Programmed Death Receptor-1 Inhibitor Research Articles

A nomogram based on the SII3 and clinical indicators predicts survival in patients with nasopharyngeal carcinoma treated with PD-1 inhibitors.

Numerous inflammatory indicators have been demonstrated to be strongly correlated with tumor prognosis. However, the association between inflammatory indicators and the prognosis of patients with nasopharyngeal carcinoma (NPC) receiving treatment with programmed death receptor-1 (PD-1) immunosuppressant monoclonal antibodies remains uncertain. Inflammatory indicators in peripheral blood were collected from 161 NPC patients at 3 weeks after initial PD-1 treatment. Through univariate and multivariate analyses, as well as nomogram and survival analyses, we aimed to identify independent prognostic factors related to 1-year progression-free survival (PFS). Subsequently, a prognostic nomogram was devised, and its predictive and discriminating abilities were assessed utilizing calibration curves and the concordance index. Our univariate and multivariate analyses indicated that age (P = .012), M stage (P < .001), and systemic immune-inflammation index (SII) during the third week following initial PD-1 treatment (SII3, P = .005) were independently correlated with the 1-year PFS of NPC patients after PD-1 treatment. Notably, we constructed a novel nomogram based on the SII3, age, and M stage. Importantly, utilizing the derived cutoff point from the nomogram, the high-risk group exhibited significantly shorter PFS than did the low-risk group (P < .001). Furthermore, the nomogram demonstrated a greater concordance index for PFS than did the tumor node metastasis stage within the entire cohort. We successfully developed a nomogram that integrates the SII3 and clinical markers to accurately predict the 1-year PFS of NPC patients receiving PD-1 inhibitor treatment.

OMA1 competitively binds to HSPA9 to promote mitophagy and activate the cGAS–STING pathway to mediate GBM immune escape

BackgroundImmunotherapy with checkpoint inhibitors, especially those targeting programmed death receptor 1 (PD-1)/PD-1 ligand (PD-L1), is increasingly recognized as a highly promising therapeutic modality for malignancies. Nevertheless, the efficiency of immune...

Risk of hepatitis B virus reactivation and its effect on survival in advanced hepatocellular carcinoma patients treated with hepatic arterial infusion chemotherapy and lenvatinib plus programmed death receptor-1 inhibitors.

Hepatitis B virus (HBV) reactivation is a common complication in hepatocellular carcinoma (HCC) patients treated with chemotherapy or immunotherapy. This study aimed to evaluate the risk of HBV reactivation and its effect on survival in HCC patients treated with HAIC and lenvatinib plus PD1s. We retrospectively collected the data of 213 HBV-related HCC patients who underwent HAIC and lenvatinib plus PD1s treatment between June 2019 to June 2022 at Sun Yat-sen University, China. The primary outcome was the risk of HBV reactivation. The secondary outcomes were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. Sixteen patients (7.5%) occurred HBV reactivation in our study. The incidence of HBV reactivation was 5% in patients with antiviral prophylaxis and 21.9% in patients without antiviral prophylaxis, respectively. The logistic regression model indicated that for HBV reactivation, lack of antiviral prophylaxis (P=0.003) and tumor diameter (P=0.036) were independent risk factors. The OS and PFS were significantly shorter in the HBV reactivation group than the non-reactivation group (P=0.0023 and P=0.00073, respectively). The number of AEs was more in HBV reactivation group than the non-reactivation group, especially hepatic AEs. HBV reactivation may occur in HCC patients treated with HAIC and lenvatinib plus PD1s. Patients with HBV reactivation had shorter survival time compared with non-reactivation. Therefore, HBV-related HCC patients should undergo antiviral therapy and HBV-DNA monitoring before and during the combination treatment.

Hepatic arterial infusion chemotherapy combined with bevacizumab plus a PD-1 inhibitor for gallbladder cancer with hepatic oligometastasis: a real-world study.

Gallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis. We retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated. A total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18F-fluorodeoxyglucose (18F-FDG) uptake may be a marker of tumor remission. The combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions.

