Immunodepletion of MDSC by AMV564, a novel bivalent, bispecific CD33/CD3 T cell engager, ex vivo in MDS and melanoma

Cheng, Pinyang; Chen, Xianghong; Dalton, Robert; Calescibetta, Alexandra; So, Tina; Gilvary, Danielle L.; Ward, Grace A; Smith, Victoria; Eckard, Sterling; Fox, Judith A.; Guenot, Jeanmarie; Markowitz, Joseph; Cleveland, John L.; Wright, Kenneth L.; List, Alan F.; Wei, Sheng; Eksioglu, Erika A.

doi:10.1016/j.ymthe.2022.02.005

Cited by 19 publications

(16 citation statements)

References 55 publications

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“…More importantly, Fultang et al uncovered that a CD33 monoclonal antibody (Gemtuzumab) increased the death of CD33 + MDSCs, restored T cell proliferation, and showed satisfactory results in subsequent clinical trials [ 145 – 147 ]. Cheng et al developed a CD33/CD3 bispecific T cell splice agent, AMV564, which effectively depleted CD33 hi MDSCs in MDS and improved T-cell antitumor activity, and its combination with immune checkpoint inhibitors improved patient resistance to AMV564 [ 148 ]. In addition, similar T cell binding bispecific antibodies in MM are capable of redirecting host T cell cytotoxicity to malignant clonal MM cells as well as MDSCs in an MHC-independent manner [ 149 ].…”

Section: Introductionmentioning

confidence: 99%

Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin

Ren

2022

Exp Hematol Oncol

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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of bone marrow cells originating from immature myeloid cells. They exert potent immunosuppressive activity and are closely associated with the development of various diseases such as malignancies, infections, and inflammation. In malignant tumors, MDSCs, one of the most dominant cellular components comprising the tumor microenvironment, play a crucial role in tumor growth, drug resistance, recurrence, and immune escape. Although the role of MDSCs in solid tumors is currently being extensively studied, little is known about their role in hematologic malignancies. In this review, we comprehensively summarized and reviewed the different roles of MDSCs in hematologic malignancies and hematopoietic stem cell transplantation, and finally discussed current targeted therapeutic strategies.Affiliation: Kindly check and confirm the processed affiliations are correct. Amend if any.correct

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Section: Introductionmentioning

confidence: 99%

Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin

Ren

2022

Exp Hematol Oncol

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“…The trial showed an OS at 1.8 years of 53%, which prompts additional clinical trials using radioimmunotherapy as part of the conditioning regimen for allogeneic HSCT [34]. In contrast with 131 I, 90 Y does not require isolation of the patient, providing a potential advantage in the management and quality of life for AML patients.…”

Section: Targeting Cd45mentioning

confidence: 93%

“…This study showed that Iomab-B can be safely combined with a RIC regimen to achieve complete remission for older, HR patients with AML, and it is currently being tested in the phase III SIERRA trial (NCT02665065) [33]. 90 Y-BC8, an anti-CD45 monoclonal antibody conjugated with 90 Y, was proven to be well tolerated in a phase I trial (NCT01300572) in combination with FLU/TBI in R/R AML ineligible for myeloablative HSCT. The trial showed an OS at 1.8 years of 53%, which prompts additional clinical trials using radioimmunotherapy as part of the conditioning regimen for allogeneic HSCT [34].…”

Section: Targeting Cd45mentioning

confidence: 99%

“…Recent studies have analyzed anti-CD33 BiTEs and trispecific killer engagers (TriKEs) in MDS. AMV564, a CD33XCD3 BiTE, was evaluated in a preclinical study, which showed its in vitro ability to reduce the MDSC count and to increase the anti-PD1 antibody activity [ 90 ]. GTB-3550 is a CD33/CD16/IL15 TriKE, consisting of a fusion of two scFv, one against CD33 and one against CD16, bridged by an IL15 linker that promotes NK activation [ 43 ].…”

Section: Target Immunotherapies In Mdsmentioning

confidence: 99%

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New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Gallazzi

Ucciero²,

Faraci³

et al. 2022

IJMS

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Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent an unmet clinical need whose prognosis is still dismal. Alterations of immune response play a prominent role in AML/MDS pathogenesis, revealing novel options for immunotherapy. Among immune system regulators, CD47, immune checkpoints, and toll-like receptor 2 (TLR2) are major targets. Magrolimab antagonizes CD47, which is overexpressed by AML and MDS cells, thus inducing macrophage phagocytosis with clinical activity in AML/MDS. Sabatolimab, an inhibitor of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which disrupts its binding to galectin-9, has shown promising results in AML/MDS, enhancing the effector functions of lymphocytes and triggering tumor cell death. Several other surface molecules, namely CD33, CD123, CD45, and CD70, can be targeted with monoclonal antibodies (mAbs) that exert different mechanisms of action and include naked and conjugated antibodies, bispecific T-cell engagers, trispecific killer engagers, and fusion proteins linked to toxins. These novel mAbs are currently under investigation for use as monotherapy or in combination with hypomethylating agents, BCL2 inhibitors, and chemotherapy in various clinical trials at different phases of development. Here, we review the main molecular targets and modes of action of novel mAb-based immunotherapies, which can represent the future of AML and higher risk MDS treatment.

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“…The suppression of CD8 + T lymphocyte function was also shown to be mediated by different mechanisms such as the STA3-ARG1 or TIM3/Gal-9 pathways [ 101 , 129 ]. Altogether, these findings clearly identify a critical role of MDSCs in the dysregulation of immune surveillance in MDS and lead, therefore, to the development of therapeutic strategies directly targeting MDSC functions in MDS patients [ 132 , 133 , 134 , 135 ].…”

Section: Abnormal Immune Cell Repartition And/or Functions During The...mentioning

confidence: 99%

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

Simoni

Chapuis

2022

Diagnostics

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Myelodysplastic syndromes (MDS) constitute a very heterogeneous group of diseases with a high prevalence in elderly patients and a propensity for progression to acute myeloid leukemia. The complexity of these hematopoietic malignancies is revealed by the multiple recurrent somatic mutations involved in MDS pathogenesis and the paradoxical common phenotype observed in these patients characterized by ineffective hematopoiesis and cytopenia. In the context of population aging, the incidence of MDS will strongly increase in the future. Thus, precise diagnosis and evaluation of the progression risk of these diseases are imperative to adapt the treatment. Dysregulations of both innate and adaptive immune systems are frequently detected in MDS patients, and their critical role in MDS pathogenesis is now commonly accepted. However, different immune dysregulations and/or dysfunctions can be dynamically observed during the course of the disease. Monitoring the immune system therefore represents a new attractive tool for a more precise characterization of MDS at diagnosis and for identifying patients who may benefit from immunotherapy. We review here the current knowledge of the critical role of immune dysfunctions in both MDS and MDS precursor conditions and discuss the opportunities offered by the detection of these dysregulations for patient stratification.

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Immunodepletion of MDSC by AMV564, a novel bivalent, bispecific CD33/CD3 T cell engager, ex vivo in MDS and melanoma

Cited by 19 publications

References 55 publications

Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin

Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin

New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

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