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T Cells:Regulation and Cellular Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Several cell-surface molecules serve as markers of T cell differentiation. The marker expressed earliest in T cell development is CD7. This early stage is not yet committed to the T cell lineage, and may enter erythroid, myeloid, or megakaryocytoid pathways. The role of CD7 in T cell differentiation is unknown. Some CD7+ cells also express CD34. Both CD7+/CD34+ and CD7+/CD34− cells may become either T cells or other cell types. The function of CD34 is also unknown.
Immunophenotypic Markers
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
CD7 is a membrane-bound glycoprotein that is expressed very early in T-cell development. CD7 is a pan-T-cell antigen expressed by peripheral (mature) T-cell lymphoproliferations (e.g., PTCL, T-PLL, ATLL, MF, SS, T-LGL leukemia, NK cell leukemia/lymphoma), and T-ALL. CD7 is very often aberrantly expressed (either negative or dim) in peripheral T-cell disorders. In precursor T-cell neoplasms, CD7 is most often positive and shows a bright expression when analyzed by flow cytometry (only ~2% cases are CD7−). Other hematopoietic tumors that may express CD7 include BPDCN, MPAL, and AML. APL and B-cell lymphoproliferations are typically CD7−.
Integrins, Integrin Regulators, and the Extracellular Matrix
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Stephen W. Hunt, Sirid-Aimée Kellermann, Yoji Shimizu
The complexity of inside-out signaling is illustrated by the identification of multiple activation stimuli that can up-regulate integrin functional activity. These activation signals can be grouped as pharmacologic agents or receptor-mediated signals. Treatment of T cells with either the phorbol ester PMA or the Ca2+ ionophore A23187 has been shown to up-regulate integrin-mediated T-cell adhesion (28,41,43,44). This suggests that both protein kinase C (PKC) activation and changes in intracellular Ca2+ are involved in the intracellular signaling events that upregulate integrin activity. More significantly, mAb-mediated cross-linking of a litany of cell surface receptors can induce an inside-out signal. Such receptors are designated “integrin regulators” in this review. Leukocytes express a wide array of integrin regulators on the cell surface. Using T cells as an example, ligation of a number of cell surface receptors can result in up-regulation of β1 and β2 integrin functional activity. T-cell integrin regulators include the CD3/TCR complex, as well as the accessory molecules CD2, CD28, and CD7 (41–43). CD2, CD7, and CD28 are all IgSF members. The CD2 antigen is a 45–55 kD protein that was initially identified as an important signaling molecule on human T cells and NK cells (45,46). Subsequently, CD2 was shown to mediate T-cell adhesion by binding to its counter-receptor, LFA-3 (47). The CD28 antigen is a 44 kD molecule that has been extensively studied because of its importance in delivering a signal to T cells that is believed to be critical to the prevention of T-cell tolerance upon encounter with antigen (48). At least two distinct CD28 counter-receptors, B7–1 and B7–2, have been identified and there has been extensive analysis of CD28-mediated signaling as it relates to T-cell proliferation and cytokine production (48). CD7 is a 40 kD antigen that is expressed on T cells and NK cells. The function of CD7 is unknown at present. All three of these integrin regulators facilitate CD3-mediated T cell proliferation, suggesting that inside-out signaling mediated by these molecules is particularly important in enhancing T cell responses to foreign antigen.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
First studies using CD7CAR T cells showed an incomplete downregulation of CD7 on transduced CAR T cells leading to fratricide [131]. Abrogating CD7 expression was then proposed by various specific techniques, such as blockade of CD7 protein trafficking [132], and CRISPR/Cas9 gene editing [133]. Consequently, a robust anti-tumor activity was observed in both preclinical and clinical studies against CD7+ T-ALL. Another risk with CD7CAR T cells is T-cell depletion and immunodeficiency. Activation of an inducible suicide gene was proposed to avoid such side effects [134]. Fratricide-resistant anti-CD7 CAR T cells have also been developed from healthy donors [133]. These allogeneic CAR T cells have the advantage to be immediately available but also to eliminate the risk of graft-versus-host disease (GvHD). Several studies using CD7CAR T cells, involving overall more than 40 T-ALL patients, have already been published [135–139]. ORR and CR ranged from 63% to 100%. CRS was observed in all cases.
Immunotoxins and nanobody-based immunotoxins: review and update
Published in Journal of Drug Targeting, 2021
Mohammad Reza Khirehgesh, Jafar Sharifi, Fatemeh Safari, Bahman Akbari
The cluster of differentiation 7 (CD7) is one of the cell surface glycoproteins that overexpresses in leukaemia and T-cell lymphoma. VHH6 is an anti-CD7 Nb that use to design two monovalent and bivalent PG001 (VHH-PE38) and PG002 (VHH-VHH-PE38) recombinant ITs, respectively. After the expression of PG001 and PG002, the binding activities of them were assessed on a high expression CD7 cell line (Jurkat) by flow cytometry assays. Also, Wst 8 assay by CD7 positive cell lines showed that PG002 was powerful than PG001 in proliferation inhibition [158]. For the immunogenicity reduction and cytotoxic activity improvement of PG002, three new formats developed include dVHH6-PE-LR, dhuVHH6-PE38, and dhuVHH6-PE-LR. After the expression of these recombinant ITs, the flow cytometry assay confirmed their high affinity to the positive CD7 cell lines (CEM and Jurkat). In vivo assessment of the humanised ITs (dhuVHH6-PE38 and dhuVHH6-PE-LR) in NOD-Prkdcem26I12rgem26Nju (NCG) mice xenotransplanted with CEM cells showed that dhuVHH6-PE38 had better antitumour activity and extends the survival of NCG [159].
Investigational treatment options in phase I and phase II trials for relapsed or refractory acute lymphoblastic leukemia in pediatric patients
Published in Expert Opinion on Investigational Drugs, 2021
Julie M. Asare, Cara A. Rabik, Bradley Muller, Patrick A. Brown, Stacy Cooper
Currently, Texas Children’s Hospital has an open phase 1 study for anti-CD5 CAR T-cells for patients with relapsed or recurrent T-cell malignancies, including T-ALL and T-lymphoblastic lymphoma (T-Lly) [47]. Of note, preclinical studies showed only limited fratricide from co-expression of CD5 on CAR T-cells, without significant ex vivo limitations of expansion. As such, manipulation of the CAR T-cells to prevent fratricide was not undertaken in this protocol [47,48]. The Baylor College of Medicine will soon be opening a study of autologous T-cells directed against CD7, using CRISPR/Cas9 to remove CD7 from the CAR T-cells prior to infusion and prevent fratricide as described above [42,46]. As CD7 is present on a number of malignancies, T-ALL and T-NHL will be included in this study (estimated opening date of March 2021) [49].