RARE DISEASE
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
Drug discovery
2
drugs
With orphan designations
Overview
B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) with recurrent genetic abnormalities is an aggressive hematologic malignancy characterized by specific cytogenetic and molecular alterations that dictate prognosis and therapeutic approaches. These include high-risk variants like BCR::ABL1 (Philadelphia chromosome) and KMT2A rearrangements, as well as favorable-risk abnormalities such as ETV6::RUNX1 fusion. Diagnosis requires immunophenotyping and genetic profiling to guide risk stratification [1][2][5].
Therapies
Targeted therapies: Tyrosine kinase inhibitors (e.g., imatinib) for BCR::ABL1+ cases; menin inhibitors for KMT2A-rearranged disease [3][7][15]
Immunotherapy: CD19-directed CAR T-cells (tisagenlecleucel) and blinatumomab for relapsed/refractory cases [7][11]
Transplant: Allogeneic HSCT recommended for high-risk genetic profiles (e.g., hypodiploidy, KMT2A rearrangements) [4][16]
Categories: rare genetic diseases, rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
249 drug discovery papers about B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
249 drug discovery papers about B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-03-21 | Different Levels of Therapeutic Strategies to Recover the Microbiome to Prevent/Delay Acute Lymphoblastic Leukemia (ALL) or Arrest Its Progression in Children
Alterations in the composition and diversity, metabolism, and products of the microbiome, and of the gut microbiome (GM), have been shown to be closely associated with the onset and progression of many human diseases, including cancer (i.e. hematological neoplasms). Acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy. Affected cases present typical alterations of GM, followed by inflammation, which contribute to its progression, response to therapy, as well as possible relapses. Recent evidence also reports that GM influences the development and functions of the newborn's hematopoietic system through the process of developmental programming during fetal life, as well as its susceptibility to the onset of onco-hematological pathologies, namely ALL. Furthermore, in children with ALL, GM has been found to vary in composition, variety, and functions during the clinical stages of ALL, and such variation may influence and predict the complications and prognosis of ALL after chemotherapy treatment or stem cell hematopoietic transplant. Here, we suggest some therapeutic strategies, which can be applied at two levels of intervention to recover the microbiome, and consequently prevent/delay ALL or arrest its progression.
2024-02-21 | Biological Markers of High-Risk Childhood Acute Lymphoblastic Leukemia
Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies.
2024-01-07 | CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders
NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.
2023-12-27 | Mutational and transcriptional landscape of pediatric B-cell precursor lymphoblastic lymphoma
Abstract Pediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in bone marrow/blood (BCP acute lymphoblastic leukemia, BCP-ALL) or less common in extramedullary tissue (BCP lymphoblastic lymphoma, BCP-LBL). Although both presentations are similar in morphology and immunophenotype molecular studies are virtually restricted to BCP-ALL so far. The lack of molecular studies on BCP-LBL is probably due to its rarity and the restriction to tiny, mostly formalin-fixed paraffin embedded (FFPE) tissues. Here we present the first comprehensive mutational and transcriptional analysis of what we consider the largest BCP-LBL cohort described to date (n=97). Whole exome sequencing indicates a mutational spectrum of BCP-LBL strikingly similar to that found in BCP-ALL. However, epigenetic modifiers were more frequently mutated in BCP-LBL, whereas BCP-ALL was more frequently affected by mutation in genes involved in B-cell development. Integrating copy number alterations, somatic mutations and gene expression by RNA-sequencing revealed virtually all molecular subtypes originally defined in BCP-ALL to be present in BCP-LBL too, with only 7% of lymphomas that were not assigned to a subtype. Therefore, the results here described may pave the way for molecular risk adapted treatment protocols for BCP-LBL patients. Keypoints Comprehensive molecular characterization of B-cell precursor lymphoblastic lymphoma allows molecular subtyping analogous to leukemias Compared to leukemias, lymphomas show more alterations in epigenetic modifiers and less in B-cell development genes
2023-12-26 | Synthetic Lethality Approaches in Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL), a remarkable cancer that mainly affects children, has seen commendable advances in its treatment. However, the occurrence of relapses after initial treatments poses a major threat and is one of the leading causes of cancer-related mortality in pediatric patients. To address this problem, innovative therapeutic approaches for ALL need to be continuously developed and refined. Synthetic lethality, an interaction between genes in which alteration of only one allows survival, but simultaneous alteration of both leads to inviability, is emerging as a promising therapeutic approach against ALL and other cancers. In this regard, the review aims to examine the documented cases of synthetic lethality in ALL reported to date (2023) and to elucidate the molecular mechanisms underlying this phenomenon. Furthermore, this review explores possible targets that have so far gone unnoticed, justifying their importance in this context.
proteins
2023-07-19 | Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies
Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients.
2022-02-23 | Expression of Ten-Eleven Translocation 1 Gene in Acute Leukemia
Abstract Background: The Ten-Eleven Translocation 1 gene (TET1) is a member of the TET methyl cytosine dioxygenase family of enzymes (TET1, TET2, and TET3). The TET1 has contrasting roles in myeloid and lymphoid transformation being either an oncogene or a tumor suppressor. This work aimed to study the expression level of TET1 gene in acute leukemia patients and its correlation with clinical and pathological criteria of these patients. Patients & methods: This study was conducted on 73 acute leukemia patients. Bone marrow samples were analyzed using Real Time PCR 7500s. Results: There was significant correlation between expression levels of TET 1 gene in acute leukemia patients and their clinical and pathological criteria. Conclusion :It has been found that expression levels of TET1 gene in patients’ samples were higher in in AML, not otherwise specified (NOS), and T lymphoblastic leukemia/lymphoma patients and lower in B lymphoblastic leukemia/lymphoma, NOS patients. Besides, this study showed the significant relation between TET1 gene and the percentage of blast cells in peripheral blood (P.B) and bone marrow (B.M) and generalized lymphadenopathy. These findings revealed the great role of TET1 gene dysregulation in leukemogenesis; also its possible usage as a potential target for treating this form of hematopoietic malignancy.
2019-03-27 | Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management
The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.
2017-10-01 | Asparaginase Toxicities: Identification and Management in Patients With Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is a common cancer in children, and outcomes have greatly improved because of the refinement of multiagent chemotherapy regimens that include intensified asparaginase therapy. Asparaginase, a cornerstone of modern pediatric chemotherapy regimens for ALL and asparaginase-containing protocols, is increasingly used in adolescent and adult patients historically treated with asparaginase-free regimens. .This article is an overview of commonly encountered asparaginase- associated toxicities and offers recommendations for treatment management. .A literature review was conducted, reviewing asparaginase and common toxicities, specifically hypersensitivity, pancreatitis, thrombosis, hyperbilirubinemia, and hyperglycemia. .The rapid identification and management of common asparaginase-associated adverse events can reduce symptom severity and limit potential interruptions to therapy, possibly improving outcomes.
