Journal of Immunotherapy最新文献

Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.

RAD51, a key recombinase that catalyzes homologous recombination (HR), is commonly overexpressed in multiple cancers. It is curial for DNA damage repair (DDR) to maintain genomic integrity which could further determine the therapeutic response. Herein, we attempt to explore the clinical value of RAD51 in therapeutic guidance in muscle-invasive bladder cancer (MIBC). In this retrospective study, a total of 823 patients with MIBC were included. Zhongshan hospital (ZSHS) cohort (n=134) and The Cancer Genome Atlas-Bladder Cancer (TCGA-BLCA) cohort (n=391) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n=298) was utilized to interrogate the predictive efficacy of RAD51 status to programmed cell death ligand-1 (PD-L1) blockade. In addition, the association of RAD51 with genomic instability and tumor immune contexture was investigated. Patients with RAD51 overexpression were more likely to benefit from both platinum-based chemotherapy and immunotherapy rather than RAD51-low patients. The TMB high PD-L1 high RAD51 high subgroup possessed the best clinical benefits from PD-L1 blockade. RAD51-high tumors featured by genomic instability were correlated to highly inflamed and immunogenic contexture with activated immunotherapeutic pathway in MIBC. RAD51 could serve as a prognosticator for treatment response to platinum-based chemotherapy and PD-L1 inhibitor in MIBC patients. Besides, it could also improve the predictive efficacy of TMB and PD-L1.

Metabolic pathways may regulate responses to cancer immunotherapy (IO). Due to its immunomodulatory properties, we sought to examine the association between serum vitamin B12 (VitB12) and survival in individuals with cancer treated with immune checkpoint inhibitors, compared with biological and chemotherapy. We collected data on patients with advanced cancer initiating intravenous antineoplastic treatment and a concomitant VitB12 measurement (elevated: >820 ng/L), between January 2010 and January 2022. Patients on IO and other regimens (control) were compared using the Mann-Whitney test for continuous variables, χ 2 test or Fisher test for categorical variables, and multivariate Cox regression models assessed the effect of VitB12 on overall survival and progression-free survival, adjusting for confounders. Patient groups (control: n = 408; IO: n = 93) were balanced for the treatment line and VitB12 (elevated 29.9% vs 23.7%; mean 762.4 vs 687.6 ng/L). In multivariate analysis, overall survival in all patients was negatively associated with VitB12 [control: hazard ratio (HR): 1.4, 95% CI: 1.01-1.96, P = 0.04, false discovery rate (FDR): 0.069; IO: HR: 2.74 as sum of linear baseline and interaction effects, log scale], age (HR: 1.03, 95% CI: 1.02-1.04, P < 0.01), male sex (HR: 0.66, 95% CI: 0.50-0.88, P < 0.01), and neutrophil-to-lymphocyte ratio (HR: 1.05, 95% CI: 0.48-0.99, P = 0.01). However, VitB12 was significantly negatively associated with progression-free survival only in the IO group ( P < 0.001, FDR < 0.001, calculated HR: 8.34; biological treatment P = 0.08; FDR: 0.111; neutrophil-to-lymphocyte ratio, P = 0.07; FDR: 0.09). Taken together, elevated VitB12 was a negative predictor for outcomes on IO, independently of other known prognostic factors. Further research is needed to elucidate the immune-metabolic interplay and its interaction with the gut microbiome, as well as interventional strategies to enhance IO responses.

The correlation between triple-negative breast cancer (TNBC) and genes related to immunity and cancer stemness, particularly shared genes, remains unclear. This study aimed to investigate the correlation of immunity and cancer stemness with the molecular subtyping and survival rates in TNBC using bioinformatics approaches. Differential gene analysis was conducted to identify TNBC-associated differentially expressed genes (DEGs). Cancer stem cell (CSC)-related genes were obtained using weighted gene coexpression network analysis. Immune-related gene sets were retrieved from the literature. Venn analysis was performed to identify the shared DEGs between immunity and cancer stemness in TNBC. Cluster analysis and survival analysis based on the expression of these genes were conducted to identify TNBC subtypes with significant survival differences. A total of 5259 TNBC-associated DEGs, 2214 CSC-related genes, 1793 immune-related genes, and 44 shared DEGs between immunity and cancer stemness were obtained. Among them, 3 shared DEGs were closely associated with TNBC survival rates ( P <0.05). Cluster and survival analyses revealed that among 3 subtypes, cluster2 exhibited the best survival rate, and cluster3 showed the worst survival rate ( P <0.05). Dendritic cells were highly infiltrated in cluster2, while plasma cells and resting mast cells were highly infiltrated in cluster3 ( P <0.05). Genes shared by immunity and cancer stemness were capable of classifying TNBC samples. TNBC patients of different subtypes exhibited significant differences in immune profiles, genetic mutations, and drug sensitivity. These findings could provide new insights into the pathogenesis of TNBC, the immune microenvironment, and the selection of therapeutic targets for drug treatment.

