Single-targeted CAR-T has exhibited notable success in treating B-cell tumors, effectively improving patient outcomes. However, the recurrence rate among patients remains above fifty percent, primarily attributed to antigen escape and the diminished immune persistence of CAR-T cells. Over recent years, there has been a surge of interest in bispecific CAR-T cell therapies, marked by an increasing number of research articles and clinical applications annually. This paper undertakes a comprehensive review of influential studies on the design of bispecific CAR-T in recent years, examining their impact on bispecific CAR-T efficacy concerning disease classification, targeted antigens, and CAR design. Notable distinctions in antigen targeting within B-ALL, NHL, and MM are explored, along with an analysis of how CAR scFv, transmembrane region, hinge region, and co-stimulatory region design influence Bi-CAR-T efficacy across different tumors. The summary provided aims to serve as a reference for designing novel and improved CAR-Ts, facilitating more efficient treatment for B-cell malignant tumors.

01 Oct 2021·Journal for ImmunoTherapy of CancerQ2 · MEDICINE

4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells

Q2 · MEDICINE

ArticleOA

Author: Boucher, Justin C ; Locke, Frederick L ; Lee, Sae Bom ; Cervantes, Estelle V ; Roselli, Emiliano ; Kotani, Hiroshi ; Spitler, Kristen ; Reid, Kayla ; Tu, Nhan ; Li, Gongbo ; Davila, Marco L ; Yu, Bin ; Bulliard, Yannick

BackgroundCo-stimulatory signals regulate the expansion, persistence, and function of chimeric antigen receptor (CAR) T cells. Most studies have focused on the co-stimulatory domains CD28 or 4-1BB. CAR T cell persistence is enhanced by 4-1BB co-stimulation leading to nuclear factor kappa B (NF-κB) signaling, while resistance to exhaustion is enhanced by mutations of the CD28 co-stimulatory domain.MethodsWe hypothesized that a third-generation CAR containing 4-1BB and CD28 with only PYAP signaling motif (mut06) would provide beneficial aspects of both. We designed CD19-specific CAR T cells with either 4-1BB or mut06 together with the combination of both and evaluated their immune-phenotype, cytokine secretion, real-time cytotoxic ability and polyfunctionality against CD19-expressing cells. We analyzed lymphocyte-specific protein tyrosine kinase (LCK) recruitment by the different constructs by immunoblotting. We further determined their ability to control growth of Raji cells in NOD scid gamma (NSG) mice. We also engineered bi-specific CARs against CD20/CD19 combining 4-1BB and mut06 and performed repeated in vitro antigenic stimulation experiments to evaluate their expansion, memory phenotype and phenotypic (PD1+CD39+) and functional exhaustion. Bi-specific CAR T cells were transferred into Raji or Nalm6-bearing mice to study their ability to eradicate CD20/CD19-expressing tumors.ResultsCo-stimulatory domains combining 4-1BB and mut06 confers CAR T cells with an increased central memory phenotype, expansion, and LCK recruitment to the CAR. This enhanced function was dependent on the positioning of the two co-stimulatory domains. A bi-specific CAR targeting CD20/CD19, incorporating 4-1BB and mut06 co-stimulation, showed enhanced antigen-dependent in vitro expansion with lower exhaustion-associated markers. Bi-specific CAR T cells exhibited improved in vivo antitumor activity with increased persistence and decreased exhaustion.ConclusionThese results demonstrate that co-stimulation combining 4-1BB with an optimized form of CD28 is a valid approach to optimize CAR T cell function. Cells with both mono-specific and bi-specific versions of this design showed enhanced in vitro and in vivo features such as expansion, persistence and resistance to exhaustion. Our observations validate the approach and justify clinical studies to test the efficacy and safety of this CAR in patients.

British Journal of Haematology

Development of novel humanized CD19/BAFFR bicistronic chimeric antigen receptor T cells with potent antitumor activity against B‐cell lineage neoplasms

Article

Author: Dong, Xiaoqing ; Luo, Qian ; Shao, Bang ; Liu, Jianwei ; Li, Feiyu ; Wu, Sungui ; Hong, Yang ; Chen, Bing ; Tan, Taochao ; Zhang, Suwen ; Zhang, Cuiling

SummaryChimeric antigen receptor T cell (CAR‐T) therapy has shown remarkable efficacy in treating advanced B‐cell malignancies by targeting CD19, but antigen‐negative relapses and immune responses triggered by murine‐derived antibodies remain significant challenges, necessitating the development of novel humanized multitarget CAR‐T therapies. Here, we engineered a second‐generation 4‐1BB‐CD3ζ‐based CAR construct incorporating humanized CD19 single‐chain variable fragments (scFvs) and BAFFR single‐variable domains on heavy chains (VHHs), also known as nanobodies. The resultant CAR‐T cells, with different constructs, were functionally compared both in vitro and in vivo. We found that the optimal tandem and bicistronic (BI) structures retained respective antigen‐binding abilities, and both demonstrated specific activation when stimulated with target cells. At the same time, BI CAR‐T cells (BI CARs) exhibited stronger tumour‐killing ability and better secretion of interleukin‐2 and tumour necrosis factor‐alpha than single‐target CAR‐T cells. Additionally, BI CARs showed less exhaustion phenotype upon repeated antigen stimulation and demonstrated more potent and persistent antitumor effects in mouse xenograft models. Overall, we developed a novel humanized CD19/BAFFR bicistronic CAR (BI CAR) based on a combination of scFv and VHH, which showed potent and sustained antitumor ability both in vitro and in vivo, including against tumours with CD19 or BAFFR deficiencies.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	KR	InnoBation Bio	22 Dec 2023

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