2017-04-28 | TET family dioxygenases and DNA demethylation in stem cells and cancers
The methylation of cytosine and subsequent oxidation constitutes a fundamental epigenetic modification in mammalian genomes, and its abnormalities are intimately coupled to various pathogenic processes including cancer development. Enzymes of the Ten–eleven translocation (TET) family catalyze the stepwise oxidation of 5-methylcytosine in DNA to 5-hydroxymethylcytosine and further oxidation products. These oxidized 5-methylcytosine derivatives represent intermediates in the reversal of cytosine methylation, and also serve as stable epigenetic modifications that exert distinctive regulatory roles. It is becoming increasingly obvious that TET proteins and their catalytic products are key regulators of embryonic development, stem cell functions and lineage specification. Over the past several years, the function of TET proteins as a barrier between normal and malignant states has been extensively investigated. Dysregulation of TET protein expression or function is commonly observed in a wide range of cancers. Notably, TET loss-of-function is causally related to the onset and progression of hematologic malignancy in vivo. In this review, we focus on recent advances in the mechanistic understanding of DNA methylation–demethylation dynamics, and their potential regulatory functions in cellular differentiation and oncogenic transformation. Proteins that remove chemical tags from DNA play key regulatory roles in cell development and the initiation of cancer. In a review article, Myunggon Ko from the Ulsan National Institute of Science and Technology in South Korea and colleagues describe how enzymes of the Ten-eleven translocation (TET) family reverse the methylation of cytosine in DNA, affecting cellular differentiation, embryonic development and cancer. The researchers detail the mechanisms by which TET proteins remove methyl groups from cytosine residues in a stepwise manner. The absence of functional TET has been implicated in a wide range of human cancers, in particular, cancers of the blood cells. In mouse models, reintroducing TET activity into blood stem cells helped prevent leukemia, suggesting that restoring TET function in people could have therapeutic benefit for cancer patients.
cell therapies
2023-11-16 | Recruiting In Vitro Transcribed mRNA against Cancer Immunotherapy: A Contemporary Appraisal of the Current Landscape
Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into proteins with therapeutic or prophylactic relevance. Simultaneously, cancer immunotherapy employs diverse strategies to mobilize the immune system in the battle against cancer. Therefore, in this review, the fundamental principles of IVT-mRNA to its recruitment in cancer immunotherapy, are discussed and analyzed. More specifically, this review paper focuses on the development of mRNA vaccines, the exploitation of neoantigens, as well as Chimeric Antigen Receptor (CAR) T-Cells, showcasing their clinical applications and the ongoing trials for the development of next-generation immunotherapeutics. Furthermore, this study investigates the synergistic potential of combining the CAR immunotherapy and the IVT-mRNAs by introducing our research group novel, patented delivery method that utilizes the Protein Transduction Domain (PTD) technology to transduce the IVT-mRNAs encoding the CAR of interest into the Natural Killer (NK)-92 cells, highlighting the potential for enhancing the CAR NK cell potency, efficiency, and bioenergetics. While IVT-mRNA technology brings exciting progress to cancer immunotherapy, several challenges and limitations must be acknowledged, such as safety, toxicity, and delivery issues. This comprehensive exploration of IVT-mRNA technology, in line with its applications in cancer therapeutics, offers valuable insights into the opportunities and challenges in the evolving landscape of cancer immunotherapy, setting the stage for future advancements in the field.
2023-07-04 | Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies
Abstract Chimeric antigen receptor (CAR) T cells and natural killer (NK) cells are genetically engineered immune cells that can detect target antigens on the surface of target cells and eliminate them following adoptive transfer. Recent progress in CAR-based therapies has led to outstanding clinical success in certain patients with leukemias and lymphomas and offered therapeutic benefits to those resistant to conventional therapies. The universal approach to stable CAR transgene delivery into the T/NK cells is the use of viral particles. Such approaches mediate semi-random transgene insertions spanning the entire genome with a high preference for integration into sites surrounding highly-expressed genes and active loci. Regardless of the variable CAR expression level based on the integration site of the CAR transgene, foreign integrated DNA fragments may affect the neighboring endogenous genes and chromatin structure and potentially change a transduced T/NK cell behavior and function or even favor cellular transformation. In contrast, site-specific integration of CAR constructs using recent genome-editing technologies could overcome the limitations and disadvantages of universal random gene integration. Herein, we explain random and site-specific integration of CAR transgenes in CAR-T/NK cell therapies. Also, we tend to summarize the methods for site-specific integration as well as the clinical outcomes of certain gene disruptions or enhancements due to CAR transgene integration. Also, the advantages and limitations of using site-specific integration methods are discussed in this review. Ultimately, we will introduce the genomic safe harbor (GSH) standards and suggest some appropriate safety prospects for CAR integration in CAR-T/NK cell therapies.
