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Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges.

ABSTRACT: MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising modality for the treatment of MM. This review article discusses the advancements and future directions of BTCE treatments for MM.

SUBMITTER: Alhallak K

PROVIDER: S-EPMC8228067 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges.

Alhallak Kinan K Sun Jennifer J Jeske Amanda A Park Chaelee C Yavner Jessica J Bash Hannah H Lubben Berit B Adebayo Ola O Khaskiah Ayah A Azab Abdel Kareem AK

Cancers 20210608 12

MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising modality for the treatment of MM. This review article discusses the advancements and future directions of BTCE treatments for MM. ...[more]

PMID: 34201007

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Project description:Bispecific T cell engagers (TCEs) are an emerging anti-cancer modality that redirects cytotoxic T cells to tumor cells expressing tumor-associated antigens (TAAs), thereby forming immune synapses to exert anti-tumor effects. Designing pharmacokinetically acceptable TCEs and optimizing their size presents a considerable protein engineering challenge, particularly given the complexity of intercellular bridging between T cells and tumor cells. Therefore, a physiologically-relevant and clinically-verified computational modeling framework is of crucial importance to understand the protein engineering trade-offs. In this study, we developed a quantitative, physiologically-based computational framework to predict immune synapse formation for a variety of molecular formats of TCEs in tumor tissues. Our model incorporates a molecular size-dependent biodistribution using the two-pore theory, extravasation of T cells and hematologic cancer cells, mechanistic bispecific intercellular binding of TCEs, and competitive inhibitory interactions by shed targets. The biodistribution of TCEs was verified by positron emission tomography imaging of [89Zr]AMG211 (a carcinoembryonic antigen-targeting TCE) in patients. Parameter sensitivity analyses indicated that immune synapse formation was highly sensitive to TAA expression, degree of target shedding, and binding selectivity to tumor cell surface TAAs over shed targets. Notably, the model suggested a "sweet spot" for TCEs' CD3 binding affinity, which balanced the trapping of TCEs in T-cell-rich organs. The final model simulations indicated that the number of immune synapses is similar (~55/tumor cell) between two distinct clinical stage B cell maturation antigen (BCMA)-targeting TCEs, PF-06863135 in an IgG format and AMG420 in a BiTE format, at their respective efficacious doses in multiple myeloma patients. This result demonstrates the applicability of the developed computational modeling framework to molecular design optimization and clinical benchmarking for TCEs, thus suggesting that this framework can be applied to other targets to provide a quantitative means to facilitate model-informed best-in-class TCE discovery and development.

Dataset Information

Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges.

Publications

Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges.

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