Use of a Single CAR T Cell and Several Bispecific Adapters Facilitates Eradication of Multiple Antigenically Different Solid Tumors

Lee, Yong Gu; Marks, Isaac; Srinivasarao, Madduri; Kanduluru, Ananda Kumar; Mahalingam, Sakkarapalayam M.; Liu, Xin; Chu, Haiyan; Low, Philip S.

doi:10.1158/0008-5472.can-18-1834

Cited by 104 publications

(97 citation statements)

References 46 publications

(58 reference statements)

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“…The kinetics of FKPB12-rapamycin disassociation depend on the availability of DARIC T cells, which will serve as binding and stabilizing partner for the FKBP12-scFv domain. Notably, several adapter-based CAR architectures have been described (21,24,40,41), using a combination of epitope-or linker-based universal CARs. The DARIC architecture combines the antigen flexibility of the universal CAR approach with the functionality and efficacy of traditional single-antigen CAR T cells.…”

Section: Discussionmentioning

confidence: 99%

Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

et al. 2019

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“…Similarly, the construction of universal CAR T cells using adapters can target multiple TAAs without re-engineering T cells. Recently universal CAR structures, such as biotin-binding immune receptor, binding fluorescein isothiocyanate (anti-FITC CAR) and antibody Fc receptor (CD16 CAR), have been developed [29][30][31]. And a SUPRA (split, universal, and programmable) CAR system has been developed, which is composed of a leucine zipper CAR (zipCAR) and a scFv binding to the leucine zipper (zipFv).…”

Section: Improving Car T Cell Antigen Recognitionmentioning

confidence: 99%

Gene modification strategies for next-generation CAR T cells against solid cancers

et al. 2020

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Immunotherapies have become the backbone of cancer treatment. Among them, chimeric antigen receptor (CAR) T cells have demonstrated great success in the treatment of hematological malignancies. However, CAR T therapy against solid tumors is less effective. Antigen targeting; an immunosuppressive tumor microenvironment (TME); and the infiltration, proliferation, and persistence of CAR T cells are the predominant barriers preventing the extension of CAR T therapy to solid tumors. To circumvent these obstacles, the next-generation CAR T cells will require more potent antitumor properties, which can be achieved by gene-editing technology. In this review, we summarize innovative strategies to enhance CAR T cell function by improving target identification, persistence, trafficking, and overcoming the suppressive TME. The construction of multi-target CAR T cells improves antigen recognition and reduces immune escape. Enhancing CAR T cell proliferation and persistence can be achieved by optimizing costimulatory signals and overexpressing cytokines. CAR T cells equipped with chemokines or chemokine receptors help overcome their poor homing to tumor sites. Strategies like knocking out immune checkpoint molecules, incorporating dominant negative receptors, and chimeric switch receptors can favor the depletion or reversal of negative T cell regulators in the TME.

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“…Application of tumour-specific ligands linked to such antigens allows them to serve as an adapter between the universal CAR and the respective tumour cell. This enables targeting of a broad variety of tumour antigens simultaneously or sequentially and without the need to engineer CAR-T cells for every single tumour under consideration, while at the same time providing better control of CAR-T cell activity [85,86].…”

Section: Novel Treatmentsmentioning

confidence: 99%

PET/CT imaging for tumour response assessment to immunotherapy: current status and future directions

Ruzicka¹,

Fabritius

Mittlmeier

et al. 2020

Eur Radiol Exp

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Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient’s own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with 18F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

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Use of a Single CAR T Cell and Several Bispecific Adapters Facilitates Eradication of Multiple Antigenically Different Solid Tumors

Abstract: Most solid tumors are comprised of multiple clones that express orthogonal antigens, suggesting that novel strategies must be developed in order to adapt chimeric antigen receptor (CAR) T-cell therapies to treat heterogeneous solid tumors.

Cited by 104 publications

References 46 publications

Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

Gene modification strategies for next-generation CAR T cells against solid cancers

PET/CT imaging for tumour response assessment to immunotherapy: current status and future directions

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