First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity.
First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity.
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DOI：
10.1186/1479-5876-8-71
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发表时间：
2010-07-23
影响因子：
7.4
通讯作者：
Triebel F
中科院分区：
文献类型：
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作者：
Brignone C;Gutierrez M;Mefti F;Brain E;Jarcau R;Cvitkovic F;Bousetta N;Medioni J;Gligorov J;Grygar C;Marcu M;Triebel F
IMP321是一种重组的可溶性LAG-3Ig融合蛋白，可高亲和力与MHC-II类分子结合，介导APC，进而激活抗原体验的记忆性CD8+T细胞。我们报道了转移性乳腺癌(MBC)患者每周接受一线紫杉醇治疗3周的I/II期临床和生物学结果。MBC患者接受一剂IMP321皮下注射。每两周一次，共24周(12次注射)。紫杉醇化疗后d2、d16重复单次给药(80 mg/m2，d1、d8、d15，共6个周期)。在第6次和第12次注射IMP321后第13天采血，测定持续的APC、NK和记忆性CD8 T细胞应答。30例MBC患者接受IMP321治疗，分3组(剂量分别为0.25、1.25和6.25 mg)。IMP321诱导APC(单核细胞和树突状细胞)数量和活性持续增加，NK细胞和长寿细胞毒性效应-记忆CD8 T细胞百分率增加。在6个月时，90%的患者只有3个进展期，临床受益。此外，与历史对照组报告的25%相比，目标肿瘤缓解率为50%是有利的。无毒和活性的展示有力地支持了这种药物在联合一线方案中临床应用的未来发展。临床试验.gov NCT00349934
IMP321 is a recombinant soluble LAG-3Ig fusion protein that binds to MHC class II with high avidity and mediates APC and then antigen-experienced memory CD8+ T cell activation. We report clinical and biological results of a phase I/II in patients with metastatic breast carcinoma (MBC) receiving first-line paclitaxel weekly, 3 weeks out of 4. MBC patients were administered one dose of IMP321 s.c. every two weeks for a total of 24 weeks (12 injections). The repeated single doses were administered the day after chemotherapy at D2 and D16 of the 28-day cycles of paclitaxel (80 mg/m2 at D1, D8 and D15, for 6 cycles). Blood samples were taken 13 days after the sixth and the twelfth IMP321 injections to determine sustained APC, NK and memory CD8 T cell responses. Thirty MBC patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). IMP321 induced both a sustained increase in the number and activation of APC (monocytes and dendritic cells) and an increase in the percentage of NK and long-lived cytotoxic effector-memory CD8 T cells. Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Also, the objective tumor response rate of 50% compared favorably to the 25% rate reported in the historical control group. The absence of toxicity and the demonstration of activity strongly support the future development of this agent for clinical use in combined first-line regimens. ClinicalTrials.gov NCT00349934