Fruquintinib with PD-1 inhibitors versus fruquintinib monotherapy in late-line mCRC: A retrospective cohort study based on propensity score matching.

139 Background: Immune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC). However, the population of MSI-H/dMMR only accounts for 5% of mCRC. And most of the remaining microsatellite stable or proficient mismatch repair (MSS/pMMR) mCRC patients appeared not to benefit from mere immunotherapy. Fruquintinib, as the standard third-line regimen for mCRC, is an oral small-molecule anti-angiogenic tyrosine kinase inhibitor. Studies demonstrated that fruquintinib combined with programmed death receptor-1 (PD-1) inhibitors (FP) can reverse the immunosuppression and achieve promising efficacy. However, due to the lack of the research comparing the efficacy between fruquintinib monotherapy (FM) and FP, it remains unclear if FP can bring extra benefit. Methods: This is a retrospective cohort study conducted in the First Affiliated Hospital of Zhengzhou University. Patients (pts) with MSS/pMMR mCRC who had received at least the 2nd line treatment were eligible. Propensity score (PS) would be calculated to balance the baseline characteristics of two cohorts. Progression-Free survival (PFS) was set as the primary endpoint. The Kaplan–Meier method and Cox proportional hazard model was used to evaluate PFS and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: From Apr 2020 to Jan 2023, 83 eligible pts in total were enrolled. According to the treatment received, 47 and 36 pts were respectively allocated into FP cohort and FM cohort. With a global median follow-up of 16.5 mo, the crude PFS was 6.8 (95% CI: 4.3-11.3) mo in FP cohort vs. 3.9 (3.1-4.7) mo in FM cohort. The HR of FP was 0.58 (95% CI: 0.34-0.98, FM as reference). Multivariate Cox regression showed that the adjusted HR was 0.49 (95% CI: 0.26-0.93), which was adjusted with sex, age greater than 65 yr, ECOG-PS, RAS mutation, BRAF mutation, location of lesion (left or right), surgery history, metastases (liver and lung), prior medication (bevacizumab and cetuximab), and current line (3 or later). With PS, we performed three statistical methods, namely inverse probability weighting, PS matching (the sample size was 37 vs. 29 after matching), and additional adjustment for propensity score with multivariate cox regression. The HR of FP were 0.49 (95% CI: 0.26-0.94), 0.40 (95% CI: 0.21-0.77), and 0.46 (95% CI: 0.24-0.90), respectively. Conclusions: Pts in FP cohort showed a significantly greater PFS than those in FM cohort. And with further analysis, FP indicated robustly lower HRs than FM. Our study suggests FP could provide additional benefits to pts with MSS/pMMR mCRC, and warrants further investigations in a large cohort.

Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. This study is registered on ClinicalTrials.gov: NCT04375384.

Serum cytokines and neutrophil-to-lymphocyte ratio as predictive biomarkers of benefit from PD-1 inhibitors in gastric cancer.

Immunotherapy is significantly revolutionizing cancer treatment and demonstrating promising efficacy in gastric cancer (GC) patients. However, only a subset of patients could derive benefits from targeted monoclonal antibody therapy against programmed death receptor 1 (PD-1). This study aims to identify suitable serum cytokines and blood cell ratios as predictive biomarkers to aid in the selection of GC patients likely to benefit from PD-1 inhibitors. This retrospective study included 41 GC patients who received PD-1 inhibitors combined with chemotherapy, 36 GC patients treated solely with chemotherapy, and 33 healthy controls. The study assessed the levels of seven cytokines: interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and various inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), total lymphocyte count (TLC), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). Measurements were obtained using the inpatient system. Univariate and multivariate Cox regression analyses were performed to evaluate the predictive significance of these hematologic parameters for clinical outcomes. Levels of IL-6, IL-10, TNF-α, NLR, and PLR were significantly elevated in GC patients compared to healthy controls, while TLC and LMR were higher in the control group. Among the 41 patients receiving PD-1 inhibitors and chemotherapy, baseline IL-2 was associated with OS and PFS. Additionally, IL-6 and IL-17A correlated with OS, while NLR was linked to PFS (all P<0.05). These factors were identified as independent prognostic indicators in both univariate and multivariate analyses. Furthermore, almost all cytokine levels increased following the initiation of PD-1 inhibitor treatment. The introduction of PD-1 inhibitors alongside chemotherapy in GC impacts serum cytokine levels. IL-2, IL-6, IL-17A, and NLR exhibit potential as reliable circulating predictive biomarkers for identifying patients who may benefit from PD-1 inhibitors combined with chemotherapy.

