Godfroid Céline, Romero Jackeline, Labiano Sara, Chuang Chia-Hsien, Kelemen Andrea, Wyss Tania, Roh Vincent, Verdeil Grégory, Klein Christian, Codarri Deak Laura, Umaña Pablo, Tolstonog Genrich V, Trumpfheller Christine, Vozenin Marie-Catherine, Romero Pedro J
Department of Oncology, University of Lausanne, Epalinges, Switzerland.
Department of Radiation Oncology, CHUV, Lausanne, Switzerland.
J Immunother Cancer. 2025 Jan 22;13(1):e009832. doi: 10.1136/jitc-2024-009832.
More efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immunotherapy combining hypofractionated radiotherapy (HRT) with muPD1-IL2v immunocytokine and muFAP-CD40 bispecific antibody.
We evaluated the changes in the lung immune microenvironment at multiple timepoints following combination therapies and investigated their underlying antitumor mechanisms. Additionally, we analyzed the tumor clonal heterogeneity upon the combination treatments to explore potential mechanisms associated with the lack of complete response.
The combination of HRT with muPD1-IL2v had a potent antitumor effect and increased survival in the SV2-OVA lung cancer model. Importantly, this combination therapy was devoid of measurable toxicity. It induced remodeling of the immune contexture through the increase of CD8 T and natural killer (NK) cells. The addition of muFAP-CD40 to the combination treatment further increased infiltrating CD8 T cells, expressing high levels of effector molecules, both in the periphery and core tumor regions. An accumulation of CD8 PD-1 TOX (exhausted) T cells, already at the 'early' timepoint, is consistent with the limited clinical benefits provided by the various combination treatments in this model. The study of the clonal dynamics of tumor cells during disease progression and therapy highlighted a clonal selection upon HRT+muPD1-IL2v therapy.
We demonstrated that HRT+muPD1-IL2v combination is a potent therapeutic strategy to delay tumor growth and increase survival in a metastatic lung cancer model, but additional studies are required to completely understand the resistance mechanisms associated with the lack of complete response in this model.
由于转移性疾病的5年生存率几乎为零，因此需要更有效的非小细胞肺癌（NSCLC）治疗方案。在这方面，我们使用转移性肺腺癌的临床前模型（SV2-OVA）来评估新型放射免疫疗法的安全性和有效性，该疗法将低分割放疗（HRT）与muPD1-IL2v免疫细胞因子和muFAP-CD40双特异性抗体相结合。
我们在联合治疗后的多个时间点评估了肺部免疫微环境的变化，并研究了其潜在的抗肿瘤机制。此外，我们分析了联合治疗后的肿瘤克隆异质性，以探索与缺乏完全缓解相关的潜在机制。
HRT与muPD1-IL2v联合使用在SV2-OVA肺癌模型中具有强大的抗肿瘤作用并提高了生存率。重要的是，这种联合疗法没有可测量的毒性。它通过增加CD8 T细胞和自然杀伤（NK）细胞诱导了免疫结构的重塑。在联合治疗中加入muFAP-CD40进一步增加了浸润性CD8 T细胞，这些细胞在外周和肿瘤核心区域均表达高水平的效应分子。即使在“早期”时间点，CD8 PD-1 TOX（耗竭）T细胞的积累也与该模型中各种联合治疗所提供的有限临床益处一致。对疾病进展和治疗期间肿瘤细胞克隆动态的研究突出了HRT+muPD1-IL2v治疗后的克隆选择。
我们证明HRT+muPD1-IL2v联合疗法是一种有效的治疗策略，可延缓转移性肺癌模型中的肿瘤生长并提高生存率，但需要进一步研究以完全了解该模型中与缺乏完全缓解相关的耐药机制。
