Adoptive transfer of genetically engineered WT1-specific cytotoxic T lymphocytes does not induce renal injury

Asai, Hiroaki; Fujiwara, Hiroshi; Kitazawa, Sohei; Kobayashi, Naoto; Ochi, Toshiki; Miyazaki, Yukihiro; Ochi, Fumihiro; Akatsuka, Yoshiki; Okamoto, Sachiko; Mineno, Junichi; Kuzushima, Kiyotaka; Ikeda, Hiroaki; Shiku, Hiroshi; Yasukawa, Masaki

doi:10.1186/1756-8722-7-3

Cited by 5 publications

(8 citation statements)

References 10 publications

(13 reference statements)

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“…8 Moreover, we observed that they exerted cytotoxic effects against podocytes in vitro; however, they did not damage podocytes in vivo. 23 On the basis of these findings, we planned to investigate the safety of the TCR-T cells in this clinical trial, and we did not detect any toxicity to normal tissues. At this time, the major approach to treat acute lymphoblastic leukemia and other B-cell malignancies by antigen-receptor-engineered T cells involves CAR-T cell therapy; in particular, CD19 is the most promising target antigen.…”

Section: Discussionmentioning

confidence: 99%

Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS

Tawara¹,

Kageyama

Miyahara

et al. 2017

Blood

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136

115

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Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.

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Section: Discussionmentioning

confidence: 99%

Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS

Tawara¹,

Kageyama

Miyahara

et al. 2017

Blood

Self Cite

136

115

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“…However, there are concerns about toxicities that may be induced by targeting WT1 expressed in normal tissues with high avidity TCRs. Low levels of expression of WT1 have been found in some normal adult tissues including kidney podocytes (25), CD34+ hematopoetic stem cells (13), and cardiac endothelial cells (42). No toxicities associated with targeting WT1 on normal cells have been reported in vaccine trials.…”

Section: Discussionmentioning

confidence: 99%

“…However, this may be due to the recruitment of T cells with low avidity TCRs that survived negative selection in the thymus (22). Some reports have suggested that WT1 reactive T cells can distinguish between tumor cells that overexpress WT1 and normal tissues with lower levels of expression (24, 25). However, caution seems warranted when using a high avidity WT1 reactive TCR since adoptively transferred T cells reactive with epitopes presented on normal tissues, even at very low levels, may induce severe toxicities (5, 9, 10).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, Gao et al reported that WT1 reactive T cells specifically lysed leukemia cell lines and inhibited colony formation by transformed CD34+ progenitor cells from patients with CML, whereas colony formation by normal CD34+ progenitor cells was unaffected (24). In addition, using a murine model, Asai et al reported that although WT1-specific T cells lysed kidney podocytes in vitro, they did not induce renal damage when adoptively transferred in vivo (25). …”

Section: Introductionmentioning

confidence: 99%

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A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells

Jaigirdar

Rosenberg²,

Parkhurst

2016

Journal of Immunotherapy

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Wilms’ Tumor Gene 1 (WT1) is an attractive target antigen for cancer immunotherapy because it is overexpressed in many hematologic malignancies and solid tumors but has limited, low-level expression in normal adult tissues. Multiple HLA class I and class II restricted epitopes have been identified in WT1, and multiple investigators are pursuing the treatment of cancer patients with WT1 based vaccines and adoptively transferred WT1 reactive T cells. Here we isolated an HLA-A*0201 restricted WT1 reactive T cell receptor (TCR) by stimulating PBL of healthy donors with the peptide WT1:126-134 in vitro. This TCR mediated peptide recognition down to a concentration of ~0.1 ng/ml when pulsed onto T2 cells as well as recognition of HLA-A*0201+ target cells transfected with full-length WT1 cDNA. However, it did not mediate consistent recognition of many HLA-A*0201+ tumor cell lines or freshly isolated leukemia cells that endogeneously expressed WT1. We dissected this pattern of recognition further and observed that WT1:126-134 was more efficiently processed by immunoproteasomes compared to standard proteasomes. However, pretreatment of WT1+ tumor cell lines with Interferon gamma (IFNγ) did not appreciably enhance recognition by our TCR. In addition, we highly overexpressed WT1 in several leukemia cell lines by electroporation with full-length WT1 cDNA. Some of these lines were still not recognized by our TCR suggesting possible antigen processing defects in some leukemias. These results suggest WT1:126-134 may not be a suitable target for T cell based tumor immunotherapies.

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“…Cells that are found in IH lesions include hemangioma endothelial cells (HemECs), hemangioma endothelial progenitor cells (HemEPCs), hemangioma stem cells (HemSc) and inflammatory cells [ 17 , 18 , 19 ]. Both HemEPCs and HemSc promote angiogenesis and vasculogenesis, respectively, while inflammatory cells secrete proangiogenic factors such as VEGF [ 20 ]. Thus, these inflammatory cells support neovessel formation.…”

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

Oncosuppressors and Oncogenes: Role in Haemangioma Genesis and Potential for Therapeutic Targeting

Mabeta

2018

IJMS

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Genetic lesions in proto-oncogenes result in the perturbation of angiogenesis, the formation of neovessels from a pre-existing microvasculature. Similarly, the subversion of tumor suppressor genes promotes tumor vascularization. Excessive neovessel formation is associated with various neoplasms such as infantile hemangiomas (IH). Hemangiomas are the most common tumors in pediatric patients and at present have no definitive treatment. The pathogenesis of IH is not well understood; however, both vasculogenesis and angiogenesis are associated with hemangioma genesis. A number of factors that modulate angiogenesis and vasculogenesis have been shown to be dysregulated in IH. Several of the oncogenes and tumor suppressors linked to the promotion of angiogenesis are also altered in infantile hemangioma. In this review, the roles of oncogenes and tumor suppressor genes during neovascularization and hemangioma genesis are explored. In addition, the potential for targeting these genes in IH therapy is discussed.

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Adoptive transfer of genetically engineered WT1-specific cytotoxic T lymphocytes does not induce renal injury

Cited by 5 publications

References 10 publications

Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS

Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS

A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells

Oncosuppressors and Oncogenes: Role in Haemangioma Genesis and Potential for Therapeutic Targeting

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