2023-02-17 | Anti-ROR1 CAR-T cells: Architecture and performance
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a membrane receptor that plays a key role in development. It is highly expressed during the embryonic stage and relatively low in some normal adult tissues. Malignancies such as leukemia, lymphoma, and some solid tumors overexpress ROR1, making it a promising target for cancer treatment. Moreover, immunotherapy with autologous T-cells engineered to express a ROR1-specific chimeric antigen receptor (ROR1 CAR-T cells) has emerged as a personalized therapeutic option for patients with tumor recurrence after conventional treatments. However, tumor cell heterogeneity and tumor microenvironment (TME) hinder successful clinical outcomes. This review briefly describes the biological functions of ROR1 and its relevance as a tumor therapeutic target, as well as the architecture, activity, evaluation, and safety of some ROR1 CAR-T cells used in basic research and clinical trials. Finally, the feasibility of applying the ROR1 CAR-T cell strategy in combination with therapies targeting other tumor antigens or with inhibitors that prevent tumor antigenic escape is also discussed. Clinical trial registration https://clinicaltrials.gov/ , identifier NCT02706392
2023-01-25 | Nanobodies in cell-mediated immunotherapy: On the road to fight cancer
The immune system is essential in recognizing and eliminating tumor cells. The unique characteristics of the tumor microenvironment (TME), such as heterogeneity, reduced blood flow, hypoxia, and acidity, can reduce the efficacy of cell-mediated immunity. The primary goal of cancer immunotherapy is to modify the immune cells or the TME to enable the immune system to eliminate malignancies successfully. Nanobodies, known as single-domain antibodies, are light chain-free antibody fragments produced from Camelidae antibodies. The unique properties of nanobodies, including high stability, reduced immunogenicity, enhanced infiltration into the TME of solid tumors and facile genetic engineering have led to their promising application in cell-mediated immunotherapy. They can promote the cancer therapy either directly by bridging between tumor cells and immune cells and by targeting cancer cells using immune cell-bound nanobodies or indirectly by blocking the inhibitory ligands/receptors. The T-cell activation can be engaged through anti-CD3 and anti-4-1BB nanobodies in the bispecific (bispecific T-cell engagers (BiTEs)) and trispecific (trispecific T-cell engager (TriTEs)) manners. Also, nanobodies can be used as natural killer (NK) cell engagers (BiKEs, TriKEs, and TetraKEs) to create an immune synapse between the tumor and NK cells. Nanobodies can redirect immune cells to attack tumor cells through a chimeric antigen receptor (CAR) incorporating a nanobody against the target antigen. Various cancer antigens have been targeted by nanobody-based CAR-T and CAR-NK cells for treating both hematological and solid malignancies. They can also cause the continuation of immune surveillance against tumor cells by stopping inappropriate inhibition of immune checkpoints. Other roles of nanobodies in cell-mediated cancer immunotherapy include reprogramming macrophages to reduce metastasis and angiogenesis, as well as preventing the severe side effects occurring in cell-mediated immunotherapy. Here, we highlight the critical functions of various immune cells, including T cells, NK cells, and macrophages in the TME, and discuss newly developed immunotherapy methods based on the targeted manipulation of immune cells and TME with nanobodies.
2022-08-25 | Current progress in CAR‑T cell therapy for tumor treatment (Review)
Chimeric antigen receptor T (CAR‑T) cells are a type of tumor immunotherapy that is a breakthrough technology in the clinical treatment of tumors. The basic principle of this method is to extract the patient's T cells and equip them with targeting recognition receptors of tumor cells and return them to the patient's body to recognize and kill tumor cells specifically. Most CAR‑T cell therapies treat hematological diseases such as leukemia or lymphoma and achieved encouraging results. The safety and effectiveness of CAR‑T cell technology in solid tumor treatment require to be improved, although it has demonstrated promising efficacy in treating hematological malignancies. It is worth noting that certain patients may experience fatal adverse reactions after receiving CAR‑T cell therapy. At present, the difficulty of this therapy mainly lies in how to reduce adverse reactions and target escape effects during the course of treatment. The improvement of CAR‑T cell therapy mainly focuses on improving CAR‑T structure, finding suitable tumor targets and combining them with immune checkpoint inhibitors to the enhance efficacy and safety of treatment. The problems in the rapid development of CAR‑T cell therapy provide both obstacles and opportunities. The present review elaborates on the clinical application of CAR‑T cell technology to provide a reference for clinical practice and research on tumor treatment.
antibodies
2023-09-26 | Progress of research on PD-1/PD-L1 in leukemia
Leukemia cells prevent immune system from clearing tumor cells by inducing the immunosuppression of the bone marrow (BM) microenvironment. In recent years, further understanding of the BM microenvironment and immune landscape of leukemia has resulted in the introduction of several immunotherapies, including checkpoint inhibitors, T-cell engager, antibody drug conjugates, and cellular therapies in clinical trials. Among them, the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is a significant checkpoint for controlling immune responses, the PD-1 receptor on tumor-infiltrating T cells is bound by PD-L1 on leukemia cells. Consequently, the activation of tumor reactive T cells is inhibited and their apoptosis is promoted, preventing the rejection of the tumor by immune system and thus resulting in the occurrence of immune tolerance. The PD-1/PD-L1 axis serves as a significant mechanism by which tumor cells evade immune surveillance, and PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of lymphomas and varieties of solid tumors. However, the development of drugs targeting PD-1/PD-L1 in leukemia remains in the clinical-trial stage. In this review, we tally up the basic research and clinical trials on PD-1/PD-L1 inhibitors in leukemia, as well as discuss the relevant toxicity and impacts of PD-1/PD-L1 on other immunotherapies such as hematopoietic stem cell transplantation, bi-specific T-cell engager, chimeric antigen receptor T-cell immunotherapy.
2023-08-09 | Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment
Summary Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour-associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy. Furthermore, there is evidence that BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the BiTE therapy blinatumomab. To overcome these inadequate T-cell responses, BiTEs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of BiTEs in solid malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination therapies and a few other less-studied combinations.
2023-04-05 | Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies
Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.
2022-05-19 | Introduction and Application of Death Protein 1
In the past few years, cancer immunotherapy has been accompanied by encouraging results.Cell death protein 1 (PD-1) plays a crucial role in suppressing immune responses and promoting self-tolerance by regulating T cell activity, activating apotheosis.Antigen-specific T cells, programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is considered a common suppressor of the immune response and can bind to PD-1, reducing the proliferation of PD-1-positive cells, inhibiting their cytokine secretion, and inducing apotheosis. 1 thus PD-L1 also plays an important role in various malignancies.It can attenuate the host immune response to tumor cells.Based on these views, the PD-1 / PD-L1 axis is responsible for immune evasion of cancer and has a tremendous impact on cancer treatment.Blockade of PD1 is important cancer immunotherapy.Taking pembrolizumab (keytruda) as an example is a humanized monoclonal anti-pd1 antibody that has been extensively studied in many malignancies.Pembrolizumab has been approved by the US FDA for the treatment of advanced melanoma and NSCLC.This review aims to improve cancer treatment by summarizing the roles of PD-1 and PD-L1 in cancer, thereby exemplifying a variety of PD-1 blockade drugs compared to typical pembrolizumab (keytruda) drugs, analyzing the comparative distinctions between modern immunotherapy and traditional chemotherapy for cancer.
