Within RCC, bladder cancer, and NSCLC, next-generation PD-(L)1 combinations are reshaping treatment across all disease stages, and the magnitude of benefit, the relevant biomarkers, and the toxicity trade-offs differ substantially by tumor type and by setting.
This review summarizes immune resistance in NSCLC through a framework that distinguishes primary resistance from acquired resistance, and discusses mechanism-based biomarkers, translational correlates, and rational therapeutic strategies for overcoming resistance.
Bo Yuan, Wenzhi Deng, Juan Luo et al.· Frontiers in Immunology· 0 citations
Immune checkpoint inhibitors (ICIs), particularly antibodies targeting PD-1/PD-L1 and CTLA-4, have reshaped the treatment landscape of lung cancers, most notably non-small cell lung cancer (NSCLC). Nevertheless, only a subset of patients achieve durable benefit due to primary and acquired resistance that arises from tumor-intrinsic factors (e.g., oncogenic drivers and adaptive signaling), tumor-extrinsic determinants in the tumor microenvironment (TME) (e.g., impaired T-cell infiltration and immunosuppressive myeloid populations), and the dynamic evolution of biomarkers. Accordingly, current clinical and translational efforts in lung cancer focus on rational combination strategies—ICIs with chemotherapy, radiotherapy, and targeted agents (including RTK- and KRAS-pathway inhibitors)—as well as alternative approaches that modulate antigen presentation, myeloid regulation, and cancer stemness. In this review, we define a lung cancer–centered scope and summarize (i) established and emerging ICI-based regimens in lung cancer, (ii) mechanisms of resistance relevant to NSCLC and SCLC, (iii) biomarker integration for patient selection and monitoring, and (iv) future directions to optimize efficacy and safety through combinatory and alternative immunotherapeutic strategies.
Junyoung Park, Choong‐Hwan Kwak, Yu-Chan Chang et al.· Frontiers in Immunology· 0 citations
Current evidence supports PD-L1 as the most widely implemented biomarker, but no single factor adequately captures the biological and temporal heterogeneity of treatment response, so integrated, dynamic, and context-specific biomarker models are required to improve precision immuno-oncology.
Longhua Lu, Ze-Yang Zeng, Zi-Qi Guan et al.· Journal of Clinical Question· 0 citations
Immune checkpoint inhibition has transformed the treatment of advanced non-small cell lung cancer (NSCLC), but primary and acquired resistance remain common. Vascular endothelial growth factor (VEGF) contributes to both tumor angiogenesis and immune suppression by promoting abnormal vasculature, limiting lymphocyte trafficking, and fostering an immunosuppressive tumor microenvironment. These complementary mechanisms provide a rationale for simultaneously targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and VEGF pathways. Bispecific antibodies integrating checkpoint blockade and VEGF neutralization within a single molecule have therefore emerged as a rapidly developing therapeutic strategy in NSCLC. Ivonescimab, a PD-1/VEGF bispecific antibody, currently has the most mature evidence, with randomized phase III trials demonstrating improvements in progression-free survival and, in selected settings, overall survival compared with established PD-1-based regimens. Other PD-1/VEGF agents, including PF-08634404, MK-2010, and JS207, have shown encouraging early activity but require randomized validation. Among PD-L1/VEGF bispecific antibodies, pumitamig, HB0025, and IMM2510 have demonstrated promising antitumor activity, although evidence is derived predominantly from early-phase or single-arm studies. Multiple phase III trials are evaluating these agents in first-line, post-immunotherapy, epidermal growth factor receptor (EGFR)-mutated, and stage III consolidation settings. VEGF-associated toxicities, including hypertension, proteinuria, hemorrhage, and thromboembolism, remain clinically relevant. Moreover, differences in checkpoint target, molecular architecture, target affinity, fragment crystallizable (Fc) engineering, pharmacokinetics, and VEGF-binding strategy preclude the assumption of a uniform class effect. The fixed bispecific configuration also prevents independent dose adjustment of the checkpoint and antiangiogenic components, which may complicate toxicity management. Mature randomized survival data, longer-term safety assessment, and biomarker development are needed to define optimal patient selection and the clinical role of PD-(L)1/VEGF bispecific antibodies in NSCLC.
Aleena Kuriakose, Salem Gogah, E. Beleva· Journal of Clinical Question...· 0 citations
The landscape of immunotherapy in oncology has markedly advanced with the development of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors, fundamentally reshaping cancer treatment by potentiating anti-tumor immune responses. PD-1/PD-L1 blockade agents, such as FDA-approved nivolumab, pembrolizumab, and dostarlimab, have demonstrated significant clinical efficacy across various malignancies. Additionally, investigational agents like envafolimab, a novel PD-L1 inhibitor, are currently under clinical evaluation for efficacy and safety in solid tumors. This review examines the emerging data on envafolimab and discusses strategies to optimize its therapeutic impact, including combination regimens and personalized approaches. Tailoring treatments based on individual genetic, immunological, and microbiome profiles holds the potential to enhance response rates and the durability of outcomes. The integration of these factors is pivotal in advancing the precision and success of immunotherapy in oncology.
M. Kciuk, D. Kołat, Katarzyna Wanke et al.· Frontiers in Immunology· 0 citations
Limited benefit in other cancer subsets highlights the need for biomarker discovery and optimization of therapeutic strategies, including addition of antibody-drug conjugates to ICIs, next-generation checkpoint modulation, personalized neoantigen vaccines, and engineered cellular immunotherapy.
Victor M. Samperio, Ruba Alchaikh Hassan, Aishwarya Ghonge et al.· Expert Opinion on Biological...· 0 citations
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