Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy

Pellegatta, Serena; Savoldo, Barbara; Ianni, Natalia Di; Corbetta, Cristina; Chen, Yuhui; Patanè, Monica; Sun, Chuang; Pollo, Bianca; Ferrone, Soldano; DiMeco, Francesco; Finocchiaro, Gaetano; Dotti, Gianpietro

doi:10.1126/scitranslmed.aao2731

Cited by 99 publications

(106 citation statements)

References 66 publications

(96 reference statements)

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“…106 All of these antigens are overexpressed in glioblastoma patient specimens, and CAR-T cells targeting them reduce glioblastoma growth in mouse models. [104][105][106] Combinatorial approaches are also being explored through the development of CAR-T cells which recognise more than one target antigen. Thus, Ahmed et al have developed tandem CAR-T cells ('TanCAR') that recognise both HER2 and IL13Ra2 via a single CAR molecule incorporating recognition domains for both antigens, as well as 'U-CAR' T cells that recognise HER2, IL-13Ra2 and EphA2 via expression of a tri-cistronic CAR transgene.…”

Section: Route Of Administrationmentioning

confidence: 99%

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

2019

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Chimeric antigen receptor (CAR)‐T cell therapy is now approved in the United States and Europe as a standard treatment for relapsed/refractory B‐cell malignancies. It has also been approved recently by the Therapeutic Goods Administration in Australia and may soon be publicly reimbursed. This advance has accentuated scientific, clinical and commercial interest in adapting this exciting technology for the treatment of solid cancers where it is widely recognised that the challenges of overcoming a hostile tumor microenvironment are most acute. Indeed, CAR‐T cell technology may be of the greatest value for those cancers that lack pre‐existing immunity because they are immunologically ‘cold’, or have a low somatic tumor mutation load, or both. These cancers are generally not amenable to therapeutic immune checkpoint blockade, but CAR‐T cell therapy may be effective because it provides an abundant supply of autologous tumor‐specific T cells. This is achieved by using genetic engineering to re‐direct autologous T‐cell cytotoxicity towards a tumor‐associated antigen, bypassing endogenous T‐cell requirements for antigen processing, MHC‐dependent antigen presentation and co‐stimulation. One of the most challenging solid cancers is glioblastoma, which has among the least permissive immunological milieu of any cancer, and which is almost always fatal. Here, we argue that CAR‐T cell technology may counter some glioblastoma defences and provide a beachhead for furthering our eventual therapeutic aims of restoring effective antitumor immunity. Although clinical investigation of CAR‐T cell therapy for glioblastoma is at an early stage, we discuss three recently published studies, which feature significant differences in target antigen, CAR‐T cell phenotype, route of administration and tumor response. We discuss the lessons, which may be learned from these studies and which may guide further progress in the field.

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Section: Route Of Administrationmentioning

confidence: 99%

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

2019

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“…Another study screened a panel of primary GBM samples representing various molecular subtypes, and identified Chondroitin sulfate proteoglycan 4 (CSPG4, also known as neuron‐glial antigen 2, NG2) to be widely expressed across these tumors . Moreover, CSPG4 expression can be induced by the immune‐stimulatory cytokine TNFα, which is produced during CAR T cell anti‐tumor responses thereby making tumor antigen escape less likely …”

Section: Overcoming Tumor Heterogeneitymentioning

confidence: 99%

“…117 Another study screened a panel of primary GBM samples representing various molecular subtypes, and identified Chondroitin sulfate proteoglycan 4 (CSPG4, also known as neuron-glial antigen 2, NG2) to be widely expressed across these tumors. 119 Moreover, CSPG4 expression can be induced by the immune-stimulatory cytokine TNFα, which is produced during CAR T cell anti-tumor responses thereby making tumor antigen escape less likely. 119 Glioblastoma tumors contain specific subsets with the characteristics of self-renewal and tumor regeneration, and studies have shown these GBM stem-like cells (GSCs) to mediate resistance against radiotherapy and chemotherapy.…”

Section: Discovering New Targetsmentioning

confidence: 99%

“…119 Moreover, CSPG4 expression can be induced by the immune-stimulatory cytokine TNFα, which is produced during CAR T cell anti-tumor responses thereby making tumor antigen escape less likely. 119 Glioblastoma tumors contain specific subsets with the characteristics of self-renewal and tumor regeneration, and studies have shown these GBM stem-like cells (GSCs) to mediate resistance against radiotherapy and chemotherapy. 120 The ability to eliminate GSCs, therefore, is essential for GBM-targeting therapies to minimize tumor recurrence.…”

Section: Discovering New Targetsmentioning

confidence: 99%

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CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

165

161

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Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

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“…Although xenograft models cannot completely model the situation in a human body, immunodeficient mice are frequently used to evaluate the in vivo antitumor effects of human T and NK cells. [36][37][38][39] Hence, we employed immunodeficient mice in the present study to test the combination of OV with human NK cells. As expected, OVs expressing CCL5 increased the intratumorous expression of this chemokine and so could be used to enhance NK cell recruitment in vivo ( figure 6), indicating the combination strategy may be applicable to humans.…”

Section: Synergistic Administration Of Ov and Nk In Vivomentioning

confidence: 99%

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

Sheng

Hou

et al. 2020

J Immunother Cancer

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BackgroundNatural killer (NK) cells have potent antitumor activities. Nevertheless, adoptive transfer therapy of NK cells has gained very limited success in patients with solid tumors as most infused NK cells remain circulating in the peripheral blood instead of entering tumor sites. Chemokines and their receptors play important roles in NK cell distribution. Enhancing chemokine receptors on immune cells to match and be driven to tumor-specific chemokines may improve the therapeutic efficacy of NK cells.MethodsThe CCR5-CCL5 axis is critical in NK cell homing to tumor sites. Thus, we analyzed CCR5 expression on NK cells from patients with cancer and healthy donors. We then upregulated CCR5 and CCL5 with lentiviruses and oncolytic viruses in NK and tumor cells, respectively. Animal experiments were also carried out to test the efficacy of the combination of oncolytic virus with NK cells.ResultsIn NK cells from patients with various solid tumors or healthy subjects, CCR5 was expressed at low levels before and after expansion in vitro. CCR5-engineered NK cells showed enhanced tumor infiltration and antitumor effects, but no complete regressions were noted in the in vivo tumor models. To further improve therapeutic efficacy, we constructed CCL5-expressing oncolytic vaccinia virus. In vitro data demonstrated that vaccinia virus can produce CCL5 in tumor cells while infectivity remained unaffected. Supernatants from tumor cells infected by CCL5-modified vaccinia virus enhanced the directional movement of CCR5-overexpressed NK cells but not green fluorescent protein (GFP)-expressing cells. More importantly, NK cells were resistant to the vaccinia virus and their functions were not affected after being in contact. In vivo assays demonstrated that CCL5-expressing vaccinia virus induced a greater accumulation of NK cells within tumor lesions compared with that of the prototype virus.ConclusionEnhancement of matched chemokines and chemokine receptors is a promising method of increasing NK cell homing and therapeutic effects. Oncolytic vaccinia viruses that express specific chemokines can synergistically augment the efficacies of NK cell-based therapy.

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Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy

Cited by 99 publications

References 66 publications

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

CAR T cells for brain tumors: Lessons learned and road ahead

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

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