2021-12-10 | Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy
Here we review the pathophysiology and management of cytokine release syndrome (CRS) secondary to immunotherapy, and potential options for CRS refractory to IL6 inhibition and glucocorticoids, for which there are no proven treatments. To illustrate, we describe a patient with B-cell acute lymphoblastic leukemia who developed refractory grade 4 CRS following CD19-directed chimeric antigen receptor T-cell therapy, treated with tocilizumab, methylprednisolone, siltuximab, and the IFNγ inhibitor emapalumab, with complete remission from leukemia for 12 months. See related article by Bailey et al., p. 136 (15).
other
2023-06-19 | miR-155 and miR-92 levels in ALL, post-transplant aGVHD, and CMV: possible new treatment options
Abstract Background Acute lymphoblastic leukemia (ALL) is a malignancy that leads to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Recently, dysregulated expression of various micro-RNAs (miRNAs) has been reported in hematologic malignancies, especially ALL. Cytomegalovirus infection can induce ALL in otherwise healthy individuals, so a more detailed evaluation of its role in ALL-endemic areas like Iran is required. Methods In this cross-sectional study, 70 newly diagnosed adults with ALL were recruited. The expression level of microRNA-155(miR-155) and microRNA-92(miR-92) was evaluated by real-time SYBR Green PCR. The correlations between the miRNAs mentioned above and the severity of disease, CMV infection, and acute graft vs. host disease after hematopoietic stem cell transplantation (HSCT) were assessed. B cell and T cell ALL distinction in the level of miRNAs was provided. Results After the statistical analysis, our results indicated a marked increase in the expression of miR-155 and miR-92 in ALL patients vs. healthy controls (* P = 0.002–* P = 0.03, respectively). Also, it was shown that the expression of miR-155 and miR-92 was higher in T cell ALL compared to B cell ALL ( P = 0.01– P = 0.004, respectively), CMV seropositivity, and aGVHD. Conclusion Our study suggests that the plasma signature of microRNA expression may act as a powerful marker for diagnosis and prognosis, providing knowledge outside cytogenetics. Elevation of miR-155 in plasma can be a beneficial therapeutic target for ALL patients, with consideration of higher plasma levels of miR-92 and miR-155 in CMV + and post-HSCT aGVHD patients.
2022-08-03 | Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context
Abstract Minichromosome maintenance proteins (Mcm2‐7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3′UTR of the Mcm2 gene (designated Mcm2 Cre ) have decreased Mcm2 expression and invariably develop precursor T‐cell lymphoblastic leukemia/lymphoma (pre‐T LBL), due to 100–1000 kb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre‐T LBL would develop non‐T‐cell malignancies, we used two approaches. Mice engrafted with Mcm2 Cre/Cre Lin − Sca‐1 + Kit + hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6 months of age. Placing the Mcm2 Cre allele onto an athymic nu / nu background completely prevented pre‐T LBL and extended survival of these mice three‐fold (median 296.5 vs. 80.5 days). Ultimately, most Mcm2 Cre/Cre ; nu / nu mice developed B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). We identified recurrent deletions of 100–1000 kb that involved genes known or suspected to be involved in BCP‐ALL, including Pax5 , Nf1 , Ikzf3 , and Bcor . Moreover, whole‐exome sequencing identified recurrent mutations of genes known to be involved in BCP‐ALL progression, such as Jak1 / Jak3 , Ptpn11 , and Kras . These findings demonstrate that an Mcm2 Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a “deletor” phenotype affecting known or suspected tumor suppressor genes.
2021-12-20 | An Evidence-based Medical Research on the Comparative Quantification of TGF? and Telomerase Experimentations, with their Molecular Pharmacological Analyses as Targets of Oncoimmunotherapeutic Vaccines
The basic oncotherapeutic vaccines used are cell based vaccines including whole cell vaccines, genetically modified tumour cell vaccines and dendritic cell vaccines, anti-idiotype antibody based vaccines, protein or peptide based vaccines, heat shock proteinbased vaccines, viral, bacterial or yeast vectors based vaccines, mRNA or DNA nucleic acid based vaccines, vaccines based on tumour associated antigens like overexpressed proteins, differentiation antigens, cancer-testis antigens and oncofoetal antigens, and tumour specific antigens including oncogenic viral antigens, antigen presenting cells or molecular neoantigens based vaccines with specific CD8+ T cells and, CD4+ T cells, and nanoparticles vectors based vaccines. The objective of this evidence-based medical research was the comparative quantification of TGF? and telomerase experimentations, with their molecular pharmacological analyses as targets of oncoimmunotherapeutic vaccines. A molecular pharmacological multi-variate, qualitative, analytical study of the retrieved literature derived through a thorough literature review from various available literature databases, was performed, to record, review, thoroughly analyse and delineate the molecular pharmacological basis of oncoimmunotherapeutic vaccines from a wide-ranged study literature containing molecular pharmacological researches, reviews, case presentations and varied databases about the pharmacooncoimmunotherapeutic rationale of the clinical use of vaccines in the treatment of cancer patients, with a specific emphasis on telomerase and TGF?, as molecular pharmacological targets of oncoimmunotherapeutic vaccines. After that, a multivariate evidence-based medical research study of comparative quantification and analysis of the global heterogenous multidisciplinary experimentations and study literature on telomerase and TGF?, as molecular pharmacological targets of pharmaco-oncoimmuno-therapeutic vaccines, affecting global malignant and borderline malign
2020-07-24 | Induction of Cell Death in the Human Acute Lymphoblastic Leukemia Cell Line Reh by Infection with Rotavirus Isolate Wt1-5
Cancer is a major health problem that poses a great challenge to health care systems worldwide. Tools for cancer treatment have rapidly advanced in recent years, resulting in therapeutic strategies which are alternative and complementary to conventional treatment. To identify the cell surface receptors used by a tumor cell-adapted rotavirus and the cell death markers induced by its infection, we use Wt1-5, a rotavirus isolate recently adapted to tumor cells, to infect the human acute lymphoblastic leukemia cell line, Reh. The expression of cell surface receptors used by Wt1-5 was determined using flow cytometry and an antibody blocking assay to test for their implication in virus infection. Viral antigens and cell death markers induced by rotavirus infection were followed by flow cytometric analysis. The present study showed that rotavirus Wt1-5 was able to use cell surface proteins such as heat shock proteins (HSPs) 90, 70, 60 and 40, Hsc70, PDI and integrin β3. Rotavirus Wt1-5 induced cytotoxic effects including changes in cell membrane permeability, alteration of mitochondrial membrane potential, DNA fragmentation and activation of cell death signaling. Wt1-5 deserves to be further studied as a candidate oncolytic agent due to its ability to induce apoptosis in lymphoblastic leukemia-derived cells.
