Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T‐cell malignancies

Perera, Liyanage P.; Zhang, Meili; Nakagawa, Masao; Petrus, Michael; Maeda, Masako; Kadin, Marshall E.; Waldmann, Thomas A.; Perera, Pin-Yu

doi:10.1002/ajh.24794

Cited by 75 publications

(54 citation statements)

References 51 publications

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“…In the advanced stage of ATL, leukemic cells are supposed to be IL-2-unresponsive, from which IL-2-dependent non-leukemic cell line, but not leukemic cell line, could be established. mechanism and the therapeutic agents effective for the therapy of ATL (Zhang et al, 2015;Perera et al, 2017;Nakagawa et al, 2018). These tumorigenic leukemic T-cell lines could also be used to search the drugs for the treatment of ATL.…”

Section: Discussionmentioning

confidence: 99%

IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia

et al. 2020

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T cells infected with human T-cell leukemia virus type 1 (HTLV-1) transform into malignant/leukemic cells and develop adult T-cell leukemia (ATL) after a long latency period. The tax (transactivator from the X-gene region) and HBZ (HTLV-1 bZIP factor) genes of HTLV-1 play crucial roles in the development of ATL. The process and mechanism by which HTLV-1-infected T cells acquire malignancy and develop ATL remain to be elucidated. Constitutive expression of interleukin-2 (IL-2) receptor α-chain (IL-2Rα/CD25), induced by the tax and HBZ genes of HTLV-1, on ATL cells implicates the involvement of IL-2/IL-2R pathway in the growth and development of ATL cells in vivo. However, the leukemic cells in the majority of ATL patients appeared unresponsive to IL-2, raising controversies on the role of this pathway for the growth of ATL cells in vivo. Here, we report the establishment of 32 IL-2-dependent T-cell lines infected with HTLV-1 from 26 ATL patients, including eight leukemic cell lines derived from five ATL patients, while no T-cell lines were established without IL-2. We have shown that the IL-2-dependent ATL cell lines evolved into IL-2-independent/unresponsive growth phase, resembling ATL cells in vivo. Moreover, the IL-2-dependent non-leukemic T-cell lines infected with HTLV-1 acquired IL-2-independency and turned into tumor-producing cancer cells as with the ATL cell lines. HTLV-1-infected T cells in vivo could survive and proliferate depending on IL-2 that was produced in vivo by the HTLV-1-infected T cells of ATL patients and patients with HTLV-1-associated diseases and, acts as a physiological molecule to regulate T-cell growth. These results suggest that ATL cells develop among the HTLV-1-infected T cells growing dependently on IL-2 and that most of the circulating ATL cells progressed to become less responsive to IL-2, acquiring the ability to proliferate without IL-2.

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Section: Discussionmentioning

confidence: 99%

IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia

et al. 2020

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“…Recently there have been dramatic advances in cancer immunotherapy which has ascended to a primary focus of new approaches for the treatment of patients with metastatic malignancy. Attractive immunotherapeutic approaches have included cell therapy with chimeric antigen receptors (45)(46)(47), as well as agents that reverse the action of checkpoint inhibitors that augment a patient's response albeit inadequate to their tumor (48). Monoclonal antibodies long have been an element in the armamentarium against cancer.…”

Section: Discussionmentioning

confidence: 99%

IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages

Zhang

Wen

Antón

et al. 2018

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

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The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies.

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“…CAR-T cells have not only been administered concomitantly with agents that modulate the tumour microenvironment 53 , but have also been engineered to directly modulate it, for example through overexpression of heparanase for degradation of the ECM, which resulted in enhanced therapeutic efficacy in a neuroblastoma tumour model 140 . CAFs involved in maintaining the ECM can also be targeted using CARs specific for fibroblast activation protein 141 , and other cancer-associated cells such as TAMs, TECs and T regs can be targeted using CARs directed against tumour-microenvironment-specific antigens 118,[142][143][144] .…”

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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Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T‐cell malignancies

Cited by 75 publications

References 51 publications

IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia

IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia

IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages

Programming CAR-T cells to kill cancer

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