Synthesis and Evaluation of 177Lu-DOTA-PD-L1-i and 225Ac-HEHA-PD-L1-i as Potential Radiopharmaceuticals for Tumor Microenvironment-Targeted Radiotherapy.

Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or stop the immune response. To evade the immune system, cancer cells overexpress a PD-1 inhibitor protein (PD-L1), which binds to the surface of T cells to activate signaling pathways that induce immune suppression. This research aimed to synthesize PD-L1 inhibitory peptides (PD-L1-i) labeled with lutetium-177 (177Lu-DOTA-PD-L1-i) and actinium-225 (225Ac-HEHA-PD-L1-i) and to preclinically evaluate their potential as radiopharmaceuticals for targeted radiotherapy at the tumor microenvironment level. Using PD-L1-i peptide as starting material, conjugation with HEHA-benzene-SCN and DOTA-benzene-SCN was performed to yield DOTA-PD-L1-i and HEHA-PD-L1-I, which were characterized by FT-IR, UV-vis spectroscopy, and HPLC. After labeling the conjugates with 225Ac and 177Lu, cellular uptake in HCC827 cancer cells (PD-L1 positive), conjugate specificity evaluation by immunofluorescence, radiotracer effect on cell viability, biodistribution, biokinetics, and assessment of radiation absorbed dose in mice with in duced lung micrometastases were performed. 225Ac-HEHA-PD-L1-i and 177Lu-DOTA-PD-L1-i, obtained with radiochemical purities of 95 ± 3% and 98.5 ± 0.5%, respectively, showed in vitro and in vivo specific recognition for the PD-L1 protein in lung cancer cells and high uptake in HCC287 lung micrometastases (>30% ID). The biokinetic profiles of 177Lu-DOTA-PD-L1-i and 225Ac-DOTA-PD-L1-i showed rapid blood clearance with renal and hepatobiliary elimination and no accumulation in normal tissues. 225Ac-DOTA-PD-L1-i produced a radiation dose of 5.15 mGy/MBq to lung micrometastases. In the case of 177Lu-DOTA-PD-L1-i, the radiation dose delivered to the lung micrometastases was ten times (43 mGy/MBq) that delivered to the kidneys (4.20 mGy/MBq) and fifty times that delivered to the liver (0.85 mGy/MBq). Therefore, the radiotherapeutic PD-L1-i ligands of 225Ac and 177Lu developed in this research could be combined with immunotherapy to enhance the therapeutic effect in various types of cancer.

Safety and efficacy of immunotherapy plus chemotherapy as neoadjuvant treatment for patients with locally advanced gastric cancer: a retrospective cohort study.

