Everett Ashlyn S, Pavlidakey Peter G, Contreras Carlo M, De Los Santos Jennifer F, Kim Ju Y, McKee Svetlana B, Kaufman Howard L, Conry Robert M
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
Dermatopathology Services, Division of Dermatology and Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
J Cutan Pathol. 2018 Jan;45(1):48-53. doi: 10.1111/cup.13048. Epub 2017 Oct 26.
Talimogene laherparepvec (TVEC) is the first oncolytic viral immunotherapy approved by the FDA, for advanced melanoma consisting of genetically modified herpes simplex type 1 virus which selectively replicates causing tumor lysis, expressing granulocyte macrophage-colony stimulating factor (GM-CSF) and activating dendritic cells. Intratumoral injection of TVEC produces objective response in 41% of stage IIB-IV M1a melanoma. However, clinical response assessment can be problematic due to immune-related inflammation at established tumor sites. Herein, we report 5 cases of granulomatous dermatitis developing at sites of TVEC injection associated with pathologic complete response in 4 of 5 patients. Over 5 months, TVEC injections were administrated in a median of 20 tumors per patient for 9 median doses prior to biopsy of persistent, indurated nodules. Granulomatous dermatitis with melanophages and melanin pigment incontinence was observed in all samples without evidence of melanoma cells in 4 patients. The fifth patient was rendered melanoma-free by resection of the 1 nodule out of 4 with persistent tumor. Repetitive administration of TVEC or other oncolytic viral immunotherapies mimicking unresolved infection can produce granulomatous inflammation confounding assessment of the degree of tumor response and need for additional TVEC therapy. Tumor biopsies are encouraged after 4 to 6 months of TVEC administration to differentiate melanoma from granulomatous inflammation. Patients with confirmed granulomatous dermatitis replace continued with remained in remission after treatment discontinuation. Inflammatory nodules typically regress spontaneously.
Talimogene laherparepvec（TVEC）是美国食品药品监督管理局（FDA）批准的首个溶瘤病毒免疫疗法，用于治疗晚期黑色素瘤，它由基因改造的1型单纯疱疹病毒组成，该病毒可选择性复制导致肿瘤溶解，表达粒细胞巨噬细胞集落刺激因子（GM-CSF）并激活树突状细胞。瘤内注射TVEC可使41%的IIB-IV M1a期黑色素瘤产生客观反应。然而，由于既定肿瘤部位存在免疫相关炎症，临床反应评估可能存在问题。在此，我们报告5例在TVEC注射部位发生的肉芽肿性皮炎病例，其中5例患者中有4例出现了病理完全缓解。在5个月的时间里，每位患者平均对20个肿瘤进行TVEC注射，在对持续存在的硬结性结节进行活检之前平均注射9次。在所有样本中均观察到伴有噬黑素细胞和黑色素色素失禁的肉芽肿性皮炎，4例患者无黑色素瘤细胞证据。第五例患者通过切除4个有持续性肿瘤的结节中的1个而实现无黑色素瘤状态。重复给予TVEC或其他模拟未解决感染的溶瘤病毒免疫疗法可产生肉芽肿性炎症，这会混淆对肿瘤反应程度的评估以及是否需要额外TVEC治疗的判断。建议在给予TVEC 4至6个月后进行肿瘤活检，以区分黑色素瘤与肉芽肿性炎症。确诊为肉芽肿性皮炎的患者在停止治疗后继续缓解。炎症结节通常会自发消退。
