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Patients who had had a relapse after receiving platinum-containing chemotherapy and a PD-1 or PD-L1 immune checkpoint inhibitor were assigned to receive enfortumab vedotin or one of three chemotherapy agents chosen by their doctor. Enfortumab vedotin prolonged progression-free and overall survival.

Lenvatinib plus either pembrolizumab or everolimus was compared with sunitinib as first-line therapy for advanced renal cell cancer. Progression-free survival was significantly longer with lenvatinib plus pembrolizumab than with sunitinib. Lenvatinib plus everolimus was also more effective than sunitinib, but the difference was smaller.

Releasing T cells from inhibitory control has been a strategy exploited by the anti–CTLA-4 antibody ipilimumab. Now an antibody against a second checkpoint molecule, programmed death 1 (PD-1), has also shown activity against cancers, including non–small-cell lung cancer. Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens that are potentially recognizable by the immune system. 1 Although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, because tumors develop multiple resistance mechanisms, including local immune suppression, induction of tolerance, and systemic dysfunction in T-cell signaling. 2 – 5 Moreover, tumors may exploit several distinct pathways to actively evade immune destruction, including endogenous “immune checkpoints” that normally terminate immune responses after antigen activation. These observations have resulted in intensive efforts to develop immunotherapeutic approaches for cancer, including immune-checkpoint-pathway inhibitors such as anti–CTLA-4 antibody . . .

BACKGROUNDThe anti-programmed cell death 1 (anti-PD-1) antibody pembrolizumab is clinically active against non-small cell lung cancer (NSCLC). In addition to T cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of patients with advanced NSCLC, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC.METHODSIn total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or higher were randomly allocated to group A (n = 55 patients given pembrolizumab plus NK cells) or group B (n = 54 patients given pembrolizumab alone). The patients received i.v. pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received 2 cycles of NK cell therapy as 1 course of treatment.RESULTSIn our study, patients in group A had longer survival than did patients in group B (median overall survival [OS]: 15.5 months vs. 13.3 months; median progression-free survival [PFS]: 6.5 months vs. 4.3 months; P < 0.05). In group A patients with a TPS of 50% or higher, the median OS and PFS was significantly longer. Moreover, the patients in group A treated with multiple courses of NK cell infusion had better OS (18.5 months) than did those who received a single course of NK cell infusion (13.5 months).CONCLUSIONPembrolizumab plus NK cell therapy yielded improved survival benefits in patients with previously treated PD-L1+ advanced NSCLC.TRIAL REGISTRATIONClinicalTrials.gov NCT02843204.FUNDINGThis work was supported by grants from the National Natural Science Foundation of China (NSFC) - Guangdong Joint Foundation of China (no. U1601225); the NSFC (no. 81671965); the Guangdong Provincial Key Laboratory Construction Project of China (no. 2017B030314034); and the Key Scientific and Technological Program of Guangzhou City (no. 201607020016).

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor. Neoadjuvant pembrolizumab promotes a survival benefit with intratumoral and systemic immune responses in patients with recurrent glioblastoma.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n  = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n  = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P  = 0.003), higher overall response rate (44.0% versus 13.0%, P  = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P  = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8 + T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 . In a randomized phase 2 trial comparing anti-PD-1 plus anti-VEGF plus an HDAC inhibitor versus anti-PD-1 plus an HDAC inhibitor in patients with MSS/pMMR colorectal cancer, the triplet combination led to significantly better 18-week progression-free survival.

The addition of pembrolizumab, an anti–PD-1 antibody, to a platinum–taxane chemotherapy combination significantly prolonged progression-free and overall survival among patients with untreated squamous cell lung cancer, regardless of the level of tumor PD-L1 expression.

