Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML).

Ravandi, Farhad; Walter, Roland B.; Subklewe, Marion; Buecklein, Veit; Jongen‐Lavrencic, Mojca; Paschka, Peter; Ossenkoppele, Gert J.; Kantarjian, Hagop M.; Hindoyan, Antreas; Agarwal, Suresh; Dai, Tian; Khaldoyanidi, Sophia; Stein, Anthony S.

doi:10.1200/jco.2020.38.15_suppl.7508

Cited by 76 publications

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“…Responding patients were allowed to proceed to allo-SCT. There were more responders among patients with a lower (<25%) leukemic burden at the time of treatment initiation, and there was no correlation between response and CD33 expression on leukemic blasts ( 71 ).…”

Section: T Cell Engagersmentioning

confidence: 96%

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

Isidori¹,

Cerchione

Daver

et al. 2021

Front. Oncol.

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In the past few years, our improved knowledge of acute myeloid leukemia (AML) pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest. A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new stimuli in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients. The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant (allo-SCT), remains a major hurdle in the path to cure for AML patients. Several clinical trials with immune-based therapies are currently ongoing in the frontline, relapsed/refractory, post-allo-SCT and minimal residual disease/maintenance setting, with the aim to improve survival of AML patients. This review summarizes the available data with immune-based therapeutic modalities such as monoclonal antibodies (naked and conjugated), T cell engagers, adoptive T-cell therapy, adoptive-NK therapy, checkpoint blockade via PD-1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade via the CD47/SIRPa axis, and leukemia vaccines. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.

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Section: T Cell Engagersmentioning

confidence: 96%

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

Isidori¹,

Cerchione

Daver

et al. 2021

Front. Oncol.

Self Cite

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show abstract

“…CRS was reversible and was associated with the dose level and leukemic burden at baseline. Among 42 patients evaluable for response, there were 3 CR and 4 complete remission with incomplete hematological recovery (CRi) observed at the dose of ≥120 μg/d [52]. In addition, preliminary results from an ongoing phase 1clincal trial (NCT03224819) have shown anti-leukemic activity of HLE-BiTE AMG 673 in the treatment of R/R AML [53].…”

Section: Clinical Advances Of Bite In Hematological Malignanciesmentioning

confidence: 99%

The landscape of bispecific T cell engager in cancer treatment

et al. 2021

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T cell-based immunotherapies have revolutionized treatment paradigms in various cancers, however, limited response rates secondary to lack of significant T-cell infiltration in the tumor site remain a major problem. To address this limitation, strategies for redirecting T cells to treat cancer are being intensively investigated, while the bispecific T cell engager (BiTE) therapy constitutes one of the most promising therapeutic approaches. BiTE is a bispecific antibody construct with a unique function, simultaneously binding an antigen on tumor cells and a surface molecule on T cells to induce tumor lysis. BiTE therapy represented by blinatumomab has achieved impressive efficacy in the treatment of B cell malignancies. However, major mechanisms of resistance to BiTE therapy are associated with antigen loss and immunosuppressive factors such as the upregulation of immune checkpoints. Thus, modification of antibody constructs and searching for combination strategies designed to further enhance treatment efficacy as well as reduce toxicity has become an urgent issue, especially for solid tumors in which response to BiTE therapy is always poor. In particular, immunotherapies focusing on innate immunity have attracted increasing interest and have shown promising anti-tumor activity by engaging innate cells or innate-like cells, which can be used alone or complement current therapies. In this review, we depict the landscape of BiTE therapy, including clinical advances with potential response predictors, challenges of treatment toxicity and resistance, and developments of novel immune cell-based engager therapy.

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“…A feasibility study to evaluate outpatient treatment of MRD-positive patients is about to start recruiting in May 2021 (NCT04506086). Besides, the anti-BCMA/CD3 BiTE AMG-420, formerly known as BI 836909, has shown promising activity in r/r MM, including MRD-negative complete responses (NCT02514239) [ 149 ], with an ongoing expansion study (NCT03836053), while the anti-CD33/CD3 BiTE AMG-330 is currently in phase 1 testing (NCT02520427) [ 150 ]. Another elegant platform is GEMoaB’s “affinity-tailored adaptors for T-cells” (ATAC) fully humanized tandem scFv platform, which employs high binding affinity to TAA and lower affinity to CD3, thus preventing T-cell auto-activation in preclinical models [ 151 ].…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Elshiaty

Schindler

Christopoulos

2021

IJMS

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Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.

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Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML).

Cited by 76 publications

References 0 publications

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

The landscape of bispecific T cell engager in cancer treatment

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

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