Development, BriaCell Therapeutics Corp, Philadelphia, PA, USA.
Hematology Oncology, Providence Medical Group Santa Rosa - Cancer Center, Santa Rosa, CA, USA.
Hum Vaccin Immunother. 2024 Dec 31;20(1):2379864. doi: 10.1080/21645515.2024.2379864. Epub 2024 Aug 20.
This Phase I/IIa open-label, single-arm clinical trial addressing advanced, refractory, metastatic breast cancer was conducted at six medical centers in the United States. We repeated inoculations with irradiated SV-BR-1-GM, a breast cancer cell line with antigen-presenting activity engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), with pre-dose low-dose cyclophosphamide and post-dose local interferon alpha. Twenty-six patients were enrolled; 23 (88.5%) were inoculated, receiving a total of 79 inoculations. There were six Grade 4 and one Grade 5 adverse events noted (judged unrelated to SV-BR-1-GM). Disease control (stable disease [SD]) occurred in 8 of 16 evaluable patients; 4 showed objective regression of metastases, including 1 patient with near-complete regressions in 20 of 20 pulmonary lesions. All patients with regressions had human leukocyte antigen (HLA) matches with SV-BR-1-GM; non-responders were equally divided between matching and nonmatching ( = .01, Chi-squared), and having ≥2 HLA matches with SV-BR-1-GM ( = 6) correlated with clinical benefit. Delayed-type hypersensitivity (DTH) testing to candida antigen and SV-BR-1-GM generated positive responses (≥5 mm) in 11 (42.3%) and 13 (50%) patients, respectively. Quantifying peripheral circulating tumor cells (CTCs) and cancer-associated macrophage-like cells (CAMLs) showed that a drop in CAMLs was significantly correlated with an improvement in progression-free survival (PFS; 4.1 months vs. 1.8 months, = .0058). Eight of 10 patients significantly upregulated programmed cell death ligand 1 (PD-L1) on CTCs/CAMLs with treatment ( = .0012). These observations support the safety of the Bria-IMT regimen, demonstrate clinical regressions, imply a role for HLA matching, and identify a possible value for monitoring CAMLs in peripheral blood.
这项在美国六个医学中心进行的 I/IIa 期开放标签、单臂临床试验旨在治疗晚期、难治性转移性乳腺癌。我们使用经过照射的 SV-BR-1-GM 进行了重复接种，SV-BR-1-GM 是一种具有抗原呈递活性的乳腺癌细胞系，经过基因工程改造后可以释放粒细胞-巨噬细胞集落刺激因子（GM-CSF）。在接种前给予低剂量环磷酰胺，接种后给予局部干扰素-α。共纳入 26 例患者；23 例（88.5%）患者进行了接种，共接种 79 次。有 6 例（23.1%）患者发生 4 级不良事件，1 例（3.8%）患者发生 5 级不良事件（判断与 SV-BR-1-GM 无关）。16 例可评估患者中有 8 例（50%）出现疾病控制（稳定疾病[SD]）；4 例患者的转移瘤出现客观消退，其中 1 例患者 20 个肺病变中有 20 个接近完全消退。所有消退的患者均与 SV-BR-1-GM 具有人类白细胞抗原（HLA）匹配；非应答者在匹配和不匹配之间平分秋色（ = .01，卡方检验），并且与 SV-BR-1-GM 具有≥2 个 HLA 匹配（ = 6）与临床获益相关。对念珠菌抗原和 SV-BR-1-GM 的迟发型超敏反应（DTH）检测在 11 例（42.3%）和 13 例（50%）患者中产生阳性反应（≥5mm）。定量检测外周循环肿瘤细胞（CTC）和癌相关巨噬样细胞（CAML）显示，CAML 下降与无进展生存期（PFS）的改善显著相关（4.1 个月 vs. 1.8 个月， = .0058）。10 例患者中有 8 例患者的 CTC/CAML 上程序性死亡配体 1（PD-L1）显著上调（ = .0012）。这些观察结果支持 Bria-IMT 方案的安全性，证明了临床消退，暗示了 HLA 匹配的作用，并确定了监测外周血中 CAML 的潜在价值。
