Case Report: Combined Intravenous Infusion and Local Injection of CAR-T Cells Induced Remission in a Relapsed Diffuse Large B-Cell Lymphoma Patient

Hu, Linhui; Wu, Fan; Wang, Huiping; Zhu, Weiwei; Wang, Juan; Yu, Fengxiang; Zhai, Zhimin

doi:10.3389/fimmu.2021.665230

Cited by 3 publications

(1 citation statement)

References 15 publications

(16 reference statements)

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“…Modification of CAR-T cells expressing specific chemokines directs CAR-T cells into the TME. Local injection of 19CAR-T cells in combination with intravenous infusion and radiotherapy before 19CAR-T cell therapy are effective alternative methods [229,230]. PETN-deficient r/r DLBCL are infiltrated with a large numbers of myeloid derived suppressor cells (MDSC), Tregs, and abundant expression of indoleamine 2,3-dioxygenase (IDO1) protein, an immunosuppressive enzyme involved in a rate-limiting step of tryptophan catabolism.…”

Section: Reviewmentioning

confidence: 99%

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

Luan¹,

Deng²

2023

Hematology and Oncology Discovery

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Refractory and/or relapsed (r/r) diffuse large B-cell lymphomas after treatment with two lines of systemic chemoimmunotherapy exhibit diversity in genetics, tissue biology, and pathology, as well as poor prognosis. Patient TCRαβ cells engineered with a CD19-specific chimeric antigen receptor (CAR) have shown promising clinical outcomes in r/r diffuse large B-cell lymphoma. The ZUMA-1 study, the JULIET study, and the TRANSCEND NHL 001 study of three prototype 19CAR-T cells have indicated an overall response rate of 52–82%, a complete response rate of 40–58%, and a 12-month progression-free survival of 33.2%–46.6%, with clinically manageable treatment related toxicity. At the 5-year follow-up, relapse was observed in approximately 57% of patients within 1 year. Understanding of the risk factors for non-response remains insufficient. In addition to intrinsic tumor resistance, such as aberrant apoptotic signaling, downregulation or loss of tumor-associated antigens (TAA), an immunosuppressive tumor microenvironment, and CAR-T cell exhaustion in vivo have been suggested to be important risk factors. Mechanisms underlying 19CAR-T cell exhaustion under chronic TAA exposure, and limited 19CAR-T cell trafficking and infiltration into the tumor mass have been reported. Moreover, tumor escape in the presence of low TAA density remains a challenge in 1928ζ CAR-T cell treatment. In this review, we provide an overview of modified modular CAR elements and their synergistic effects in controlling T-cell function. We then briefly discuss novel strategies against tumors with low TAA density, such as bispecific tandem or loop CAR recognition domains, the development of human leukocyte antigen-independent synthetic TCRαβ double-chain receptors integrated into the constant region of the TCRα chain, and armored CAR-T cells targeting the tumor microenvironment.

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Section: Reviewmentioning

confidence: 99%

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

Luan¹,

Deng²

2023

Hematology and Oncology Discovery

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Locoregional delivery of CAR-T cells in the clinic

Sagnella

White

Yeo

et al. 2022

Pharmacological Research

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Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers

Owens,

Rahman,

Bozic

2024

Preprint

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The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These find- ings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.

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Case Report: Combined Intravenous Infusion and Local Injection of CAR-T Cells Induced Remission in a Relapsed Diffuse Large B-Cell Lymphoma Patient

Cited by 3 publications

References 15 publications

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

Locoregional delivery of CAR-T cells in the clinic

Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers

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