Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma.
Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma.
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DOI：
10.1007/s00262-016-1846-1
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Galili U
中科院分区：
文献类型：
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作者：
Albertini MR;Ranheim EA;Zuleger CL;Sondel PM;Hank JA;Bridges A;Newton MA;McFarland T;Collins J;Clements E;Henry MB;Neuman HB;Weber S;Whalen G;Galili U
在临床前，通过用与天然存在的抗-Gal抗体结合的α-gal糖脂原位标记肿瘤，可以实现抗原呈递细胞对肿瘤细胞衍生抗原的有效摄取。我们评估了瘤内注射 α-gal 糖脂作为黑色素瘤患者 (pts) 的自体肿瘤抗原靶向免疫疗法的毒性和可行性。患有不可切除的转移性黑色素瘤，至少有一个皮肤、皮下或可触及的淋巴结转移，且血清抗 Gal 效价 > 1:50 的患者有资格接受 2 次肿瘤内 α-gal 糖脂注射，间隔 4 周（队列 I：0.1 mg/注射；队列 II：1.0 mg/注射；队列 III：10 mg/注射）。监测包括用于临床、自身免疫和免疫学分析的血液以及核心肿瘤活检。第一次 α-gal 糖脂注射后 8 周确定治疗结果。 9 名患者接受了 2 次 α-gal 糖脂瘤内注射（3 名患者/队列）。注射部位毒性轻微，且治疗不会导致全身毒性或自身免疫。根据 RECIST 数据，两名患者病情稳定持续 8 个月和 7 个月。肿瘤结节活检显示治疗前和治疗后活检之间的炎症浸润变化极小甚至没有变化，除了 1 名患者（队列 III）出现治疗后炎症浸润。注射后 2 周和 4 周，9 名患者中的 5 名接受治疗的结节表现出肿瘤细胞坏死，但没有中性粒细胞或淋巴细胞炎症反应。 4 名可评估患者中有 2 名未经治疗的肿瘤结节也显示坏死。反复瘤内注射α-半乳糖糖脂耐受性良好，肿瘤注射α-半乳糖糖脂后，部分肿瘤结节活检可见肿瘤坏死。
Effective uptake of tumor cell derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with α-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of α-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer > 1:50 were eligible for 2 intratumoral α-gal glycolipid injections given 4 weeks apart (Cohort I: 0.1 mg/injection; Cohort II: 1.0 mg/injection; Cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first α-gal glycolipid injection. Nine pts received 2 intratumoral injections of α-gal glycolipids (3 pts/cohort). Injection site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (Cohort III) with a post-treatment inflammatory infiltrate. Two and 4 weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of α-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with α-gal glycolipids.