some patients. To make further progress in successfully promoting GvL without GvHD, we must transform our limited understanding of the cellular and molecular basis of GvL and GvHD. Specifically, in most patients we do not understand the antigenic basis of immune responses in GvL and GvHD. Identification of antigens important for GvL but not GvHD, and vice versa, could impact on donor selection, allow us to track GvL immune responses and begin to specifically harness and strengthen anti-leukemic immune res...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research

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This article reviews the current landscape of antibody-based and cellular immunotherapies under current clinical evaluation with an emphasis on active or soon-to-open phase 1 trials for children with relapsed/refractory AML. PMID: 31808843 [PubMed - in process]
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
Conclusion Several TISC-based immunotherapeutic approaches are under development in various stages of preclinical studies. As outlined in this review article, a careful and more exhaustive genetic and metabolic understanding of TISC-associated phenotypes is critical to develop novel TISC based immunotherapies. Various components within the tumor microenvironment such as tumor cells, infiltrating immune cells, and supporting stromal cells impact the TISC metabolism. This unique metabolic profile leads to upregulation of certain enzymes and proteins such as ALDH1, CEP55, IDO COA1 etc., which can be utilized for development ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In this study we analyzed the outcome of all the patients that were referred to our center from January 1st 2007 to May 31st 2018 with a diagnosis of AML with complex karyotype and/or monosomy 7/del(7q) and that were fit for receiving an induction treatment.49 patients were included. Median age at diagnosis was 52; 22 were female, 27 were male. 20/49 had chromosome 7 abnormalities (isolated in 12 patients; in a complex karyotype in 8 patients). 11 patients received a hypomethylating agent as first line treatment, while the other 38 patients received high-dose chemotherapy. We performed 30 HSCT procedures in 25 patients; 5 ...
Source: Blood - Category: Hematology Authors: Tags: 732. Clinical Allogeneic Transplantation: Results: Poster I Source Type: research
Our group developed a 161533 trispecific killer engager (TriKE) molecule to target acute myeloid leukemia (AML) cells using Natural Killer (NK) cells. This molecule contains an anti-CD16 camelid nanobody to activate NK cells, an anti-CD33 single chain variable fragment (scFv) to engage cancer targets, and an IL-15 molecule that drives NK cell priming, expansion and survival. Using an earlier version of this molecule, we have shown that the CD33 TriKE is effective at activating NK cells against AML targets in vitro and in vivo. This preclinical data has lead to the establishment of a clinical trial in refractory AML patient...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I Source Type: research
Acute myeloid leukemia (AML) blasts and leukemia stem cells highly express the α chain of the IL-3 receptor (CD123), compared to normal hematopoietic stem cells. CD123 expression is associated with high-risk features, increased risk of induction failure and poor prognosis (Vergez F, et al. Haematologica 2011 96: 1792-8). Flotetuzumab (FLZ), a CD123 x CD3 bispecific DART molecule, is being tested in a phase 1/2 study in patients with relapsed/refractory (R/R) AML.The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day (d) administered as a 7-day/week continuous infusion. Patients receive a lead-in dose (30 ng/kg/d...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: New Treatment Strategies Source Type: research
Despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT), the outcome of children with relapsed acute lymphoblastic leukemia (ALL) has not significantly improved over the last 2 decades. About 50% of children with relapsed leukemia still die from their disease and ALL is still the first cause of death by cancer in children. A new hope of cure for patients with chemo-resistant cancers has emerged with the development of cancer immunotherapy. However, the major risk of post-transplant immunotherapy is the exacerbation of life-threatening Graft-versus-Host Disease (GvHD) mediated by donor-derived T ...
Source: Blood - Category: Hematology Authors: Tags: 703. Adoptive Immunotherapy: Poster I Source Type: research
We presently forget 98% of everything we experience. That will go away in favor of perfect, controllable, configurable memory. Skills and knowledge will become commodities that can be purchased and installed. We will be able to feel exactly as we wish to feel at any given time. How we perceive the world will be mutable and subject to choice. How we think, the very fundamental basis of the mind, will also be mutable and subject to choice. We will merge with our machines, as Kurzweil puts it. The boundary between mind and computing device, between the individual and his or her tools, will blur. Over the course of the ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study, we have shown that the lipid chaperones FABP4/FABP5 are critical intermediate factors in the deterioration of metabolic systems during aging. Consistent with their roles in chronic inflammation and insulin resistance in young prediabetic mice, we found that FABPs promote the deterioration of glucose homeostasis; metabolic tissue pathologies, particularly in white and brown adipose tissue and liver; and local and systemic inflammation associated with aging. A systematic approach, including lipidomics and pathway-focused transcript analysis, revealed that calorie restriction (CR) and Fabp4/5 deficiency result ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
This study aims to quantify the associations of hematological malignancies and solid cancers with red cell alloimmunization in patients receiving red cell transfusions. We performed a nested multicenter case-control study in a source population of 24,063 patients receiving their first and subsequent red cell transfusions during an eight year follow-up period. Cases (N=505), defined as patients developing a first transfusion-induced red cell alloantibody, were each compared with two non-alloimmunized controls (N=1,010) who received a similar number of red cell units. Using multivariate logistic regression analyses, we evalu...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
ee DA Abstract Cell therapy is a promising alternative to harsh chemotherapy and radiation therapy for cancer. Natural killer (NK) cells in particular have great potential for direct use in adoptive immunotherapy (AI) for cancer and to improve the graft-vs-leukemia (GVL) effect of hematopoietic stem cell transplants (HSCTs). NK cell number and function are associated with a strong GVL effect without inducing graft-versus-host disease in most settings. Clinical trials demonstrating the therapeutic role of NK cells in HSCT recipients or testing the safety and efficacy of AI with NK cells have been primarily directed...
Source: Clinical Immunology - Category: Allergy & Immunology Authors: Tags: Clin Immunol Source Type: research
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