2012-06-02 | Role of microRNAs in leukemia stem cells
Leukemia cells can carry a small subset of poorly differentiated cells, which are considered to be precursors of lymphoblasts, myeloblasts, or monoblasts. Thus these cells are also called leukemia stem cells (LSCs) because they are capable of instigating, maintaining and serially propagating leukemia in vivo, while retaining the ability to differentiate into committed progeny that lack these properties. Like hematopoietic stem cells (HSCs), LSCs possess the ability of self-renewal under a complex regulatory system. The recent discovery of microRNAs may shed new light on regulation of LSCs and leukemogenesis. As master gene regulators, microRNAs participate in these processes through coordinated work with key transcription factors required for hematopoiesis. Therefore, microRNAs could play a critical role in normal HSCs as well as LSCs. The purpose of this review is to provide updates on the role of microRNAs in HSCs and LSCs and to highlight their potential in differentiation therapy of leukemias.
small molecules
2024-03-21 | Different Levels of Therapeutic Strategies to Recover the Microbiome to Prevent/Delay Acute Lymphoblastic Leukemia (ALL) or Arrest Its Progression in Children
Alterations in the composition and diversity, metabolism, and products of the microbiome, and of the gut microbiome (GM), have been shown to be closely associated with the onset and progression of many human diseases, including cancer (i.e. hematological neoplasms). Acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy. Affected cases present typical alterations of GM, followed by inflammation, which contribute to its progression, response to therapy, as well as possible relapses. Recent evidence also reports that GM influences the development and functions of the newborn's hematopoietic system through the process of developmental programming during fetal life, as well as its susceptibility to the onset of onco-hematological pathologies, namely ALL. Furthermore, in children with ALL, GM has been found to vary in composition, variety, and functions during the clinical stages of ALL, and such variation may influence and predict the complications and prognosis of ALL after chemotherapy treatment or stem cell hematopoietic transplant. Here, we suggest some therapeutic strategies, which can be applied at two levels of intervention to recover the microbiome, and consequently prevent/delay ALL or arrest its progression.
2024-02-21 | Biological Markers of High-Risk Childhood Acute Lymphoblastic Leukemia
Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies.
2024-01-07 | CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders
NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.
2023-12-27 | Mutational and transcriptional landscape of pediatric B-cell precursor lymphoblastic lymphoma
Abstract Pediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in bone marrow/blood (BCP acute lymphoblastic leukemia, BCP-ALL) or less common in extramedullary tissue (BCP lymphoblastic lymphoma, BCP-LBL). Although both presentations are similar in morphology and immunophenotype molecular studies are virtually restricted to BCP-ALL so far. The lack of molecular studies on BCP-LBL is probably due to its rarity and the restriction to tiny, mostly formalin-fixed paraffin embedded (FFPE) tissues. Here we present the first comprehensive mutational and transcriptional analysis of what we consider the largest BCP-LBL cohort described to date (n=97). Whole exome sequencing indicates a mutational spectrum of BCP-LBL strikingly similar to that found in BCP-ALL. However, epigenetic modifiers were more frequently mutated in BCP-LBL, whereas BCP-ALL was more frequently affected by mutation in genes involved in B-cell development. Integrating copy number alterations, somatic mutations and gene expression by RNA-sequencing revealed virtually all molecular subtypes originally defined in BCP-ALL to be present in BCP-LBL too, with only 7% of lymphomas that were not assigned to a subtype. Therefore, the results here described may pave the way for molecular risk adapted treatment protocols for BCP-LBL patients. Keypoints Comprehensive molecular characterization of B-cell precursor lymphoblastic lymphoma allows molecular subtyping analogous to leukemias Compared to leukemias, lymphomas show more alterations in epigenetic modifiers and less in B-cell development genes
2023-12-26 | Synthetic Lethality Approaches in Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL), a remarkable cancer that mainly affects children, has seen commendable advances in its treatment. However, the occurrence of relapses after initial treatments poses a major threat and is one of the leading causes of cancer-related mortality in pediatric patients. To address this problem, innovative therapeutic approaches for ALL need to be continuously developed and refined. Synthetic lethality, an interaction between genes in which alteration of only one allows survival, but simultaneous alteration of both leads to inviability, is emerging as a promising therapeutic approach against ALL and other cancers. In this regard, the review aims to examine the documented cases of synthetic lethality in ALL reported to date (2023) and to elucidate the molecular mechanisms underlying this phenomenon. Furthermore, this review explores possible targets that have so far gone unnoticed, justifying their importance in this context.
proteins
2023-07-19 | Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies
Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients.
2022-02-23 | Expression of Ten-Eleven Translocation 1 Gene in Acute Leukemia
Abstract Background: The Ten-Eleven Translocation 1 gene (TET1) is a member of the TET methyl cytosine dioxygenase family of enzymes (TET1, TET2, and TET3). The TET1 has contrasting roles in myeloid and lymphoid transformation being either an oncogene or a tumor suppressor. This work aimed to study the expression level of TET1 gene in acute leukemia patients and its correlation with clinical and pathological criteria of these patients. Patients & methods: This study was conducted on 73 acute leukemia patients. Bone marrow samples were analyzed using Real Time PCR 7500s. Results: There was significant correlation between expression levels of TET 1 gene in acute leukemia patients and their clinical and pathological criteria. Conclusion :It has been found that expression levels of TET1 gene in patients’ samples were higher in in AML, not otherwise specified (NOS), and T lymphoblastic leukemia/lymphoma patients and lower in B lymphoblastic leukemia/lymphoma, NOS patients. Besides, this study showed the significant relation between TET1 gene and the percentage of blast cells in peripheral blood (P.B) and bone marrow (B.M) and generalized lymphadenopathy. These findings revealed the great role of TET1 gene dysregulation in leukemogenesis; also its possible usage as a potential target for treating this form of hematopoietic malignancy.
2019-03-27 | Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management
The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.
2017-10-01 | Asparaginase Toxicities: Identification and Management in Patients With Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is a common cancer in children, and outcomes have greatly improved because of the refinement of multiagent chemotherapy regimens that include intensified asparaginase therapy. Asparaginase, a cornerstone of modern pediatric chemotherapy regimens for ALL and asparaginase-containing protocols, is increasingly used in adolescent and adult patients historically treated with asparaginase-free regimens. .This article is an overview of commonly encountered asparaginase- associated toxicities and offers recommendations for treatment management. .A literature review was conducted, reviewing asparaginase and common toxicities, specifically hypersensitivity, pancreatitis, thrombosis, hyperbilirubinemia, and hyperglycemia. .The rapid identification and management of common asparaginase-associated adverse events can reduce symptom severity and limit potential interruptions to therapy, possibly improving outcomes.
