肿瘤细胞治疗研究
英文原题：Toxoplasmosis-associated hemophagocytic lymphohistiocytosis during tumor-infiltrating lymphocyte therapy.
这是TIL治疗期间首例弓形虫病相关HLH。它强调了区分药物不耐受与真正过敏的重要性，确保深度免疫抑制患者接受抗弓形虫活性预防，并认识到HIV来源的CD4阈值可能不适用于非HIV免疫抑制人群。
噬血细胞性淋巴组织细胞增生症（HLH）是一种由感染、恶性肿瘤或自身免疫性疾病触发的严重高炎症综合征。TIL（肿瘤浸润淋巴细胞）治疗需要淋巴细胞清除性化疗和白细胞介素-2，会产生深度免疫抑制。虽然CAR-T 细胞治疗后已有HLH样综合征的报道，但TIL治疗背景下尚未有HLH的报道。刚地弓形虫是继发性HLH公认但少见的寄生虫触发因素。病例摘要：一名正在接受TIL治疗的68岁转移性黑色素瘤男性患者出现精神状态改变。他有慢性淋巴细胞减少症，并报告对甲氧苄啶-磺胺甲噁唑胃肠道不耐受，记录为磺胺类药物过敏但未经正式检测，因此预防用药仅限于吸入喷他脒，而该药无抗弓形虫活性。入院时，他发热（39.3°C），伴全血细胞减少、低纤维蛋白原血症（44 mg/dL [正常 200-400]）、高铁蛋白血症（>30,000 ng/mL [正常 30-300]）、高甘油三酯血症（410 mg/dL [正常 150]）和可溶性CD25升高（6,979.4 pg/mL [正常 175.3-858.2]）；HScore为283（HLH概率>99%）。骨髓活检显示缓殖子、速殖子、假包囊和噬血现象。播散性弓形虫病经血清弓形虫IgG阳性、IgM阴性及脑脊液弓形虫PCR 13,700拷贝/mL（参考值：未检出）确诊，脑MRI显示靶样强化病灶。开始使用乙胺嘧啶、磺胺嘧啶和亚叶酸钙治疗，但患者持续恶化并转为舒适治疗。
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome triggered by infections, malignancies, or autoimmune disorders. Tumor-infiltrating lymphocyte (TIL) therapy requires lymphodepleting chemotherapy and interleukin-2, producing profound immunosuppression. While HLH-like syndromes have been characterized after chimeric antigen receptor T-cell therapy, HLH has not been reported in the setting of TIL therapy. Toxoplasma gondii is a recognized but uncommon parasitic trigger of secondary HLH. CASE SUMMARY: A 68-year-old male with metastatic melanoma undergoing TIL therapy presented with altered mental status. He had chronic lymphopenia and reported gastrointestinal intolerance to trimethoprim-sulfamethoxazole, documented as a sulfonamide allergy without formal testing, limiting prophylaxis to inhaled pentamidine, which has no anti- Toxoplasma activity. On admission, he was febrile (39.3°C) with pancytopenia, hypofibrinogenemia (44 mg/dL [normal 200-400]), hyperferritinemia (>30,000 ng/mL [normal 30-300]), hypertriglyceridemia (410 mg/dL [normal 150]), and elevated soluble CD25 (6,979.4 pg/mL [normal 175.3-858.2]); HScore was 283 (>99% probability of HLH). Bone marrow biopsy revealed bradyzoites, tachyzoites, pseudocysts, and hemophagocytosis. Disseminated toxoplasmosis was confirmed by positive serum Toxoplasma IgG, negative IgM, and cerebrospinal fluid Toxoplasma PCR of 13,700 copies/mL (reference: not detected), with brain MRI demonstrating targetoid enhancing lesions. Treatment with pyrimethamine, sulfadiazine, and leucovorin was initiated, but the patient continued to deteriorate and transitioned to comfort measures. CONCLUSION: This represents the first toxoplasmosis-associated HLH during TIL therapy. It underscores the importance of distinguishing drug intolerance from true allergy, ensuring Toxoplasma -active prophylaxis in profoundly immunosuppressed patients, and recognizing that HIV-derived CD4 thresholds may not apply to non-HIV immunocompromised populations.
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