PURPOSE To evaluate the safety and feasibility of preoperative locoregional cytokine therapy (IRX-2 regimen) in early-stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity. EXPERIMENTAL DESIGN Sixteen patients with stage I-III early-stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive preoperative locoregional immunotherapy with the IRX-2 cytokine biological (2 mL subcutaneous × 10 days to periareolar skin). The regimen also included single-dose cyclophosphamide (300 mg/m2) on day 1 to deplete T-regulatory cells and oral indomethacin to modulate suppressive myeloid subpopulations. The primary objective was to evaluate feasibility (i.e., receipt of therapy without surgical delays or grade 3/4 treatment-related adverse events). The secondary objective was to evaluate changes in stromal tumor-infiltrating lymphocyte score. The exploratory objective was to identify candidate pharmacodynamic changes for future study using a variety of assays, including flow cytometry, RNA and T-cell receptor DNA sequencing, and multispectral immunofluorescence. RESULTS Preoperative locoregional cytokine administration was feasible in 100% (n = 16/16) of subjects and associated with increases in stromal tumor-infiltrating lymphocytes (P < 0.001). Programmed death ligand 1 (CD274) was upregulated at the RNA (P < 0.01) and protein level [by Ventana PD-L1 (SP142) and immunofluorescence]. Other immunomodulatory effects included upregulation of RNA signatures of T-cell activation and recruitment and cyclophosphamide-related peripheral T-regulatory cell depletion. CONCLUSIONS IRX-2 is safe in early-stage breast cancer. Potentially favorable immunomodulatory changes were observed, supporting further study of IRX-2 in early-stage breast cancer and other malignancies.

中文翻译：

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早期乳腺癌患者术前局部区域IRX-2细胞因子免疫治疗的Ib期研究。

目的评估术前局部区域细胞因子治疗（IRX-2方案）在早期乳腺癌中的安全性和可行性，并评估其肿瘤内和外周免疫调节活性。实验设计招募了16例行手术肿块切除术或乳房切除术的I-III期早期乳腺癌（任何组织学类型）患者，接受IRX-2细胞因子生物学术前局部局部免疫治疗（皮下腔周皮肤2 mL皮下注射×10天） 。该方案还包括在第1天使用单剂量环磷酰胺（300 mg / m2）来消耗T调节细胞，并口服吲哚美辛来调节抑制性髓样亚群。主要目的是评估可行性（即接受治疗而无手术延迟或3/4级治疗相关不良事件）。次要目的是评估基质肿瘤浸润淋巴细胞评分的变化。探索性目标是使用多种测定方法，包括未来的研究，鉴定候选药效学变化，包括流式细胞仪，RNA和T细胞受体DNA测序以及多光谱免疫荧光。结果术前局部区域细胞因子的施用在100％（n = 16/16）的受试者中是可行的，并且与基质肿瘤浸润淋巴细胞的增加有关（P <0.001）。程序性死亡配体1（CD274）在RNA（P <0.01）和蛋白质水平上被上调[通过Ventana PD-L1（SP142）和免疫荧光检测]。其他免疫调节作用包括上调T细胞活化和募集的RNA信号以及环磷酰胺相关的外周T调节细胞的消耗。结论IRX-2在早期乳腺癌中是安全的。观察到潜在的有利的免疫调节变化，支持对早期乳腺癌和其他恶性肿瘤中IRX-2的进一步研究。