2017-04-28 | TET family dioxygenases and DNA demethylation in stem cells and cancers
The methylation of cytosine and subsequent oxidation constitutes a fundamental epigenetic modification in mammalian genomes, and its abnormalities are intimately coupled to various pathogenic processes including cancer development. Enzymes of the Ten–eleven translocation (TET) family catalyze the stepwise oxidation of 5-methylcytosine in DNA to 5-hydroxymethylcytosine and further oxidation products. These oxidized 5-methylcytosine derivatives represent intermediates in the reversal of cytosine methylation, and also serve as stable epigenetic modifications that exert distinctive regulatory roles. It is becoming increasingly obvious that TET proteins and their catalytic products are key regulators of embryonic development, stem cell functions and lineage specification. Over the past several years, the function of TET proteins as a barrier between normal and malignant states has been extensively investigated. Dysregulation of TET protein expression or function is commonly observed in a wide range of cancers. Notably, TET loss-of-function is causally related to the onset and progression of hematologic malignancy in vivo. In this review, we focus on recent advances in the mechanistic understanding of DNA methylation–demethylation dynamics, and their potential regulatory functions in cellular differentiation and oncogenic transformation. Proteins that remove chemical tags from DNA play key regulatory roles in cell development and the initiation of cancer. In a review article, Myunggon Ko from the Ulsan National Institute of Science and Technology in South Korea and colleagues describe how enzymes of the Ten-eleven translocation (TET) family reverse the methylation of cytosine in DNA, affecting cellular differentiation, embryonic development and cancer. The researchers detail the mechanisms by which TET proteins remove methyl groups from cytosine residues in a stepwise manner. The absence of functional TET has been implicated in a wide range of human cancers, in particular, cancers of the blood cells. In mouse models, reintroducing TET activity into blood stem cells helped prevent leukemia, suggesting that restoring TET function in people could have therapeutic benefit for cancer patients.
cell therapies
2023-11-16 | Recruiting In Vitro Transcribed mRNA against Cancer Immunotherapy: A Contemporary Appraisal of the Current Landscape
Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into proteins with therapeutic or prophylactic relevance. Simultaneously, cancer immunotherapy employs diverse strategies to mobilize the immune system in the battle against cancer. Therefore, in this review, the fundamental principles of IVT-mRNA to its recruitment in cancer immunotherapy, are discussed and analyzed. More specifically, this review paper focuses on the development of mRNA vaccines, the exploitation of neoantigens, as well as Chimeric Antigen Receptor (CAR) T-Cells, showcasing their clinical applications and the ongoing trials for the development of next-generation immunotherapeutics. Furthermore, this study investigates the synergistic potential of combining the CAR immunotherapy and the IVT-mRNAs by introducing our research group novel, patented delivery method that utilizes the Protein Transduction Domain (PTD) technology to transduce the IVT-mRNAs encoding the CAR of interest into the Natural Killer (NK)-92 cells, highlighting the potential for enhancing the CAR NK cell potency, efficiency, and bioenergetics. While IVT-mRNA technology brings exciting progress to cancer immunotherapy, several challenges and limitations must be acknowledged, such as safety, toxicity, and delivery issues. This comprehensive exploration of IVT-mRNA technology, in line with its applications in cancer therapeutics, offers valuable insights into the opportunities and challenges in the evolving landscape of cancer immunotherapy, setting the stage for future advancements in the field.
2023-07-04 | Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies
Abstract Chimeric antigen receptor (CAR) T cells and natural killer (NK) cells are genetically engineered immune cells that can detect target antigens on the surface of target cells and eliminate them following adoptive transfer. Recent progress in CAR-based therapies has led to outstanding clinical success in certain patients with leukemias and lymphomas and offered therapeutic benefits to those resistant to conventional therapies. The universal approach to stable CAR transgene delivery into the T/NK cells is the use of viral particles. Such approaches mediate semi-random transgene insertions spanning the entire genome with a high preference for integration into sites surrounding highly-expressed genes and active loci. Regardless of the variable CAR expression level based on the integration site of the CAR transgene, foreign integrated DNA fragments may affect the neighboring endogenous genes and chromatin structure and potentially change a transduced T/NK cell behavior and function or even favor cellular transformation. In contrast, site-specific integration of CAR constructs using recent genome-editing technologies could overcome the limitations and disadvantages of universal random gene integration. Herein, we explain random and site-specific integration of CAR transgenes in CAR-T/NK cell therapies. Also, we tend to summarize the methods for site-specific integration as well as the clinical outcomes of certain gene disruptions or enhancements due to CAR transgene integration. Also, the advantages and limitations of using site-specific integration methods are discussed in this review. Ultimately, we will introduce the genomic safe harbor (GSH) standards and suggest some appropriate safety prospects for CAR integration in CAR-T/NK cell therapies.
2023-02-17 | Anti-ROR1 CAR-T cells: Architecture and performance
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a membrane receptor that plays a key role in development. It is highly expressed during the embryonic stage and relatively low in some normal adult tissues. Malignancies such as leukemia, lymphoma, and some solid tumors overexpress ROR1, making it a promising target for cancer treatment. Moreover, immunotherapy with autologous T-cells engineered to express a ROR1-specific chimeric antigen receptor (ROR1 CAR-T cells) has emerged as a personalized therapeutic option for patients with tumor recurrence after conventional treatments. However, tumor cell heterogeneity and tumor microenvironment (TME) hinder successful clinical outcomes. This review briefly describes the biological functions of ROR1 and its relevance as a tumor therapeutic target, as well as the architecture, activity, evaluation, and safety of some ROR1 CAR-T cells used in basic research and clinical trials. Finally, the feasibility of applying the ROR1 CAR-T cell strategy in combination with therapies targeting other tumor antigens or with inhibitors that prevent tumor antigenic escape is also discussed. Clinical trial registration https://clinicaltrials.gov/ , identifier NCT02706392
2023-01-25 | Nanobodies in cell-mediated immunotherapy: On the road to fight cancer
The immune system is essential in recognizing and eliminating tumor cells. The unique characteristics of the tumor microenvironment (TME), such as heterogeneity, reduced blood flow, hypoxia, and acidity, can reduce the efficacy of cell-mediated immunity. The primary goal of cancer immunotherapy is to modify the immune cells or the TME to enable the immune system to eliminate malignancies successfully. Nanobodies, known as single-domain antibodies, are light chain-free antibody fragments produced from Camelidae antibodies. The unique properties of nanobodies, including high stability, reduced immunogenicity, enhanced infiltration into the TME of solid tumors and facile genetic engineering have led to their promising application in cell-mediated immunotherapy. They can promote the cancer therapy either directly by bridging between tumor cells and immune cells and by targeting cancer cells using immune cell-bound nanobodies or indirectly by blocking the inhibitory ligands/receptors. The T-cell activation can be engaged through anti-CD3 and anti-4-1BB nanobodies in the bispecific (bispecific T-cell engagers (BiTEs)) and trispecific (trispecific T-cell engager (TriTEs)) manners. Also, nanobodies can be used as natural killer (NK) cell engagers (BiKEs, TriKEs, and TetraKEs) to create an immune synapse between the tumor and NK cells. Nanobodies can redirect immune cells to attack tumor cells through a chimeric antigen receptor (CAR) incorporating a nanobody against the target antigen. Various cancer antigens have been targeted by nanobody-based CAR-T and CAR-NK cells for treating both hematological and solid malignancies. They can also cause the continuation of immune surveillance against tumor cells by stopping inappropriate inhibition of immune checkpoints. Other roles of nanobodies in cell-mediated cancer immunotherapy include reprogramming macrophages to reduce metastasis and angiogenesis, as well as preventing the severe side effects occurring in cell-mediated immunotherapy. Here, we highlight the critical functions of various immune cells, including T cells, NK cells, and macrophages in the TME, and discuss newly developed immunotherapy methods based on the targeted manipulation of immune cells and TME with nanobodies.
