Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma

Bielamowicz, Kevin; Fousek, Kristen; Byrd, Tiara; Samaha, Hebatalla; Mukherjee, Malini; Aware, Nikita; Wu, Meng-Fen; Orange, Jordan S.; Sumazin, Pavel; Man, Tsz-Kwong; Joseph, Sujith; Hegde, Meenakshi; Ahmed, Nabil

doi:10.1093/neuonc/nox182

Cited by 328 publications

(278 citation statements)

References 36 publications

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“…CAR (bearing a E13Y for added specificity). All the intracranial and spinal tumors regressed though, unfortunately, soon after the treatment completion, 4 additional foci emerged and the patient relapsed probably due to escape variants [180] Since gliomas can express additional tumor associated antigens, bivalent CAR-T cells targeting HER2 via scFv and IL13Ra2 via IL13-mutein in tandem [181] or trivalent CAR-T cells specific for the HER2, IL13Ra2 and EphA2 [182] may represent a valuable treatment option. Lately,…”

Section: Non Scfv-based Carsmentioning

confidence: 99%

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Eisenberg

Hoogi

Shamul

et al. 2019

Advanced Drug Delivery Reviews

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Section: Non Scfv-based Carsmentioning

confidence: 99%

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Eisenberg

Hoogi

Shamul

et al. 2019

Advanced Drug Delivery Reviews

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“…One major area of study is the identification and validation of new target antigens, including chondroitin sulphate proteoglycan 4 (CSPG4), 104 podoplanin 105 and CD70. 107,108 These approaches have the distinct advantage of broadening the specificity of the CAR-T cell product, to address antigenic heterogeneity of tumors and reduce the chance of adaptive resistance to therapy mediated by antigen loss. [104][105][106] Combinatorial approaches are also being explored through the development of CAR-T cells which recognise more than one target antigen.…”

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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“…Alternative formats of multi-antigen CAR therapies involve co-expressing two or more CARs of different specificities in the same cell using ribosomal skip sequences, or treatment with mixed CAR-T cell populations [177][178][179] . This combinatorial approach circumvents the need for engineering and optimizing a new CAR construct; yet it is important to note that dual expression of two full-length CARs substantially increases the genetic payload to be delivered to cells, whereas adding an additional scFv module has only a minimal impact on the payload.…”

Section: Nature Biomedical Engineeringmentioning

confidence: 99%

Programming CAR-T cells to kill cancer

2018

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T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumourspecific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

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Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma

Abstract: UCAR T cells can overcome antigenic heterogeneity in GBM and lead to improved treatment outcomes.

Cited by 328 publications

References 36 publications

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

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

Programming CAR-T cells to kill cancer

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