The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic/advanced squamous cell carcinomas of the head and neck (SCCHN). We evaluated the outcomes of SCCHN patients in Ontario, Canada, treated with nivolumab through retrospective review of the provincial treatment registry. Kaplan-Meier method was used to estimate overall survival (OS) and Cox regression to evaluate the prognostic effect of selected factors. Nivolumab was used as second-line therapy after disease relapse for curative-intent platinum chemotherapy (PC) (indication 1-I1), as second-line therapy post-PC in noncurative intent (indication 2-I2), and as first-line therapy in noncurative intent due to contraindication for PC (indication 3-I3). The median OS for patients treated with nivolumab was 5.8 months (95% CI: 4.5-7.3), and the 1-year OS was 28.4% (CI: 2.10-36.1). When patients with I3 were excluded to match inclusion criteria for CheckMate-141, median OS was 4.8 months (CI: 3.6-6.7) with 1-year OS of 21.8% (14.4-30.1). Patients with lower body surface area (BSA) (<1.81) had a median OS of 3.9 months (CI: 3.1-6.7) versus 9.0 months (CI: 6.5-14.8) in those with higher BSA, hazard ratio (HR)=0.12 (CI: 0.04-0.39, P <0.001). Patients receiving nivolumab for I1 had a median OS of 7.2 months (CI 3.8-9.8) versus 11.9 months (CI: 6.2-not reached) for I3, HR=1.73 (CI: 0.94-3.16). Patients receiving nivolumab for I2 had a median OS of 3.9 months (CI: 2.9-5.4) as compared with I3, HR=3.27 (CI: 1.80-5.94). Real-world analysis of patients with advanced/metastatic SCCHN in Ontario, Canada, treated with nivolumab demonstrates poorer median OS compared with CheckMate-141 trial. Lower BSA was a predictor of poorer median OS.

Immunosuppressants are increasingly being used in the clinic to manage immune-related adverse effects. Consequently, the incidence of secondary infections associated with immunosuppression is increasing. However, little is known about primary infections during immune checkpoint inhibitor (ICI) treatment without immunosuppressants. We aimed to evaluate primary infectious diseases during antiprogrammed death ligand-1 immunotherapy without immunosuppressants. We retrospectively screened medical records of 233 patients who underwent ICI treatment for advanced non-small cell lung cancer between January 2014 and May 2018 at National Cancer Center, Republic of Korea. Subsequently, we evaluated the clinical characteristics and treatment outcomes of selected patients hospitalized for potential infectious disease without immunosuppressive treatment (n=80). Eight cases (3.4%) were identified as bacterial pneumonia (n=5) and cellulitis, inflamed epidermoid cyst, and wound infection (n=1 each). The bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae were identified in 4 patients with pneumonia. The period between the start of ICI treatment and infection varied between 3 and 189 days (median, 24.5 days). Five (62.5%) patients were infected within a month after ICI treatment initiation. All patients were treated with empirical antibiotics and discharged without complications. The median progression-free and overall survival for ICI treatment was 11.5 and 25.5 months, respectively. Six patients experienced ICI-associated adverse effects postinfection: Herpes zoster infection (n=4) and pneumonitis (n=2). Infectious disease independent of immunosuppression is a rare, but possible event in patients with lung cancer receiving ICI treatment. Clinical awareness would enable prompt diagnosis of primary infection during immunotherapy.

The therapeutic landscape for patients with advanced or metastatic non-small cell lung cancer (NSCLC) is rapidly evolving due to advances in molecular testing and the development of new targeted therapies and immunotherapies. However, the efficacy of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in advanced or metastatic patients with NSCLC whose tumors harbor BRAF V600E mutation, HER2/ERBB2 alteration, MET exon 14 skipping mutation, or RET rearrangement is not completely understood. A systematic literature review was performed to summarize evidence from clinical trials and observational studies on objective response rate, progression-free survival, and overall survival in patients whose tumors express these biomarkers and who were treated with PD-1/PD-L1 inhibitors. Searches of Embase, MEDLINE, conference abstracts, and a clinical trial registry identified a total of 12 unique studies: 4 studies included patients with BRAF V600E mutation, 6 studies included patients with HER2/ERBB2 alteration, 7 studies included patients with MET exon 14 skipping mutation, and 5 studies included patients with RET rearrangement. Across studies, there was heterogeneity in treatment and patient characteristics and a lack of reporting on many important predictive and prognostic factors, including treatment regimens, patients' line of therapy, and tumor PD-L1 expression, which may explain the wide variation in objective response rate, progression-free survival, and overall survival across studies. Therefore, additional studies prospectively evaluating clinical outcomes of PD-1/PD-L1 inhibitors among patients with advanced or metastatic NSCLC whose tumors harbor emerging predictive or prognostic biomarkers are needed to determine whether this class of immunotherapy can provide additional survival benefits for these patients.