2022-08-25 | Current progress in CAR‑T cell therapy for tumor treatment (Review)
Chimeric antigen receptor T (CAR‑T) cells are a type of tumor immunotherapy that is a breakthrough technology in the clinical treatment of tumors. The basic principle of this method is to extract the patient's T cells and equip them with targeting recognition receptors of tumor cells and return them to the patient's body to recognize and kill tumor cells specifically. Most CAR‑T cell therapies treat hematological diseases such as leukemia or lymphoma and achieved encouraging results. The safety and effectiveness of CAR‑T cell technology in solid tumor treatment require to be improved, although it has demonstrated promising efficacy in treating hematological malignancies. It is worth noting that certain patients may experience fatal adverse reactions after receiving CAR‑T cell therapy. At present, the difficulty of this therapy mainly lies in how to reduce adverse reactions and target escape effects during the course of treatment. The improvement of CAR‑T cell therapy mainly focuses on improving CAR‑T structure, finding suitable tumor targets and combining them with immune checkpoint inhibitors to the enhance efficacy and safety of treatment. The problems in the rapid development of CAR‑T cell therapy provide both obstacles and opportunities. The present review elaborates on the clinical application of CAR‑T cell technology to provide a reference for clinical practice and research on tumor treatment.
antibodies
2023-09-26 | Progress of research on PD-1/PD-L1 in leukemia
Leukemia cells prevent immune system from clearing tumor cells by inducing the immunosuppression of the bone marrow (BM) microenvironment. In recent years, further understanding of the BM microenvironment and immune landscape of leukemia has resulted in the introduction of several immunotherapies, including checkpoint inhibitors, T-cell engager, antibody drug conjugates, and cellular therapies in clinical trials. Among them, the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is a significant checkpoint for controlling immune responses, the PD-1 receptor on tumor-infiltrating T cells is bound by PD-L1 on leukemia cells. Consequently, the activation of tumor reactive T cells is inhibited and their apoptosis is promoted, preventing the rejection of the tumor by immune system and thus resulting in the occurrence of immune tolerance. The PD-1/PD-L1 axis serves as a significant mechanism by which tumor cells evade immune surveillance, and PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of lymphomas and varieties of solid tumors. However, the development of drugs targeting PD-1/PD-L1 in leukemia remains in the clinical-trial stage. In this review, we tally up the basic research and clinical trials on PD-1/PD-L1 inhibitors in leukemia, as well as discuss the relevant toxicity and impacts of PD-1/PD-L1 on other immunotherapies such as hematopoietic stem cell transplantation, bi-specific T-cell engager, chimeric antigen receptor T-cell immunotherapy.
2023-08-09 | Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment
Summary Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour-associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy. Furthermore, there is evidence that BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the BiTE therapy blinatumomab. To overcome these inadequate T-cell responses, BiTEs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of BiTEs in solid malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination therapies and a few other less-studied combinations.
2023-04-05 | Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies
Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.
2022-05-19 | Introduction and Application of Death Protein 1
In the past few years, cancer immunotherapy has been accompanied by encouraging results.Cell death protein 1 (PD-1) plays a crucial role in suppressing immune responses and promoting self-tolerance by regulating T cell activity, activating apotheosis.Antigen-specific T cells, programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is considered a common suppressor of the immune response and can bind to PD-1, reducing the proliferation of PD-1-positive cells, inhibiting their cytokine secretion, and inducing apotheosis. 1 thus PD-L1 also plays an important role in various malignancies.It can attenuate the host immune response to tumor cells.Based on these views, the PD-1 / PD-L1 axis is responsible for immune evasion of cancer and has a tremendous impact on cancer treatment.Blockade of PD1 is important cancer immunotherapy.Taking pembrolizumab (keytruda) as an example is a humanized monoclonal anti-pd1 antibody that has been extensively studied in many malignancies.Pembrolizumab has been approved by the US FDA for the treatment of advanced melanoma and NSCLC.This review aims to improve cancer treatment by summarizing the roles of PD-1 and PD-L1 in cancer, thereby exemplifying a variety of PD-1 blockade drugs compared to typical pembrolizumab (keytruda) drugs, analyzing the comparative distinctions between modern immunotherapy and traditional chemotherapy for cancer.
2021-12-10 | Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy
Here we review the pathophysiology and management of cytokine release syndrome (CRS) secondary to immunotherapy, and potential options for CRS refractory to IL6 inhibition and glucocorticoids, for which there are no proven treatments. To illustrate, we describe a patient with B-cell acute lymphoblastic leukemia who developed refractory grade 4 CRS following CD19-directed chimeric antigen receptor T-cell therapy, treated with tocilizumab, methylprednisolone, siltuximab, and the IFNγ inhibitor emapalumab, with complete remission from leukemia for 12 months. See related article by Bailey et al., p. 136 (15).
other
2023-06-19 | miR-155 and miR-92 levels in ALL, post-transplant aGVHD, and CMV: possible new treatment options
Abstract Background Acute lymphoblastic leukemia (ALL) is a malignancy that leads to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Recently, dysregulated expression of various micro-RNAs (miRNAs) has been reported in hematologic malignancies, especially ALL. Cytomegalovirus infection can induce ALL in otherwise healthy individuals, so a more detailed evaluation of its role in ALL-endemic areas like Iran is required. Methods In this cross-sectional study, 70 newly diagnosed adults with ALL were recruited. The expression level of microRNA-155(miR-155) and microRNA-92(miR-92) was evaluated by real-time SYBR Green PCR. The correlations between the miRNAs mentioned above and the severity of disease, CMV infection, and acute graft vs. host disease after hematopoietic stem cell transplantation (HSCT) were assessed. B cell and T cell ALL distinction in the level of miRNAs was provided. Results After the statistical analysis, our results indicated a marked increase in the expression of miR-155 and miR-92 in ALL patients vs. healthy controls (* P = 0.002–* P = 0.03, respectively). Also, it was shown that the expression of miR-155 and miR-92 was higher in T cell ALL compared to B cell ALL ( P = 0.01– P = 0.004, respectively), CMV seropositivity, and aGVHD. Conclusion Our study suggests that the plasma signature of microRNA expression may act as a powerful marker for diagnosis and prognosis, providing knowledge outside cytogenetics. Elevation of miR-155 in plasma can be a beneficial therapeutic target for ALL patients, with consideration of higher plasma levels of miR-92 and miR-155 in CMV + and post-HSCT aGVHD patients.
