PDF(Pubmed)
Abstract：
Immune checkpoint inhibition (ICI) therapies have reshaped the therapeutic landscape in lung cancer management, providing first-time improvements in patient response, prognosis, and overall survival. Despite their clinical effectiveness, variability in treatment responsiveness, as well as drug resistance, have led to a compelling need for predictive biomarkers facilitating the individualized selection of the most efficient therapeutic approach. Significant progress has been made in the identification of such biomarkers, with tumor mutation burden (ΤΜΒ) appearing as the leading and most promising predictive biomarker for the efficacy of ICIs in non-small cell lung cancer (NSCLC) among other tumors. Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies have been extensively studied and clinically utilized. However, the overall efficiency of these drugs remains unsatisfactory, urging for the investigation of novel inhibitors, such as those targeting LAG-3, TIM-3, TIGIT and VISTA, which could be used either as a monotherapy or synergistically with the PD-1/PD-L1 or CTLA-4 blockers. Here, we investigate the role of TMB and cancer neoantigens as predictive biomarkers in the response of lung cancer patients to different ICI therapies, specifically focusing on the most recent immune checkpoint inhibitors, against LAG-3, TIM-3, TIGIT and VISTA. We further discuss the new trends in immunotherapies, including CAR T-cell therapy and personalized tumor vaccines. We also review further potential biomarkers that could be used in lung cancer response to immunotherapy, such as PD-L1+ IHC, MSI/dMMR, tumor infiltrating lymphocytes (TILs), as well as the role of the microbiome and circulating tumor DNA (ctDNA). Finally, we discuss the limitations and challenges of each.
摘要：
免疫检查点抑制（ICI）疗法重塑了肺癌管理的治疗前景，首次改善患者反应，预后,和总体生存率。尽管他们的临床效果，治疗反应性的变异性，以及抗药性，导致了对预测性生物标志物的迫切需求，以促进最有效的治疗方法的个性化选择。在识别此类生物标志物方面取得了重大进展，肿瘤突变负荷（TΜΒ）似乎是ICIs在非小细胞肺癌（NSCLC）等肿瘤中的疗效的主要和最有希望的预测生物标志物。抗PD-1/PD-L1和抗CTLA-4抗体已被广泛研究和临床利用。然而,这些药物的整体疗效仍不能令人满意，敦促研究新型抑制剂，例如针对LAG-3，TIM-3，TIGIT和VISTA的那些，可以作为单一疗法或与PD-1/PD-L1或CTLA-4阻断剂协同使用。这里,我们研究了TMB和癌症新抗原作为预测生物标志物在肺癌患者对不同ICI疗法的反应中的作用，特别关注最新的免疫检查点抑制剂，针对LAG-3、TIM-3、TIGIT和VISTA。我们进一步讨论免疫疗法的新趋势，包括CAR-T细胞疗法和个性化肿瘤疫苗。我们还回顾了可用于肺癌免疫疗法反应的其他潜在生物标志物。如PD-L1+IHC，MSI/DMMR,肿瘤浸润淋巴细胞（TIL），以及微生物组和循环肿瘤DNA（ctDNA）的作用。最后,我们讨论了每一个的局限性和挑战。
