CAR T Cells Redirected to CD44v6 Control Tumor Growth in Lung and Ovary Adenocarcinoma Bearing Mice

Porcellini, Simona; Asperti, Claudia; Corna, Stefano; Cicoria, Eleonora; Valtolina, Veronica; Stornaiuolo, Anna; Valentinis, Barbara; Bordignon, Claudio; Traversari, Catia

doi:10.3389/fimmu.2020.00099

Cited by 48 publications

(60 citation statements)

References 37 publications

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“…The results were compared to the historical data reported in Porcellini and colleagues. 15 As shown in Figure 8B, CD44v6-NWN2.CAR T cells were able to extend overall survival, more efficiently than CD44v6-NWL.CAR T cells (P ≤0.0075). Altogether, the data obtained in the two tumor models, suggest that the changes introduced in the spacer region of the CD44v6-NWN2 CAR, improve CAR T antitumor efficacy.…”

Section: Cd44v6-nwn2car T Cells Mediates In Vivo Antitumor Activity mentioning

confidence: 76%

“…Recently, we demonstrated that CD44v6.CAR T based adoptive therapy led to tumor growth control in human ovarian and lung carcinoma models, 15 therefore, we investigated CD44v6-NWN2.CAR T antitumor activity in the CD44v6 positive IGROV-1 ovarian carcinoma model. Following our well-established protocol, 15 NSG mice (n=5/group) were implanted subcutaneously with 3x10 5 IGROV-1 cells, six days later were infused iv with 4.5x10 6…”

Section: Cd44v6-nwn2car T Cells Mediates In Vivo Antitumor Activity mentioning

confidence: 99%

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Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer

et al. 2021

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Effectiveness of adoptively transferred chimeric antigen receptor (CAR) T cells strongly depends on the quality of CAR-mediated interaction of the effector cells with the target antigen on tumor cells. A major role in this interaction is played by the affinity of the scFv for the antigen, and by the CAR design. In particular, the spacer domain may impact on the CAR T cell function by affecting the length and flexibility of the resulting CAR. This study addresses the need to improve the manufacturing process and the antitumor activity of CD44v6-specific CAR T cells by defining the optimal structure of a spacer region derived from the extracellular domain of the human low affinity nerve growth factor receptor (LNGFR). We tailored the LNGFR spacer to modulate CAR length in order to efficiently recognize distal or proximal epitopes and to allow selection of transduced CAR T cells by the use of clinical grade validated manufacturing systems. The different LNGFR spacers investigated in this study are responsible for the generation of CAR T cells with a different memory phenotype, which is mainly related to the level of CAR expression and the extent of the associated tonic signaling. In particular, the CD44v6-NWN2.CAR T cells are enriched in central memory cells and show improved in vitro functions in term of killing capability, and in vivo antitumor activity against hematological and solid tumors.

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Section: Cd44v6-nwn2car T Cells Mediates In Vivo Antitumor Activity mentioning

confidence: 76%

Section: Cd44v6-nwn2car T Cells Mediates In Vivo Antitumor Activity mentioning

confidence: 99%

Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer

et al. 2021

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“…Majority of CAR designed to target AML can recognize normal cells including hematopoietic stem cells, and hence, are associated with risks of BM failure [ 92 ]. To mitigate the treatment associated toxicities while utilizing the potency of CAR-based therapies, multiple studies focused on identification of antigens selectively expressed on AML cell surface and identified spliced variants of Flt3, NOTCH, and CD44 [ 93 , 94 , 95 ]. These targets showed comparable levels of anti-leukemic activity and lower off-tumor toxicity towards hematopoietic stem cells (HSCs) in preclinical models, but their safety and efficacy profile in clinical settings are not yet determined [ 96 , 97 ].…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

State-of-Art of Cellular Therapy for Acute Leukemia

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Vasic

Kang

et al. 2021

IJMS

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With recent clinical breakthroughs, immunotherapy has become the fourth pillar of cancer treatment. Particularly, immune cell-based therapies have been envisioned as a promising treatment option with curative potential for leukemia patients. Hence, an increasing number of preclinical and clinical studies focus on various approaches of immune cell-based therapy for treatment of acute leukemia (AL). However, the use of different immune cell lineages and subsets against different types of leukemia and patient disease statuses challenge the interpretation of the clinical applicability and outcome of immune cell-based therapies. This review aims to provide an overview on recent approaches using various immune cell-based therapies against acute B-, T-, and myeloid leukemias. Further, the apparent limitations observed and potential approaches to overcome these limitations are discussed.

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“…CD44v6-CAR T cells have been generated to target leukemia and myeloma cells. These CAR T cells display potent in vitro and in vivo anti-tumor reactivity ( 92 – 94 ). However, because CD44v6 is also highly expressed in some normal tissues, especially in the skin, the safety of this treatment has to be proven before applying this therapy to humans.…”

Section: Search For Novel Antigens: Targeting Of Car T Cells To Cancementioning

confidence: 99%

Identification of Targets to Redirect CAR T Cells in Glioblastoma and Colorectal Cancer: An Arduous Venture

2020

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The chimeric antigen receptor (CAR) is an artificial molecule engineered to induce cytolytic T cell reactions in tumors. Generally, this molecule combines an extracellular single-chain variable fragment (scFv) able to recognize tumor-associated epitopes together with the intracellular signaling domains that are required for T cell activation. When expressed by T cells, the CAR enables the recognition and subsequent destruction of cancer cells expressing the complementary antigen on their surface. Although the clinical application for CAR T cells is currently limited to some hematological malignancies, researchers are trying to develop CAR T cell-based therapies for the treatment of solid tumors. However, while in the case of CD19, or other targets restricted to the hematopoietic compartment, the toxicity is limited and manageable, the scarcity of specific antigens expressed by solid tumors and not by healthy cells from vital organs makes the clinical development of CAR T cells in this context particularly challenging. Here we summarize relevant research and clinical trials conducted to redirect CAR T cells to surface antigens in solid tumors and cancer stem cells with a focus on colorectal cancer and glioblastoma. Finally, we will discuss current knowledge of altered glycosylation of CSCs and cancer cells and how these novel epitopes may help to target CAR T cell-based immunotherapy in the future.

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CAR T Cells Redirected to CD44v6 Control Tumor Growth in Lung and Ovary Adenocarcinoma Bearing Mice

Cited by 48 publications

References 37 publications

Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer

Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer

State-of-Art of Cellular Therapy for Acute Leukemia

Identification of Targets to Redirect CAR T Cells in Glioblastoma and Colorectal Cancer: An Arduous Venture

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