The combined use of programmed death receptor-1 (PD-1) inhibitors and chemotherapy has reshaped the treatment landscape of advanced or metastatic gastric cancer (GC). This study aimed to assess the efficacy and safety of PD-1 inhibitors combined with chemotherapy in a neoadjuvant setting for locally advanced GC (LAGC). Patients diagnosed with clinical stage II-III GC undergoing neoadjuvant PD-1 inhibitors plus chemotherapy were enrolled from December 2019 to July 2022. Clinicopathological characteristics, pathological information, and survival data were recorded and analyzed. A total of 42 eligible patients were enrolled, of whom 37 (88.1%) had clinical stage III disease. All the patients underwent surgery, and the R0 resection rate was 90.5%. Major pathological response (MPR) and pathological complete response (pCR) rates were 42.9% and 26.2%, respectively. The overall TNM downstaging rate was 76.2%. A total of 36 (85.7%) patients received adjuvant chemotherapy. With a median follow-up of 23.1 months, four patients died after tumor recurrence, and three were alive with recurrence. The 1-year overall survival (OS) and disease-free survival (DFS) rates were 94.4% and 89.5%, respectively, and the median OS and DFS were not reached. Neoadjuvant treatment was well tolerated with no grade 4-5 treatment-related adverse events (TRAEs) observed. The most common grade 3 TRAEs were anemia and alanine aminotransferase increase (n = 2 each, 9.6%). PD-1 inhibitors plus chemotherapy demonstrated promising efficacy, with encouraging pCR and survival outcomes in a neoadjuvant setting for patients with LAGC. The combined therapy also showed a good safety profile.

Efficacy and safety of programmed cell death receptor 1 inhibition-based regimens in patients with pediatric malignancies: the real-world study in China.

Programmed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies. We conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan-Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity. A total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis. This largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients.

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma.

Programmed death receptor-1 (PD-1) inhibitors have been approved as second-line treatment regimen in hepatocellular carcinoma (HCC), but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy. To estimate the clinical outcome of transarterial chemoembolization (TACE) and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC (uHCC). We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022. 45 patients received the PD-1 inhibitors, lenvatinib, TACE (PD-1-Lenv-T) therapy, and 20 received the lenvatinib, TACE (Lenv-T) therapy. In terms of the dose of lenvatinib, 8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg. Of the patients in the PD-1 inhibitor combination group, 15 received Toripalimab, 14 received Toripalimab, 14 received Camrelizumab, 4 received Pembrolizumab, 9 received Sintilimab, and 2 received Nivolumab, 1 with Tislelizumab. According to the investigators' assessment, TACE was performed every 4-6 wk when the patient had good hepatic function (Child-Pugh class A or B) until disease progression occurred. We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors (mRECIST criteria). We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events, v 5.0. The key adverse events (AEs) after the initiation of combination therapy were observed. Patients with uHCC who received PD-1-Lenv-T therapy (n = 45) had a clearly longer overall survival than those who underwent Lenv-T therapy (n = 20, 26.8 vs 14.0 mo; P = 0.027). The median progression-free survival time between the two treatment regimens was also measured {11.7 mo [95% confidence interval (CI): 7.7-15.7] in the PD-1-Lenv-T group vs 8.5 mo (95%CI: 3.0-13.9) in the Lenv-T group (P = 0.028)}. The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4% and 20% (P = 0.059) according to the mRECIST criteria, meanwhile the disease control rates were 93.3% and 64.0% (P = 0.003), respectively. The type and frequency of AEs showed little distinction between patients received the two treatment regimens. Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis.

Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor-1 (PD-1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD-1 inhibitor on the advanced HCC beyond oligometastasis. In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD-1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD-1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression-free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). The 6-, 12- and 24-month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30-0.66; p < .001). The 6-, 12- and 18-month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33-0.63; p < .001) between the two collections. Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD-1 inhibitor led to significant improvements in survival.

Photodynamic Therapy Combined with PD-1 Inhibitor for Bronchial Tumors: One Case Report and Literature Review

Recent experimental studies have found that photodynamic therapy (PDT) combined with programmed death receptor 1 (PD-1)/programmed cell death-Ligand 1 (PD-L1) inhibitors can effectively inhibit in situ tumor growth and prevent tumor recurrence and metastasis, and has emerged as a new therapeutic option. However, clinical data is still limited.

