Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.

ChatGPT (OpenAI), a cutting-edge natural language processing model, holds immense promise for revolutionizing medical education. With its remarkable performance in language-related tasks, ChatGPT offers personalized and efficient learning experiences for medical students and doctors. Through training, it enhances clinical reasoning and decision-making skills, leading to improved case analysis and diagnosis. The model facilitates simulated dialogues, intelligent tutoring, and automated question-answering, enabling the practical application of medical knowledge. However, integrating ChatGPT into medical education raises ethical and legal concerns. Safeguarding patient data and adhering to data protection regulations are critical. Transparent communication with students, physicians, and patients is essential to ensure their understanding of the technology’s purpose and implications, as well as the potential risks and benefits. Maintaining a balance between personalized learning and face-to-face interactions is crucial to avoid hindering critical thinking and communication skills. Despite challenges, ChatGPT offers transformative opportunities. Integrating it with problem-based learning, team-based learning, and case-based learning methodologies can further enhance medical education. With proper regulation and supervision, ChatGPT can contribute to a well-rounded learning environment, nurturing skilled and knowledgeable medical professionals ready to tackle health care challenges. By emphasizing ethical considerations and human-centric approaches, ChatGPT’s potential can be fully harnessed in medical education, benefiting both students and patients alike.

Purpose: Low-dose radiotherapy (LDRT) may enhance the synergistic antitumor effect of combined immunotherapy and stereotactic body radiotherapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non–small cell lung cancer (NSCLC). Patients and Methods: This prospective phase I study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT [30 Gray (Gy)/3f] to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a programmed death-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAE) occurred in 96.6% (28/29) of patients [grade ≥ 3; 20.7% (6/29)]; 2 patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval, 3.7–16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging T-cell receptor clonotypes were associated with better PFS. Conclusions: The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with programmed death ligand-1–positive, driver gene–negative primary metastatic NSCLC.

Future implications of ChatGPT in pharmaceutical industry: drug discovery and development

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6 substrate retinoblastoma (Rb) protein, while the anti-tumor effect of CDK4/6 inhibitors on Rb-deficient tumors is not clear. Most small cell lung cancers (SCLCs) are Rb-deficient and show very modest response to immune checkpoint blockade (ICB) despite recent advances in the use of immunotherapy. Here, we aimed to investigate the direct effect of CDK4/6 inhibition on SCLC cells and determine its efficacy in combination therapy for SCLC. Methods: The immediate impact of CDK4/6 inhibitor abemaciclib on cell cycle, cell viability and apoptosis in four SCLC cell lines was initially checked. To explore the effect of abemaciclib on double-strand DNA (ds-DNA) damage induction and the combination impact of abemaciclib coupled with radiotherapy (RT), western blot, immunofluorescence (IF) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. An Rb-deficient immunocompetent murine SCLC model was established to evaluate efficacy of abemaciclib in combination therapy. Histological staining, flow cytometry analysis and RNA sequencing were performed to analyze alteration of infiltrating immune cells in tumor microenvironment (TME). Results: Here, we demonstrated that abemaciclib induced increased ds-DNA damage in Rb-deficient SCLC cells. Combination of abemaciclib and RT induced more cytosolic ds-DNA, and activated the STING pathway synergistically. We further showed that combining low doses of abemaciclib with low-dose RT (LDRT) plus anti-programmed cell death protein-1 (anti-PD-1) antibody substantially potentiated CD8⁺ T cell infiltration and significantly inhibited tumor growth and prolonged survival in an Rb-deficient immunocompetent murine SCLC model. Conclusions: Our results define previously uncertain DNA damage-inducing properties of CDK4/6 inhibitor abemaciclib in Rb-deficient SCLCs, and demonstrate that low doses of abemaciclib combined with LDRT inflame the TME and enhance the efficacy of anti-PD-1 immunotherapy in SCLC model, which represents a potential novel therapeutic strategy for SCLC.