Cord blood (CB)-derived chimeric antigen receptor (CAR)-natural killer (NK) cells targeting CD19 have been shown to be effective against B cell malignancies. While human CD56
To the Editor[colon] Febrile episodes are frequently encountered during the chemotherapy course, especially with neutropenia, but it is not always easy to evaluate the cause of fever. Fever induced by vincristine (VCR) is well known, but its pathophysiology is poorly understood. We describe here a case of VCR-induced fever, in which cellular hypersensitivity to VCR was demonstrated by leukocyte migration test (LMT). Fever repeatedly occurred after combination chemotherapy including VCR in a 2-year-old boy with advanced rhabdomyosarcoma, and it also occurred after a single administration of VCR. There were no other clinical symptoms except for fever, and laboratory tests showed normal findings. Fever resolved spontaneously within 24 hours without any antibiotics. The course with chemotherapy that consisted of cisplatin and actinomycin D was uneventful. The course with prophylactic administration of hydrocortisone just before VCR administration was also uneventful. These clinical observations suggested that an allergic response to VCR might be involved in the pathophysiology of fever. Leukocyte migration testing was performed according to the manner previously reported with a slight modification (1). The results of LMT are provided in Table 1. Migration index with VCR concentration of 2.5ng/mL and the patient's serum were significantly higher than that of normal controls (P [lt] 0.01). The LMT was considered positive at this concentration, and high migration index was interpreted as indicating the detection of leukocyte migration activating factor. Lymphocyte stimulation test with VCR was negative, with a stimulation index of 102[percnt].TABLE 1: Results of leukocyte migration testThe LMT is one of the sensitive tests for the detection of delayed type hypersensitivity (1). Concerning this method, Uno et al. (2,3) speculated that lymphocytes cultured with a stimulator secreted some cytokines in the culture medium, and the cytokines could inhibit or enhance the migration of human leukocytes (granulocytes). It may be considered that a hypersensitive reaction was reduced in the bioassay, such as LMT or lymphocyte stimulation test with cytotoxic drugs. However, in this case, leukocyte migration was enhanced despite the presence of VCR in the supernatant fluid. These findings indicated the possible involvement of cell-mediated hypersensitivity to VCR in the pathophysiology of fever in this patient. Only LMT with the patient's serum revealed a positive result. Because VCR is of relatively low molecular weight (923.05), it may be combined with some substances in the serum and form a complete antigen capable of stimulating lymphocytes. Ishii (4) reported that VCR-induced fever was observed in 9 of 31 children undergoing maintenance chemotherapy for leukemia or lymphoma. They also reported that the duration of fever was more prolonged during a chemotherapy course without corticosteroids than in those with corticosteroids, suggesting the possible involvement of an allergic mechanism. To our best knowledge, this is the first case of cellular hypersensitivity to VCR in VCR-induced fever. Fujimori (5) reported a case of hypersensitivity pneumonitis, in which delayed type hypersensitivity to paclitaxel was demonstrated by LMT. Leukocyte migration testing may be useful for the detection of cellular hypersensitivity to other cytotoxic drugs. In evaluating the cause of fever in patients with chemotherapy including VCR, physicians should pay attention to the possible involvement of an allergic mechanism. Chihaya Imai M.D. Katsuji Uno Ph.D. Toshio Kakihara M.D., Ph.D. Atsushi Tanaka M.D., Ph.D. Makoto Uchiyama M.D., Ph.D.
Abstract Introduction: In Japan since 2019, CAR-T cell therapy has been used to treat patients with relapsed or refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma and has shown excellent clinical results. Clinical studies of CAR-T cell therapies targeting various antigens, such as HER2, have been conducted, but the therapeutic outcome in sarcoma is still limited. We have previously reported that HER2-targeted CAR-T cells show antitumor effects for synovial sarcoma in vitro. The purpose of this study is to compare HER2-targeted CAR-T cells and NKG2D-based CAR-T cells in antitumor effect and specific responses for synovial sarcoma in vitro. Materials and Methods: Surface expressions of HER2 and NKG2D ligands on three synovial sarcoma cell lines were detected by using recombinant human HER2 Fc chimeric protein and that of NKG2D, followed by staining with PE-conjugated anti-human IgG secondary antibody. We generated 4-1BB-type second generation CAR-T cells targeting NKG2D ligands and examined their antitumor effects and specific responses against synovial sarcoma cells. In addition, we compared the differences between HER2-targeted CAR-T cells and NKG2D-based CAR-T cells by co-culturing with synovial sarcoma cells using short-term assay (WST-8 assay), long-term assay (Real-time Cell Analysis) and CD107a assay. Results: HER2 and NKG2D ligands were found to be expressed by flow cytometry in three synovial sarcoma cell lines. In vitro, NKG2D-based CAR-T cells showed antitumor effects against synovial sarcoma cells, including degranulation and cytokine production. Furthermore, NKG2D-based CAR-T cells showed stronger antitumor effects than HER2-targeted CAR-T cells in both short- and long-term assays and expressed higher levels of CD107a. Conclusions: In this study, NKG2D-based CAR-T cells showed more antitumor effects than HER2-targeted CAR-T cells in vitro. Although the reason for this is not clear, we hypothesize that NKG2D ligands may be induced in synovial sarcoma cells by co-culture with CAR-T cells because HER2 is a cancer-specific antigen, whereas NKG2D ligands are ligands for activating receptors of natural killer cells. Further studies, including in vivo studies, will be conducted to verify the difference in anti-tumor effects between these CAR-T cells. Citation Format: Tomohiro Miyazaki, Chihaya Imai, Naoki Oike, Yudai Murayama, Takashi Ariizumi, Minori Baba, Yasushi Kasahara, Hiroyuki Kawashima. Effectiveness and comparison of CAR-T cell therapies for synovial sarcoma; HER2-targeted CAR-T and NKG2D-based CAR-T [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7259.
To clarify the mechanism of progression and acquired drug resistance of leukemia, we searched for an overexpressed gene in drug-resistant leukemia cells and identified an approximately 5-kb transcript by using the subtraction method. The nucleotide sequence of the gene was highly homologous to those of human endogenous retrovirus (HERV) transcripts. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that the gene was overexpressed in cells from 6 childhood acute lymphoblastic leukemia patients (60%) but not in bone marrow cells at remission. Peripheral blood mononuclear cells from normal controls (n=11) and bone marrow cells from non-leukemia patients (n=13) did not express the gene. These findings indicate that the gene may play a role in leukemogenesis and may be a novel leukemia marker. Further studies on the functional role of the gene are needed.
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