Neoadjuvant toripalimab combined with gemcitabine and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoTGP01): An open label, single-arm, phase Ib clinical trial

BackgroundNeoadjuvant programmed death receptor-1 (PD-1) inhibitors have drawn increasing attention in locally advanced head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the safety and efficacy of gemcitabine and cisplatin (GP), combined with a PD-1 inhibitor, in patients with locally advanced HNSCC.Materials and methodsA total of 23 eligible patients were administered two cycles of toripalimab and GP followed by surgical resection. The primary endpoints were safety, treatment-related adverse events (TRAEs), and non-operation delay rates. The secondary endpoints consisted of pathological complete response (pCR) rate, major pathological response (MPR) rate, objective response rate (ORR), and R0 resection rate.ResultsThe incidence of TRAEs from grades 1 to 4 was 43.5%, 34.8%, 13.0%, and 8.7%, respectively. Grade 3/4 TRAEs included neutropenia, fatigue, hyperglycemia, nausea and vomiting, decreased appetite, rash, and diarrhea. No treatment-related surgical delay was observed. The radiographic response rates were 5.0% (CR), 40.0% (PR), and 55.0% (SD). The ORR reached 45.0%. Eighteen patients underwent successful surgical resection. The R0 resection rate was 100%. The pathological response rates were 16.7% (pCR), 27.8% (MPR, two of five near-pCR), 16.7% (PPR), and 38.8% (NPR). CD4, CD8, CD20, and CD38 expression in the tumors significantly increased after neoadjuvant chemotherapy. The increase in CD20 levels after neoadjuvant treatment in patients with pCR/MPR was significantly higher than in patients with PPR/NPR.ConclusionTriweekly neoadjuvant toripalimab-GP is feasible and achieves promising pCR and MPR rates in patients with resectable locally advanced HNSCC.Trial registrationChinese clinical trial registry, ChiCTR2100043743, Registered 27 Febrary 2021- Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=120570

Aptamer-siRNA chimera and gold nanoparticle modified collagen membrane for the treatment of malignant pleural effusion.

Malignant pleural effusion is one of the most common complications of advanced lung cancer and there is no effective clinical treatment at present. Here, we constructed an aptamer-siRNA chimeras/PEI/PEG/gold nanoparticle (AuNP)/collagen membrane that can progressively activate T cells by layer by layer assembly. Electron microscope showed this collagen membrane could be divided into 10 layers with a total thickness of 50–80μm, and AuNPs could be observed. Aptamer-siRNA chimeras could bind specifically to OX40+ cells and silencing programmed death receptor-1 (PD-1) gene. In vitro experiments demonstrated that chimeras/PEI/PEG/AuNPs gradually activated T cells to continuously kill lung adenocarcinoma cells in malignant pleural effusion. Animal experiments showed that chimeras/PEI/PEG/AuNP/collagen membrane effectively treated malignant pleural effusion. Compared with PD-1 inhibitor group, the number of cancer cells, ki-67 proliferation index and CD44 expression in the pleural effusion was significantly decreased and the lymphocyte/cancer cell ratio was significantly increased in the chimeras/AuNP-CM group. Flow cytometry showed that compared with PD-1 inhibitor group, T cell number in the chimeras/AuNP-CM group was significantly increased, while the proportion of PD-1+ T cells was markedly decreased. In conclusion, we constructed an chimeras/PEI/PEG/AuNP/collagen membrane, which was more effective in the treatment of malignant pleural effusion, and had less side effects than PD-1 inhibitors.

PD-1 inhibitor-associated type 1 diabetes: A case report and systematic review

ObjectiveThis study aimed to summarize the clinical characteristics of programmed death receptor 1 (PD-1) inhibitor-associated type 1 diabetes so as to improve the ability of clinicians to correctly diagnose and treat it.MethodsWe reported a case of a 70-year-old woman with gastric cancer who developed hyperosmolar hyperglycemic coma during camrelizumab (a PD-1 inhibitor) treatment and was diagnosed with PD-1 inhibitor-associated type 1 diabetes. We conducted a systematic review of 74 case reports of type 1 diabetes associated with PD-1 inhibitor therapy published before June 2022.ResultsThe patient developed type 1 diabetes with hyperosmolar hyperglycemic coma after receiving camrelizumab chemotherapy for 6 months (9 cycles). We searched 69 English articles comprising 75 patients, all of whom had been treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and progressed to diabetes after an average of 6.11 (1–28) cycles. Nivolumab combined with ipilimumab (a cytotoxic T lymphocyte-associated protein 4 inhibitor) had the shortest onset (4.47 cycles on average). A total of 76% (57/75) of patients developed diabetic ketoacidosis (DKA) at onset, and 50.67% (38/75) of patients had C-peptide <0.1 ng/mL. Most of the patients were tested for insulin autoantibodies, with a positive rate of 33.33% (23/69); of these, 86.96% (20/23) were tested for glutamate decarboxylase antibody and 46.67% (35/75) were tested for human leukocyte antigen (HLA). HLA-DR4 was the most common type.ConclusionsThe progression of type 1 diabetes induced by PD-1 inhibitors is relatively rapid. Islet failure often occurs when detected, seriously endangering patients' lives. Patients treated with PD-1 inhibitors should closely monitor their plasma glucose level during treatment to detect, diagnose, and treat diabetes on time.

