Engineering CAR-T cells: Design concepts

Srivastava, Shivani; Riddell, Stanley R.

doi:10.1016/j.it.2015.06.004

Cited by 366 publications

(321 citation statements)

References 85 publications

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“…Although the epitope of FMC63 and corresponding structure of the CD19 antigen are not known (41), we hypothesized that this trend was because of a decreased distance between the target cell and sCAR-T cell. In the case of the immunological synapse formed by the native T-cell receptor, the distance between the T cell and antigen presenting cell is reported to be ∼130-150 Å (42,43). This distance is important to sterically exclude inhibitory phosphatases such as CD45 and CD148 from the synapse, which act to dephosphorylate signaling molecules and down-regulate T-cell activation (44).…”

Section: Discussionmentioning

confidence: 99%

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

Rodgers

Mazagova

Hampton

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

335

328

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Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR–T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.

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Section: Discussionmentioning

confidence: 99%

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

Rodgers

Mazagova

Hampton

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

335

328

View full text Add to dashboard Cite

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“…5,6,18 T cells expressing a CAR can specifically recognize a targeted antigen, which is an advantage of CAR T cells over nonspecific cellular therapies such as allogeneic hematopoietic stem cell transplantation. 5,6,[18][19][20] CARs are not HLA-restricted, so patients of any HLA type can be treated with CAR-T; this is an advantage of CAR-Ts over T cells engineered to express HLA-restricted TCRs. 5,21,22 In addition to an antigenrecognition domain, CARs include hinge and transmembrane regions that connect the extracellular antigen-recognition domain to cytoplasmic signaling domains.…”

Section: Chimeric Antigen Receptorsmentioning

confidence: 99%

“…5,6 CAR design and T-cell culture methods continue to undergo iterations to optimize the many factors that determine patient outcomes after infusions of CAR-Ts. 18,24,26,41 …”

Section: Implementation Of Car-t Therapiesmentioning

confidence: 99%

Chimeric antigen receptor T-cell therapies for multiple myeloma

Mikkilineni¹,

Kochenderfer

2017

Blood

184

176

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Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte–activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.

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“…Targeting of the CD19 antigen has been highly successful, with complete responses reported in up to 90% of patients with acute lymphoblastic leukemia (ALL; refs. 3,4). Despite these results, objective responses reported for solid malignancies have been less frequent (5,6).…”

Section: Introductionmentioning

confidence: 99%

A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells

et al. 2017

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Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic a-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of a-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that a-4-

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Engineering CAR-T cells: Design concepts

Cited by 366 publications

References 85 publications

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

Chimeric antigen receptor T-cell therapies for multiple myeloma

A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells

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