Background A combination of programmed cell death protein‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) inhibitors and radiotherapy (RT) is increasingly being used to treat non‐small‐cell lung cancer (NSCLC). However, the safety and efficacy of this approach remains controversial. We performed a systematic review and meta‐analysis to summarize the related research. Methods We searched the China Biology Medicine, EMBASE, Cochrane Library, and PubMed databases for all the relevant studies. The Stata software, version 12.0 was used for the meta‐analysis. Results The study included 20 clinical trials that enrolled 2027 patients with NSCLC. Compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT was associated with prolonged overall survival (OS) (1‐year OS: odds ratio [OR] 1.77, 95% confidence interval [CI] 1.35–2.33, p = 0.000; 2‐year OS: OR 1.77, 95% CI 1.35–2.33, p = 0.000) and progression‐free survival (PFS) (0.5‐year PFS: OR 1.83, 95% CI 1.13–2.98, p = 0.014; 1‐year PFS: OR 2.09, 95% CI 1.29–3.38, p = 0.003; 2‐year PFS: OR 2.47, 95% CI 1.13–5.37, p = 0.023). Combination therapy also improved the objective response rate (OR 2.76, 95% CI 1.06–7.19, p = 0.038) and disease control rate (OR 1.80, 95% CI 1.21–2.68, p = 0.004). This meta‐analysis showed that compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT did not increase the serious adverse event rates (≥grade 3); however, this approach increased the rate of grade 1–2 immune‐related or radiation pneumonitis. Subgroup analyses revealed that the sequence of PD‐1/PD‐L1 inhibitors followed RT outperformed in which concurrent PD‐1/PD‐L1 inhibitor and RT followed PD‐1/PD‐L1 inhibitor. Combination of stereotactic body RT or stereotactic radiosurgery with PD‐1/PD‐L1 inhibitors may be more effective than a combination of conventional RT with PD‐1/PD‐L1 inhibitors in patients with advanced NSCLC. Conclusion Combination therapy using PD‐1/PD‐L1 inhibitors and RT may improve OS, PFS, and tumor response rates without an increase in serious adverse events in patients with advanced NSCLC. However, combination therapy was shown to increase the incidence of mild pneumonitis. Radiotherapy combined with PD‐1/PD‐L1 inhibitors in the treatment of advanced NSCLC showed clinical long‐term survival benefit and short‐term efficacy benefit, and might not increase the serious adverse events.

In China, lung cancer is a primary cancer type with high incidence and mortality. Risk factors for lung cancer include tobacco use, family history, radiation exposure, and the presence of chronic lung diseases. Most early‐stage non‐small cell lung cancer (NSCLC) patients miss the optimal timing for treatment due to the lack of clinical presentations. Population‐based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China. The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC, thus prolonging survival in patients with positive drivers. In the exploration of immune escape mechanisms, programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitor monotherapy and PD‐1/PD‐L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China. In the Chinese Society of Clinical Oncology's guidelines for NSCLC, maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy. Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC. In this review, we summarized recent advances in NSCLC in China in terms of epidemiology, biology, molecular pathology, pathogenesis, screening, diagnosis, targeted therapy, and immunotherapy.

PD1 was originally discovered in 1992 as a molecule associated with activation-induced cell death in T cells. Over the past 30 years, it was found that PD1 has a critical role in avoiding overactivation-induced cell death and autoimmunity, whereas its inhibition unleashes anticancer immunity. Here, we outline the journey from the discovery of PD1 to its role as a breakthrough target in cancer immunotherapy. We describe its regulation and function and examine how a mechanistic understanding of PD1 signalling suggests a central function in setting the T cell activation threshold, thereby controlling T cell proliferation, differentiation, exhaustion and metabolic status. This threshold theory, in combination with new insights into T cell metabolism and a better understanding of immune cell modulation by the microbiota, can provide guidance for the development of efficient combination therapies. Moreover, we discuss the mechanisms underlying immune-related adverse events after PD1-targeted therapy and their possible treatment.In this Perspective, Honjo and co-workers describe the discovery of PD1 and its journey to become a major target for cancer immunotherapy. It discusses the complex regulatory systems that govern PD1 expression as well as recent insights into PD1 function and the mechanisms of PD1-blocking therapies.