Vetrei Cinzia, Passariello Margherita, Froechlich Guendalina, Rapuano Lembo Rosa, Sasso Emanuele, Zambrano Nicola, De Lorenzo Claudia
Ceinge-Biotecnologie Avanzate s.c.a.r.l., Via Gaetano Salvatore 486, 80145 Naples, Italy.
Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131 Napoli, Italy.
Cancers (Basel). 2021 Dec 27;14(1):121. doi: 10.3390/cancers14010121.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by a higher mortality rate among breast cancer subtypes. Poly(ADP-ribose) polymerase (PARP) inhibitors are used in clinics to treat a subgroup of TNBC patients, but other targeted therapies are urgently needed. Programmed death-ligand 1 (PD-L1), involved in tumor immune escape, was recently identified as a target for TNBC; accordingly, the anti-PD-L1 monoclonal antibody (mAb), atezolizumab, has been approved by FDA in combination with Paclitaxel for the therapy of metastatic TNBC. Here, we tested novel combinations of fully human immunomodulatory mAbs, including anti-PD-L1 mAbs generated in our laboratory and atezolizumab, on TNBC and other tumor cell lines. We evaluated their anti-tumor efficacy when used as single agents or in combinatorial treatments with anti-CTLA-4 mAbs in in vitro co-cultures of hPBMCs with tumor cells, by measuring tumor cell lysis and IL-2 and IFNγ cytokines secretion by lymphocytes. In parallel, by using co-cultures of hPBMCs and cardiomyocytes, we analyzed the potential cardiotoxic adverse side effects of the same antibody treatments by measuring the cardiac cell lysis and the secretion of pro-inflammatory cytokines. We identified novel combinations of immunomodulatory mAbs endowed with more potent anti-cancer activity on TNBC and lower cardiotoxic side effects than the combination of atezolizumab and ipilimumab.
三阴性乳腺癌（TNBC）是一种侵袭性很强的乳腺癌亚型，在乳腺癌各亚型中死亡率较高。聚（ADP - 核糖）聚合酶（PARP）抑制剂在临床上用于治疗一部分TNBC患者，但迫切需要其他靶向治疗方法。程序性死亡配体1（PD - L1）参与肿瘤免疫逃逸，最近被确定为TNBC的一个靶点；因此，抗PD - L1单克隆抗体（mAb）阿特珠单抗已被美国食品药品监督管理局（FDA）批准与紫杉醇联合用于治疗转移性TNBC。在此，我们测试了包括我们实验室产生的抗PD - L1 mAb和阿特珠单抗在内的全人源免疫调节mAb的新型组合对TNBC和其他肿瘤细胞系的作用。在人外周血单个核细胞（hPBMC）与肿瘤细胞的体外共培养中，我们通过测量肿瘤细胞裂解以及淋巴细胞分泌白细胞介素 - 2（IL - 2）和干扰素γ（IFNγ）细胞因子，评估了它们作为单药或与抗细胞毒性T淋巴细胞相关抗原4（CTLA - 4）mAb联合治疗时的抗肿瘤疗效。同时，通过使用hPBMC与心肌细胞的共培养，我们通过测量心肌细胞裂解和促炎细胞因子的分泌，分析了相同抗体治疗潜在的心脏毒性副作用。我们确定了新型免疫调节mAb组合，其对TNBC具有更强的抗癌活性，且心脏毒性副作用低于阿特珠单抗和伊匹单抗的组合。
