Extracellular Vesicles Derived from Chimeric Antigen Receptor-T Cells: A Potential Therapy for Cancer

Aharon, Anat; Horn, Galit; Bar-Lev, Tali Hana; Yohay, Einav Zagagi; Waks, Tova; Levin, Maya; Unger, Naamit Deshet; Avivi, Irit; Levin, Anat Globerson

doi:10.1089/hum.2021.192

Cited by 33 publications

(35 citation statements)

References 43 publications

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“…The expression of CAR was confirmed by flow cytometry based on the co-expressed GFP fluorescence ( Figure 1 B). The correlation between the GFP and ErbB2CAR expression was previously established by our group [ 21 ]. ErbB2CAR was efficiently expressed in T cells with a 50% ± 4.2% transduction on average ( Figure 1 C).…”

Section: Resultsmentioning

confidence: 99%

Comparing Intraperitoneal and Intravenous Personalized ErbB2CAR-T for the Treatment of Epithelial Ovarian Cancer

et al. 2022

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High-grade serous ovarian carcinoma (HGSOC) is the most common type of epithelial ovarian cancer. The majority of cases are diagnosed at advanced stages, when intraperitoneal (IP) spread has already occurred. Despite significant surgical and chemotherapeutic advances in HGSOC treatment over the past decades, survival rates with HGSOC have only modestly improved. Chimeric antigen receptor (CAR)-T cells enable T cells to directly bind to tumor-associated antigens in a major histocompatibility complex-independent manner, thereby inducing tumor rejection. While CAR-T cell therapy shows great promise in hematological malignancies, its use in solid tumors is limited. Therefore, innovative approaches are needed to increase the specificity of CAR-modified T cells against solid tumors. The aim of this study was to assess the efficacy and safety of intraperitoneal (IP) versus intravenous (IV) CAR-T cell therapy in the treatment of HGSOC. We constructed a CAR that targets the ErbB2/HER2 protein (ErbB2CAR), which is overexpressed in HGSOC, and evaluated the functionality of ErbB2CAR on ovarian cancer cell lines (OVCAR8, SKOV3, and NAR). Our findings show that an IP injection of ErbB2CAR-T cells to tumor-bearing mice led to disease remission and increased survival compared to the IV route. Moreover, we found that IP-injected ErbB2CART cells circulate to a lesser extent, making them safer for non-tumor tissues than IV-injected cells. Further supporting our findings, we show that the effect of ErbB2CAR-T cells on primary HGSOC tumors is correlated with ErbB2 expression. Together, these data demonstrate the advantages of an IP administration of CAR-T cells over IV administration, offering not only a safer strategy but also the potential for counteracting the effect of ErbB2CAR in HGSOC. Significance: IP-injected ErbB2CAR-T cells led to disease remission and increased survival compared to the IV route. These findings demonstrate the advantages of IP administration, offering a safe treatment strategy with the potential for counteracting the effect of ErbB2CAR in HGSOC.

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Section: Resultsmentioning

confidence: 99%

Comparing Intraperitoneal and Intravenous Personalized ErbB2CAR-T for the Treatment of Epithelial Ovarian Cancer

et al. 2022

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“…Also, exosomes derived from immunogenically dying tumor cells have been exploited as nanovaccines for immunotherapy (Zhou et al, 2022). EVs derived from chimeric antigen receptor (CAR)-T cells expressed lower cytokine levels than CAR-T cells in stimulated tumor cells (Aharon et al, 2021). Overall, EVs, a natural drug delivery vehicle, can overcome the disadvantages of liposomal formulations and have a great potential for drug delivery as an alternative to cell-based therapies.…”

Section: High Efficient Drug Delivery Vehicles and Anticancer Vaccinesmentioning

confidence: 99%

Biological Features of Extracellular Vesicles and Challenges

Zeng

Qiu

Jiang

et al. 2022

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) are vesicles with a lipid bilayer membrane on the outside, which are widely found in various body fluids and contain biological macromolecules such as DNA, RNA, lipids and proteins on the inside. EVs were once thought to be vesicles for the removal of waste materials, but are now known to be involved in a variety of pathophysiological processes in many diseases. This study examines the advantage of EVs and the challenges associated with their application. A more rational use of the advantageous properties of EVs such as composition specificity, specific targeting, circulatory stability, active penetration of biological barriers, high efficient drug delivery vehicles and anticancer vaccines, oxidative phosphorylation activity and enzymatic activity, and the resolution of shortcomings such as isolation and purification methods, storage conditions and pharmacokinetics and biodistribution patterns during drug delivery will facilitate the clinical application of EVs.

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“…Since CAR is an artificial molecule containing the CD3ζ intracellular signaling and localization domain, it was unknown whether CAR was present in exosomes and shedding vesicles, and whether CAR conferred a specific cytotoxic effect, until recent reports characterized CAR expression and function in exosomes [ 55 ] and shedding vesicles [ 137 ]. This prerequisite has been endorsed in several preclinical studies by using exosomes and/or EV produced by CAR T cells [ 55 , 80 , 138 ] ( Table 1 ).…”

Section: Chimeric Antigen Receptor (Car) T Cells and Car T Cell-deriv...mentioning

confidence: 99%

“…These CAR T cell-derived exosomes specifically induce apoptosis of tumor cells expressing the antigens recognized by CAR on the cell surface but do not kill tumor cells that do not express these antigens [ 55 ]. Comparable results have been obtained using HEK-derived exosomes, showing that only when exosome entry into cells is mediated via binding to the CD19 antigen on the surface of CD19 + B-cells does pro-apoptotic signaling occur resulting in selective cytotoxicity [ 80 , 138 ]. Certainly, the evoked apoptotic mechanism does not depend on FasL, Apo2L, perforin and granzymes, as for CAR T-cell derived exosomes, since HEK293 cells do not express these molecules.…”

Section: Chimeric Antigen Receptor (Car) T Cells and Car T Cell-deriv...mentioning

confidence: 99%

“…Fourth, it is remarkable that engineered CAR T cells are cultured during 7–9 days in the presence of interleukin-2 to expand the culture, after the initial stimulation with anti-CD3/CD28 to facilitate CAR transduction [ 55 , 80 , 138 ]. Subsequently, the induction of exosome secretion requires restimulation of the expanded CAR T cells with antigen-expressing cells or anti-CD3/CD28.…”

Section: Future Developments In the Field And Concluding Remarksmentioning

confidence: 99%

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T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy

Calvo

Izquierdo

2022

Cells

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Extracellular vesicles (EV) are a very diverse group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular exchange, both nearby and systemically, since they induce signals and transmit their cargo (proteins, lipids, miRNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. However, cell surface receptor-induced EV release is limited to cells from the immune system, including T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptors for antigen and several bioactive molecules, including proapoptotic proteins. These EV are specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we examine the generation of EV by T lymphocytes and CAR-T cells and some potential therapeutic approaches of these EV.

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Extracellular Vesicles Derived from Chimeric Antigen Receptor-T Cells: A Potential Therapy for Cancer

Cited by 33 publications

References 43 publications

Comparing Intraperitoneal and Intravenous Personalized ErbB2CAR-T for the Treatment of Epithelial Ovarian Cancer

Comparing Intraperitoneal and Intravenous Personalized ErbB2CAR-T for the Treatment of Epithelial Ovarian Cancer

Biological Features of Extracellular Vesicles and Challenges

T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy

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