CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target

Le, Quy; Hadland, Brandon; Smith, Jenny L.; Leonti, Amanda R.; Huang, Benjamin; Ries, Rhonda E.; Hylkema, Tiffany; Castro, Sommer; Tang, Thao T.; McKay, Cyd Nourigat; Perkins, LaKeisha; Pardo, Laura; Sarthy, Jay F.; Beckman, Amy K.; Williams, Robin; Idemmili, Rhonda; Furlan, Scott N.; Ishida, Takashi; Call, Lindsey; Srivastava, Shivani; Loeb, Anisha; Milano, Filippo; Imren, Suzan; Morris, Shelli M.; Pakiam, Fiona; Olson, James M.; Loken, Michael R.; Brodersen, Lisa Eidenschink; Riddell, Stanley R.; Tarlock, Katherine; Bernstein, Irwin D.; Loeb, Keith R.; Meshinchi, Soheil

doi:10.1172/jci157101

Cited by 26 publications

(31 citation statements)

References 44 publications

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“…[76][77][78][79] Other antigen targets of interest in paediatric AML include mesothelin, CLEC12A (CLL-1, CD371), FLT3, FOL1R, and e-selectin ligand. [80][81][82][83][84][85][86] Early-phase paediatric studies of antibody-based or cellular immunotherapies against these targets are planned.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Relapsed pediatric acute myeloid leukaemia: state-of-the-art in 2023

Egan

Tasian

2023

haematol

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Although outcomes for children and adolescents with newly-diagnosed acute myeloid leukaemia (AML) have improved significantly over the past two decades, more than one-third of patients nonetheless continue to relapse and experience suboptimal long-term outcomes. Given the small numbers of patients with relapsed AML and historic logistical barriers to international collaboration including poor trial funding and drug availability, management of AML relapse has varied amongst paediatric oncology cooperative groups with several utilised salvage regimens and a lack of universally-defined response criteria. The landscape of relapsed paediatric AML treatment is rapidly changing, however, as the international AML community harnesses collective knowledge and resources to characterize the genetic and immunophenotypic heterogeneity of relapsed disease, identify biologic targets of interest within specific AML subtypes, develop new precision medicine approaches for collaborative investigation in earlyphase clinical trials, and tackle challenges of universal drug access across the globe. This review provides a comprehensive overview of progress achieved to date in the treatment of paediatric patients with relapsed AML and highlights modern, state-of-the-art therapeutic approaches under active and emerging clinical investigation that have been facilitated by international collaboration amongst academic paediatric oncologists, laboratory scientists, regulatory agencies, pharmaceutical partners, cancer research sponsors, and patient advocates.

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Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Relapsed pediatric acute myeloid leukaemia: state-of-the-art in 2023

Egan

Tasian

2023

haematol

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“…cord blood stem cells generated leukemia phenotypically similar to de novo disease. 20 Recent advancements in next-generation sequencing (NGS) have improved our understanding of the genomic landscape of AML. Several recent publications have identified cryptic or previously undetected translocations using NGS approaches.…”

Section: Molecular Targetsmentioning

confidence: 99%

“…The KMT2A gene at 11q23 can rearrange to create novel fusion proteins with a number of partner genes. More recent data demonstrate that specific fusions in infant AML delivered in a context appropriate manner may indeed be sufficient for malignant transformation, where transduction of CBFA2T3::GLIS2 or NUP98::KDM5A fusion transcript into normal cord blood stem cells generated leukemia phenotypically similar to de novo disease 20 …”

Section: Introductionmentioning

confidence: 99%

Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms

Cooper

Alonzo

Tasian

et al. 2023

Pediatric Blood & Cancer

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During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5‐year event‐free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high‐risk disease, who have 5‐year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A‐rearranged AML and/or FLT3 internal tandem duplication (FLT3‐ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti‐CD33 antibody–drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3‐ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data‐driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard‐of‐care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.

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“…Analyses of transcriptomes were also a basis for identifying novel targets of C/G acute myeloid leukemia [ 66 ]. Namely, CAR-T cells directed against folate receptor α, encoded by the FOLR1 gene and identified in transcriptomic studies as a potential new target, revealed high efficacy in vitro and in experiments with xenograft models [ 66 ]. Interestingly, other transcriptomic investigations led to the proposal of development of a cellular therapy alternative based on CAR-T cells [ 67 ].…”

Section: Transcriptomics In Identifying New Target Diseases For Car-t...mentioning

confidence: 99%

Transcriptomic Approaches in Studies on and Applications of Chimeric Antigen Receptor T Cells

et al. 2023

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Chimeric antigen receptor T (CAR-T) cells are specifically modified T cells which bear recombinant receptors, present at the cell surface and devoted to detect selected antigens of cancer cells, and due to the presence of transmembrane and activation domains, able to eliminate the latter ones. The use of CAR-T cells in anti-cancer therapies is a relatively novel approach, providing a powerful tool in the fight against cancer and bringing new hope for patients. However, despite huge possibilities and promising results of preclinical studies and clinical efficacy, there are various drawbacks to this therapy, including toxicity, possible relapses, restrictions to specific kinds of cancers, and others. Studies desiring to overcome these problems include various modern and advanced methods. One of them is transcriptomics, a set of techniques that analyze the abundance of all RNA transcripts present in the cell at certain moment and under certain conditions. The use of this method gives a global picture of the efficiency of expression of all genes, thus revealing the physiological state and regulatory processes occurring in the investigated cells. In this review, we summarize and discuss the use of transcriptomics in studies on and applications of CAR-T cells, especially in approaches focused on improved efficacy, reduced toxicity, new target cancers (like solid tumors), monitoring the treatment efficacy, developing novel analytical methods, and others.

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CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target

Cited by 26 publications

References 44 publications

Relapsed pediatric acute myeloid leukaemia: state-of-the-art in 2023

Relapsed pediatric acute myeloid leukaemia: state-of-the-art in 2023

Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms

Transcriptomic Approaches in Studies on and Applications of Chimeric Antigen Receptor T Cells

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