Schenk Erin L
Division of Medical Oncology, Department of Medicine, University of Colorado - Anschutz Medical Campus, Colorado, USA.
Transl Lung Cancer Res. 2023 Feb 28;12(2):322-336. doi: 10.21037/tlcr-22-883. Epub 2023 Feb 25.
Patients with metastatic anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC) often experience years of disease control on targeted therapies but the disease eventually develops resistance and progresses. Multiple clinical trial efforts to incorporate PD-1/PD-L1 immunotherapy into the treatment paradigm for ALK+ NSCLC have resulted in significant toxicities without clear improvement in patient outcomes. Observations from clinical trials, translational studies, and preclinical models suggest the immune system interacts with ALK+ NSCLC and this interaction is heightened with the initiation of targeted therapy. The objective of this review is to summarize knowledge to date about current and potential immunotherapy approaches for patients with ALK+ NSCLC.
To identify the relevant literature and clinical trials the databases PubMed.gov and ClinicalTrials.gov were queried with keywords "ALK" and "lung cancer". PubMed search was further refined with terms such as "immunotherapy", "tumor microenvironment or TME", "PD-1", and "T cells". The search for clinical trials was limited to interventional studies.
In this review, the current status of PD-1/PD-L1 immunotherapy for ALK+ NSCLC is updated and alternative immunotherapy approaches are highlighted in the context of available patient level and translational data on the ALK+ NSCLC tumor microenvironment (TME). An increase in CD8 T cells within the ALK+ NSCLC TME has been observed with targeted therapy initiation across multiple studies. Therapies to augment this including tumor infiltrating lymphocyte (TIL) therapy, modified cytokines, and oncolytic viruses are reviewed. Furthermore, the contribution of innate immune cells in TKI mediated tumor cell clearance is discussed as a future target for novel immunotherapy approaches that promote cancer cell phagocytosis.
Immune modulating strategies derived from current and evolving knowledge of the ALK+ NSCLC TME may have a role in ALK+ NSCLC beyond PD-1/PD-L1 based immunotherapy.
转移性间变性淋巴瘤激酶（ALK）阳性非小细胞肺癌（NSCLC）患者通常能通过靶向治疗实现数年的疾病控制，但疾病最终会产生耐药并进展。多项将PD-1/PD-L1免疫疗法纳入ALK阳性NSCLC治疗模式的临床试验努力，导致了显著的毒性反应，而患者预后并未得到明显改善。来自临床试验、转化研究和临床前模型的观察结果表明，免疫系统与ALK阳性NSCLC相互作用，且这种相互作用在靶向治疗开始后会增强。本综述的目的是总结目前关于ALK阳性NSCLC患者现有及潜在免疫治疗方法的知识。
为识别相关文献和临床试验，在PubMed.gov和ClinicalTrials.gov数据库中使用关键词“ALK”和“肺癌”进行查询。PubMed搜索进一步用“免疫疗法”、“肿瘤微环境或TME”、“PD-1”和“T细胞”等术语进行细化。对临床试验的搜索仅限于干预性研究。
在本综述中，更新了PD-1/PD-L1免疫疗法治疗ALK阳性NSCLC的现状，并在关于ALK阳性NSCLC肿瘤微环境（TME）的可用患者水平和转化数据的背景下，突出了替代免疫治疗方法。多项研究观察到，在ALK阳性NSCLC TME中，随着靶向治疗的开始，CD8 T细胞数量增加。对增强这种作用的疗法进行了综述，包括肿瘤浸润淋巴细胞（TIL）疗法、修饰的细胞因子和溶瘤病毒。此外，还讨论了先天免疫细胞在TKI介导的肿瘤细胞清除中的作用，将其作为促进癌细胞吞噬作用的新型免疫治疗方法的未来靶点。
基于目前对ALK阳性NSCLC TME的认识及不断发展的知识所衍生的免疫调节策略，可能在ALK阳性NSCLC中发挥作用，超越基于PD-1/PD-L1的免疫疗法。