With the development of immune checkpoints inhibitors (ICIs), immunotherapy has recently taken center stage in cancer treatment. Dendritic cells exert complicated and important functions in antitumor immunity. This study aims to construct a novel dendritic cell marker gene signature (DCMGS) to predict the prognosis and immunotherapy response of lung adenocarcinoma (LUAD). DC marker genes in LUAD were identified by analysis of single-cell RNA sequencing data. 6 genes (G0S2, KLF4, ALDH2, IER3, TXN, CD69) were screened as the most prognosis-related genes for constructing DCMGS on a training cohort from TCGA data set. Patients were divided into high-risk and low-risk groups by DCMGS risk score based on overall survival time. Then, the predictive ability of the risk model was validated in 6 independent cohorts. DCMGS was verified to be an independent prognostic factor in multivariate analysis. Furthermore, we performed pathway enrichment analysis to explore possible biological mechanisms of the powerful predictive ability of DCMGS, and immune cell infiltration landscape and inflammatory activities were exhibited to reflect the immune profile. Notably, we bridged DCMGS with expression of immune checkpoints and TCR/BCR repertoire diversity that can inflect immunotherapy response. Finally, the predictive ability of DCMGS in immunotherapy response was also validated by 2 cohorts that had received immunotherapy. As a result, the patients with lower DCMGS risk scores showed a better prognosis and immunotherapy response. In conclusion, DCMGS was suggested to be a promising prognostic indicator for LUAD and a desirable predictor for immunotherapy response.

Immune checkpoint inhibitors are increasingly being utilized for the treatment of advanced neoplastic disease and have been associated with wide-ranging cutaneous adverse effects. Though exceedingly rare, eruptive keratoacanthomas have been associated with the use of immune checkpoint inhibitors such as pembrolizumab and nivolumab, whose molecular target is the programmed cell death protein 1. Herein, we detail a case of numerous eruptive keratoacanthomas arising in a patient one month after initiation of nivolumab for recurrent metastatic oropharyngeal squamous cell carcinoma. Treatment with multiple rounds of intralesional corticosteroids and a several-month course of oral acitretin resulted in partial improvement. Subsequent treatment with intralesional 5-fluorouracil demonstrated near-complete resolution of the keratoacanthomas without discontinuation of nivolumab. Although eruptive keratoacanthomas secondary to immune checkpoint inhibitors are exceptionally rare, physicians should be aware of this cutaneous adverse effect as their use becomes more widespread.

In the tumor microenvironment, wherein cytotoxic lymphocytes interact with cancer cells, lymphocyte exhaustion, an immune checkpoint inhibitor target, is promoted. However, the efficacy of these inhibitors is limited, and improving response rates remains challenging. We previously reported that protein tyrosine phosphatase nonreceptor type (PTPN) 3 is a potential immune checkpoint molecule for activated lymphocytes and that PTPN3 inhibition should be a focus area for cancer immunotherapy development. Therefore, in this study, we focused on PTPN3-suppressive therapy in terms of lymphocyte exhaustion under hypoxic conditions, which are a cancer microenvironment, and investigated measures for improving the response to anti-programmed death receptor (PD)-1 antibody drugs. We found that PTPN3 expression was upregulated in activated lymphocytes under hypoxic conditions, similar to the findings for other immune checkpoint molecules, such as PD-1, T cell immunoglobulin mucin-3, and lymphocyte-activation gene-3; furthermore, it functioned as a lymphocyte exhaustion marker. In addition, PTPN3-suppressed activated lymphocytes promoted the mammalian target of rapamycin (mTOR)-Akt signaling pathway activation and enhanced proliferation, migration, and cytotoxic activities under hypoxic conditions. Furthermore, PTPN3 suppression in activated lymphocytes increased PD-1 expression and enhanced the antitumor effects of anti-PD-1 antibody drugs against head and neck cancer in vitro and in vivo. These results suggest that the suppression of PTPN3 expression in activated lymphocytes enhances the therapeutic effect of anti-PD-1 antibody drugs in head and neck cancer, especially under hypoxic conditions that cause lymphocyte exhaustion.