A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib

Li, Kexin; Wu, Huifang; Pan, Wenwei; Guo, Mengye; Qiu, De-zhi; He, Yanjie; Li, Yuhua; Yang, Dong‐Hua; Huang, Yuxian

doi:10.1186/s12943-022-01541-9

Cited by 25 publications

(26 citation statements)

References 75 publications

(66 reference statements)

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“…One was two distinct scFvs 'hand-in-hand' on one cell, whereas the other was two independent CAR monomers with distinct scFvs on a single cell. Recent studies showed that bispecific CAR-T cells could enhance tumor-suppression capacity through dual antigen recognition and internal activation to effectively eradicate tumor cells 174 , 175 .…”

Section: Up-to-date Strategies For Car-t Cell Therapy To Address the ...mentioning

confidence: 99%

Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy

Zhou¹,

Dang²,

Xu³

et al. 2022

Theranostics

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Chimeric antigen receptor (CAR)-T cell therapy represents a landmark advance in personalized cancer treatment. CAR-T strategy generally engineers T cells from a specific patient with a new antigen-specificity, which has achieved considerable success in hematological malignancies, but scarce benefits in solid tumors. Recent studies have demonstrated that tumor immune microenvironment (TIME) cast a profound impact on the immunotherapeutic response. The immunosuppressive landscape of TIME is a critical obstacle to the effector activity of CAR-T cells. Nevertheless, every cloud has a silver lining. The immunosuppressive components also shed new inspiration on reshaping a friendly TIME by targeting them with engineered CARs. Herein, we summarize recent advances in disincentives of TIME and discuss approaches and technologies to enhance CAR-T cell efficacy via addressing current hindrances. Simultaneously, we firmly believe that by parsing the immunosuppressive components of TIME, rationally manipulating the complex interactions of immunosuppressive components, and optimizing CAR-T cell therapy for each patient, the CAR-T cell immunotherapy responsiveness for solid malignancies will be substantially enhanced, and novel therapeutic targets will be revealed.

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Section: Up-to-date Strategies For Car-t Cell Therapy To Address the ...mentioning

confidence: 99%

Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy

Zhou¹,

Dang²,

Xu³

et al. 2022

Theranostics

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“…Other clinical trials have targeted NKG2D, which is expressed on several subtypes of T cells, NK cells, and NKT cells [ 130 , 131 , 132 , 133 ]. Recent clinical trials of CAR-T therapy in AML and/or MDS are summarized in Table 3 .…”

Section: Car-tmentioning

confidence: 99%

Therapeutic Advances in Immunotherapies for Hematological Malignancies

Nogami

Sasaki

2022

IJMS

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Following the success of immunotherapies such as chimeric antigen receptor transgenic T-cell (CAR-T) therapy, bispecific T-cell engager therapy, and immune checkpoint inhibitors in the treatment of hematologic malignancies, further studies are underway to improve the efficacy of these immunotherapies and to reduce the complications associated with their use in combination with other immune checkpoint inhibitors and conventional chemotherapy. Studies of novel therapeutic strategies such as bispecific (tandem or dual) CAR-T, bispecific killer cell engager, trispecific killer cell engager, and dual affinity retargeting therapies are also underway. Because of these studies and the discovery of novel immunotherapeutic target molecules, the use of immunotherapy for diseases initially thought to be less promising to treat with this treatment method, such as acute myeloid leukemia and T-cell hematologic tumors, has become a reality. Thus, in this coming era of new transplantation- and chemotherapy-free treatment strategies, it is imperative for both scientists and clinicians to understand the molecular immunity of hematologic malignancies. In this review, we focus on the remarkable development of immunotherapies that could change the prognosis of hematologic diseases. We also review the molecular mechanisms, development processes, clinical efficacies, and problems of new agents.

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“…The bispecific CAR T cells eliminated both primary FLT3mut and FLT3wt AML blasts, although the treatment effect on the FLT3mut AML blasts was more profound. The tumor-killing efficacy of CAR T cells improved dramatically when they were administered in combination with Gilteritinib both in vitro and in vivo [ 98 ].…”

Section: Flt3i: Indications Mechanisms Of Resistance In Vitro and In ...mentioning

confidence: 99%

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Capelli

Menotti

Fiorentini

et al. 2022

Cancers

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FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.

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A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib

Cited by 25 publications

References 75 publications

Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy

Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy

Therapeutic Advances in Immunotherapies for Hematological Malignancies

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

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