2022-08-03 | Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context
Abstract Minichromosome maintenance proteins (Mcm2‐7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3′UTR of the Mcm2 gene (designated Mcm2 Cre ) have decreased Mcm2 expression and invariably develop precursor T‐cell lymphoblastic leukemia/lymphoma (pre‐T LBL), due to 100–1000 kb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre‐T LBL would develop non‐T‐cell malignancies, we used two approaches. Mice engrafted with Mcm2 Cre/Cre Lin − Sca‐1 + Kit + hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6 months of age. Placing the Mcm2 Cre allele onto an athymic nu / nu background completely prevented pre‐T LBL and extended survival of these mice three‐fold (median 296.5 vs. 80.5 days). Ultimately, most Mcm2 Cre/Cre ; nu / nu mice developed B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). We identified recurrent deletions of 100–1000 kb that involved genes known or suspected to be involved in BCP‐ALL, including Pax5 , Nf1 , Ikzf3 , and Bcor . Moreover, whole‐exome sequencing identified recurrent mutations of genes known to be involved in BCP‐ALL progression, such as Jak1 / Jak3 , Ptpn11 , and Kras . These findings demonstrate that an Mcm2 Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a “deletor” phenotype affecting known or suspected tumor suppressor genes.
2021-12-20 | An Evidence-based Medical Research on the Comparative Quantification of TGF? and Telomerase Experimentations, with their Molecular Pharmacological Analyses as Targets of Oncoimmunotherapeutic Vaccines
The basic oncotherapeutic vaccines used are cell based vaccines including whole cell vaccines, genetically modified tumour cell vaccines and dendritic cell vaccines, anti-idiotype antibody based vaccines, protein or peptide based vaccines, heat shock proteinbased vaccines, viral, bacterial or yeast vectors based vaccines, mRNA or DNA nucleic acid based vaccines, vaccines based on tumour associated antigens like overexpressed proteins, differentiation antigens, cancer-testis antigens and oncofoetal antigens, and tumour specific antigens including oncogenic viral antigens, antigen presenting cells or molecular neoantigens based vaccines with specific CD8+ T cells and, CD4+ T cells, and nanoparticles vectors based vaccines. The objective of this evidence-based medical research was the comparative quantification of TGF? and telomerase experimentations, with their molecular pharmacological analyses as targets of oncoimmunotherapeutic vaccines. A molecular pharmacological multi-variate, qualitative, analytical study of the retrieved literature derived through a thorough literature review from various available literature databases, was performed, to record, review, thoroughly analyse and delineate the molecular pharmacological basis of oncoimmunotherapeutic vaccines from a wide-ranged study literature containing molecular pharmacological researches, reviews, case presentations and varied databases about the pharmacooncoimmunotherapeutic rationale of the clinical use of vaccines in the treatment of cancer patients, with a specific emphasis on telomerase and TGF?, as molecular pharmacological targets of oncoimmunotherapeutic vaccines. After that, a multivariate evidence-based medical research study of comparative quantification and analysis of the global heterogenous multidisciplinary experimentations and study literature on telomerase and TGF?, as molecular pharmacological targets of pharmaco-oncoimmuno-therapeutic vaccines, affecting global malignant and borderline malign
2020-07-24 | Induction of Cell Death in the Human Acute Lymphoblastic Leukemia Cell Line Reh by Infection with Rotavirus Isolate Wt1-5
Cancer is a major health problem that poses a great challenge to health care systems worldwide. Tools for cancer treatment have rapidly advanced in recent years, resulting in therapeutic strategies which are alternative and complementary to conventional treatment. To identify the cell surface receptors used by a tumor cell-adapted rotavirus and the cell death markers induced by its infection, we use Wt1-5, a rotavirus isolate recently adapted to tumor cells, to infect the human acute lymphoblastic leukemia cell line, Reh. The expression of cell surface receptors used by Wt1-5 was determined using flow cytometry and an antibody blocking assay to test for their implication in virus infection. Viral antigens and cell death markers induced by rotavirus infection were followed by flow cytometric analysis. The present study showed that rotavirus Wt1-5 was able to use cell surface proteins such as heat shock proteins (HSPs) 90, 70, 60 and 40, Hsc70, PDI and integrin β3. Rotavirus Wt1-5 induced cytotoxic effects including changes in cell membrane permeability, alteration of mitochondrial membrane potential, DNA fragmentation and activation of cell death signaling. Wt1-5 deserves to be further studied as a candidate oncolytic agent due to its ability to induce apoptosis in lymphoblastic leukemia-derived cells.
2012-06-02 | Role of microRNAs in leukemia stem cells
Leukemia cells can carry a small subset of poorly differentiated cells, which are considered to be precursors of lymphoblasts, myeloblasts, or monoblasts. Thus these cells are also called leukemia stem cells (LSCs) because they are capable of instigating, maintaining and serially propagating leukemia in vivo, while retaining the ability to differentiate into committed progeny that lack these properties. Like hematopoietic stem cells (HSCs), LSCs possess the ability of self-renewal under a complex regulatory system. The recent discovery of microRNAs may shed new light on regulation of LSCs and leukemogenesis. As master gene regulators, microRNAs participate in these processes through coordinated work with key transcription factors required for hematopoiesis. Therefore, microRNAs could play a critical role in normal HSCs as well as LSCs. The purpose of this review is to provide updates on the role of microRNAs in HSCs and LSCs and to highlight their potential in differentiation therapy of leukemias.
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Drug Discovery Landscape
2 orphan drug designations for B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality, including 1 approved therapy.
2 orphan drug designations for B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Surovatamig | antibodies | EMA | 2025-11-21 | — | AstraZeneca AB |
Autologous T cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD19 [Kymriah] | cell therapies | EMA | 2014-04-29 | 2018-08-27 | Novartis Europharm Limited |
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