Ménager Jérémie, Gorin Jean-Baptiste, Maurel Catherine, Drujont Lucile, Gouard Sébastien, Louvet Cédric, Chérel Michel, Faivre-Chauvet Alain, Morgenstern Alfred, Bruchertseifer Frank, Davodeau François, Gaschet Joëlle, Guilloux Yannick
CRCNA-UMR 892 INSERM, Nantes, France; 6299 CNRS, Nantes, France; Université de Nantes, Nantes, France.
INSERM UMR 1064 -ITUN, Nantes, France.
PLoS One. 2015 Jun 22;10(6):e0130249. doi: 10.1371/journal.pone.0130249. eCollection 2015.
Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established.
电离辐射可直接和间接杀伤癌细胞,长期以来一直被认为具有免疫抑制作用。然而,在过去几年中这一概念有所发展,因为有证据表明辐射可增加肿瘤免疫原性,实际上有利于针对肿瘤细胞实施免疫应答。过继性T细胞转移(ACT)也用于治疗癌症,多项研究表明,这种免疫疗法与放射治疗联合使用时疗效会增强。α放射免疫疗法(α-RIT)是一种正在研发用于治疗播散性肿瘤的内放射疗法。α粒子确实能高效破坏小簇癌细胞,对周围健康组织的影响最小。因此,我们推测,在α-RIT的情况下,像ACT这样的免疫疗法可能会受益于辐射诱导的免疫环境。因此,我们决定进一步研究将α-RIT和ACT联合使用以促进高效持久抗肿瘤反应的可能性。为进行此类研究,我们建立了一种表达肿瘤抗原CD138和卵清蛋白(OVA)的多发性骨髓瘤小鼠模型。然后,我们使用与铋-213偶联的抗CD138抗体对小鼠进行α-RIT治疗,随后过继转移OVA特异性CD8+T细胞(OT-I CD8+T细胞),评估治疗效果。我们观察到联合治疗的动物肿瘤生长得到显著控制,生存期延长。这些结果证明了在我们建立的多发性骨髓瘤模型中联合使用α-RIT和ACT的疗效。
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