RWD80 Gastrointestinal Adverse Events in Lung Cancer Patients Treated with Ipilimumab and Nivolumab Using Real-World Data

Evidence shows that programmed death receptor-1 (PD-1)-blocking and human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibodies display apparent benefits in lung cancer therapy. Further, lung cancer patients who receive nivolumab (PD-1 inhibitor) plus ipilimumab (CLTA-4 inhibitor) in combination have higher overall survival rate than those treated with ipilimumab alone. However, adverse events (AE) are still a concern, especially gastrointestinal (GI) AEs. Since GI AE is one of the most common reasons for patients stopping immunotherapy, we utilized real-world data to gain insight in the incidence and severity of GI AEs among lung cancer patients treated with nivolumab and ipilimumab.

Short-term outcomes of neoadjuvant sintilimab with chemotherapy in stage III non-small cell lung cancer: a case series.

BackgroundNeoadjuvant chemoimmunotherapy seems to be a promising treatment option for stage III non-small cell lung cancer (NSCLC). Sintilimab, as a programmed death receptor-1 inhibitor, has exhibited a fine performance in treating NSCLC. However, the efficiency of sintilimab combined with chemotherapy for stage IIIA/IIIB NSCLC remains inconclusive. The purpose of this study was to share our experience on sintilimab in neoadjuvant chemoimmunotherapy for stage III NSCLC.MethodsThis study retrospectively reviewed patients who received surgical resection following 1–3 cycles of neoadjuvant sintilimab (200 mg) with chemotherapy for stage III NSCLC between June 2020 and March 2022 in our center. Patients characteristics, surgical factors, surgery-related complications 30 days postoperatively, and treatment-related adverse events (TRAEs) before surgery were recorded through reviewing medical record data and telephone follow-up.ResultsA total of eight patients were enrolled, including six cases of squamous cell carcinoma and two cases of adenocarcinoma. All of the patients received 1–3 cycles of neoadjuvant therapy. There were no treatment-related surgical delays. All patients underwent lobectomy, among which two underwent sleeve lobectomy and one received bronchoplasty. Five patients underwent open thoracotomy. Fibrosis of the primary tumor and lymph nodes was observed in all the cases. There were no surgery-related complications > grade 2 at 30 days postoperatively. According to the radiographic findings, one patient had stable disease and all of the others achieved a partial response. The median of maximum standardized uptake value change from baseline was a 52.75% reduction (range, 37.2–68.8%). Five patients achieved a major pathological response. R0 resection was achieved in all eight cases. One grade 4 event was observed. Neutropenia was the most common TRAE > grade 2 (3/8). There were no cases of treatment discontinuation or dose reduction due to TRAEs.ConclusionsThe current study found that neoadjuvant sintilimab plus chemotherapy bring a high rate of major pathological response and acceptable TRAEs. Even though it increased the difficulties of surgery, there is still no evidence suggesting that it will brings additional surgical death. We believe that neoadjuvant sintilimab plus chemotherapy might be feasible for stage III NSCLC.

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma.

BackgroundBasal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment.MethodsWe conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0.ResultsA total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate.ConclusionsThe clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease.