Bilateral maxillary, sphenoid sinuses and lumbosacral spinal cord extramedullary relapse of CML following allogeneic stem cell transplant

Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. There is a case report of a child who developed a granulocytic sarcoma of the maxillary and sphenoid sinuses and lumbosacral spinal cord mass 18 months after allogeneic bone marrow transplant for CML. He was presented with per orbital edema and neurological deficit of lower extremities and a mass lesion was found on spinal cord imaging. No evidence of hematologic relapse was identified at that time by bone marrow histology or cytogenetic. The patient died 1 month later with a picture of pneumonia, left ventricular dysfunction and a cardiopulmonary arrest on a presumed underlying sepsis with infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic bone marrow transplantation for CML, even if there is no evidence of bone marrow involvement. © 2016, Tehran University of Medical Sciences (TUMS). All Rights Reserved

HSP70/IL-2 treated NK cells effectively cross the blood brain barrier and target tumor cells in a rat model of induced glioblastoma multiforme (GBM)

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein 70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intracranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2-treated NK cells as compared to those subjected to nontreated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2-treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Glioblastoma cancer stem cell biology: Potential theranostic targets

Glioblastoma multiforme (GBM) is among the most incurable cancers. GBMs survival rate has not markedly improved, despite new radical surgery protocols, the introduction of new anticancer drugs, new treatment protocols, and advances in radiation techniques. The low efficacy of therapy, and short interval between remission and recurrence, could be attributed to the resistance of a small fraction of tumorigenic cells to treatment. The existence and importance of cancer stem cells (CSCs) is perceived by some as controversial. Experimental evidences suggest that the presence of therapy-resistant glioblastoma stem cells (GSCs) could explain tumor recurrence and metastasis. Some scientists, including most of the authors of this review, believe that GSCs are the driving force behind GBM relapses, whereas others however, question the existence of GSCs. Evidence has accumulated indicating that non-tumorigenic cancer cells with high heterogeneity, could undergo reprogramming and become GSCs. Hence, targeting GSCs as the �root cells� initiating malignancy has been proposed to eradicate this devastating disease. Most standard treatments fail to completely eradicate GSCs, which can then cause the recurrence of the disease. To effectively target GSCs, a comprehensive understanding of the biology of GSCs as well as the mechanisms by which these cells survive during treatment and develop into new tumor, is urgently needed. Herein, we provide an overview of the molecular features of GSCs, and elaborate how to facilitate their detection and efficient targeting for therapeutic interventions. We also discuss GBM classifications based on the molecular stem cell subtypes with a focus on potential therapeutic approaches. © 201

Glioblastoma cancer stem cell biology: Potential theranostic targets

Glioblastoma multiforme (GBM) is among the most incurable cancers. GBMs survival rate has not markedly improved, despite new radical surgery protocols, the introduction of new anticancer drugs, new treatment protocols, and advances in radiation techniques. The low efficacy of therapy, and short interval between remission and recurrence, could be attributed to the resistance of a small fraction of tumorigenic cells to treatment. The existence and importance of cancer stem cells (CSCs) is perceived by some as controversial. Experimental evidences suggest that the presence of therapy-resistant glioblastoma stem cells (GSCs) could explain tumor recurrence and metastasis. Some scientists, including most of the authors of this review, believe that GSCs are the driving force behind GBM relapses, whereas others however, question the existence of GSCs. Evidence has accumulated indicating that non-tumorigenic cancer cells with high heterogeneity, could undergo reprogramming and become GSCs. Hence, targeting GSCs as the �root cells� initiating malignancy has been proposed to eradicate this devastating disease. Most standard treatments fail to completely eradicate GSCs, which can then cause the recurrence of the disease. To effectively target GSCs, a comprehensive understanding of the biology of GSCs as well as the mechanisms by which these cells survive during treatment and develop into new tumor, is urgently needed. Herein, we provide an overview of the molecular features of GSCs, and elaborate how to facilitate their detection and efficient targeting for therapeutic interventions. We also discuss GBM classifications based on the molecular stem cell subtypes with a focus on potential therapeutic approaches. © 201

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?—A multicenter EBMT-PDWP study

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.Transplantation and immunomodulatio

One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCT were reported by 1,662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous HCT and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCT were performed by 2019 since 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCT were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCT are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated HCT is plateauing and cord blood HCT is in decline

A VHH-based anti-MUC1 chimeric antigen receptor for specific retargeting of human primary T cells to MUC1-positive cancer cells

Objective: Immunotherapy with redirected T cells that express a chimeric antigen receptor (CAR) is a promising prospect in cancer treatment. Most CARs use murine-derived single-chain variable fragments (scFvs) as an antigen targeting moiety, which may lead to host immunogenic responses and engineered T cell disappearance. It seems that development of less immunogenic CARs, such as CARs composed of the camelid variable domain of heavy chain antibodies (VHHs) may likely overcome this obstacle. Here, we improved the expression of the VHH-based anti-MUC1 CAR gene construct using a third generation lentiviral vector in primary human T cells and assessed its effect on antigen specific targeting, activation and cytotoxicity of redirected human T cells. Materials and Methods: In this experimental study, we established a second generation novel CAR (VHH-based anti-MUC1 CAR) that contained a camelid-derived anti-MUC1 VHH followed by an IgG3 hinge, a CD28 transmembrane domain and signalling endodomains of CD28 and CD3æ. Next, we constructed lentiviral vectors that contained this CAR gene construct using an optimized transiently virus production method and transduced it into human T cells. Cell surface expression of CAR, cytokine secretion and cytotoxic activity were assessed in the transduced CD3+ T cells. Results: The transduced T cells had high levels of surface expression of CAR. T cells that expressed anti-MUC1 CAR showed significantly increased secretion of Th1 cytokines, including IL-2, TNF alpha and IFN-γ, as well as cytotoxic activity upon recognition of MUC1 on tumour cells after co-incubation with T47D or MCF-7 (MUC1-positive) compared with A431 (MUC1-negative) or untransduced T cells. Conclusion: Our results suggested that, given the unique properties of VHHs to prevent immunogenic responses and tonic signalling, our novel VHH-based anti-MUC1 CAR might be effective for clinical purposes in cancer immunotherapy. © 2021 Royan Institute (ACECR). All rights reserved

Radiation-Free myeloablative allogeneic hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia: A comparison of outcomes between patients with and without central nervous system involvement

For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), total body irradiation (TBI) has been particularly advocated as a part of the conditioning regimen in case of extramedullary involvement in sanctuary sites such as the central nervous system (CNS), to ensure greater tissue penetration. In resource-limited countries lacking TBI facilities; however, ALL patients undergo radiation-free myeloablative conditioning, though its impacts on post-HSCT outcomes of the patients with pre-HSCT CNS involvement have not been analyzed. In this 14-year series of 278 adult (> 18 y) ALL patients undergoing TBI-free busulfan/cyclophosphamide conditioning allo-HSCT, we found that the long-term probabilities of overall survival, disease free survival, relapse and non-relapse mortality were not significantly different between CNS-involved and CNS-spared patients. Moreover, there was no statistically significant difference in the incidence of post-HSCT CNS relapse between CNS-involved and CNS-spared patients. Pre-HSCT cranial radiation therapy (CRT) showed no significant preventive effect on the likelihood of post-HSCT CNS relapse. Through multivariable regression analysis, grade III-IV acute graft-versus-host disease (GvHD), extensive chronic GvHD and post-HSCT relapse were ascertained as independent determinants of mortality (Adj.R2 = 53.9 , F(12,265) = 28.1, P < 0.001), while other parameters including Philadelphia translocation, pre-HSCT CNS involvement and CRT were found to have no independent effect. Although this study was not an attempt to compare TBI-based vs. non-TBI conditioning, the TBI-free myeloablative allo-HSCT was shown to be feasible and an option for adult ALL patients with CNS involvement, considering the comparable outcomes between patients with and without CNS involvement. © 2021 Elsevier Lt