Real-world outcomes of nivolumab plus ipilimumab and pembrolizumab with platinum-based chemotherapy in advanced non-small cell lung cancer: a multicenter retrospective comparative study.

INTRODUCTION: Nivolumab plus ipilimumab with chemotherapy (NICT) and pembrolizumab with chemotherapy (PCT) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). Compared with immune checkpoint inhibitor (ICI) monotherapy, ICI combination therapy can increase immune-related toxicity instead of prolonging survival. This study aimed to compare the efficacy and safety of NICT and PCT to decide on the favorable treatment. METHODS: We conducted a multi-center retrospective cohort study on patients who underwent NICT or PCT between December 2018 and May 2022. Propensity score matching (PSM) was performed with the variables age, sex, smoking status, performance status, stage, histology, and programmed cell death ligand-1 (PD-L1). The Kaplan-Meier method was used to compare survival for the matched patients. RESULTS: Six hundred consecutive patients were included. After PSM, 81 and 162 patients were enrolled in the NICT and PCT groups, respectively. The baseline characteristics were well-balanced. The median progression-free survival was equivalent (11.6 vs. 7.4 months; P = 0.582); however, the median overall survival (OS) was significantly longer in the NICT group than in the PCT group (26.0 vs. 16.8 months; P = 0.005). Furthermore, OS was better in PD-L1-negative patients who underwent NICT than in those who underwent PCT (26.0 vs. 16.8 months; P = 0.045). Safety profiles did not differ significantly in terms of severe adverse event and treatment-related death rates (P = 0.560, and 0.722, respectively). CONCLUSIONS: Real-world data suggests that NICT could be a favorable treatment option compared with PCT for patients with advanced NSCLC. Further follow-up is needed to determine the long-term prognostic benefit.

A randomized phase 2 study on demeclocycline in patients with mild-to-moderate COVID-19.

Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/µL in the number of CD4+ T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/µL-377.6/µL) (p = 0.023), whereas that in the control group was 47.8/µL (95% CI - 151.2/µL to 246.8/µL), which was not significant (p = 0.271). The change rates of CD4+ T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = - 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability.Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020).

Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation.

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer.

Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases. Findings from bronchoalveolar lavage might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify patients with non-small cell lung cancer (NSCLC) who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis of 12 patients were compared with regard to therapeutic effect. Compared with ICI nonresponders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and the balance of CXCL9 and lung TME microbiome could contribute to nivolumab sensitivity in patients with NSCLC. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.

IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity.

Cancer immunotherapy has shown great promise as a new standard therapeutic strategy against cancer. However, the response rate and survival benefit remain unsatisfactory because most current approaches, such as the use of immune checkpoint inhibitors, depend on spontaneous antitumor immune responses. One possibility for improving the efficacy of immunotherapy is to promote antitumor immunity using adjuvants or specific cytokines actively. IL-33 has been a candidate for such cytokine therapies, but it remains unclear how and in which situations IL-33 exerts antitumor immune effects. In this study, we demonstrate the potent antitumor effects of IL-33 using syngeneic mouse models, which included marked inhibition of tumor growth and upregulation of IFN-γ production by tumor-infiltrating CD8+ T cells. Of note, IL-33 induced dendritic cells to express semaphorin 4A (Sema4A), and the absence of Sema4A abolished the antitumor activity of IL-33, indicating that Sema4A is intrinsically required for the antitumor effects of IL-33 in mice. Collectively, these results not only present IL-33 and Sema4A as potential therapeutic targets but also shed light on the potential use of Sema4A as a biomarker for dendritic cell activation status, which has great value in various fields of cancer research, including vaccine development.

Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood.

Immune checkpoint inhibitors, including PD-1-blocking antibodies, have significantly improved treatment outcomes in various types of cancer. The pharmacological efficacy of these immunotherapies is long lasting, extending even beyond the discontinuation of their injections, due to persistent blood concentrations. Here we developed a simple flow cytometry assay to evaluate the T cell binding status of the PD-1-blocking antibodies nivolumab and pembrolizumab. Like a glucose test, this assay requires just a single drop of peripheral blood. Visualizing antibody binding on T cells is more reliable than measuring antibody blood concentrations. In addition, if necessary, we can potentially analyze many distinctive immune-related markers on T cells bound to PD-1-blocking antibodies. Thus, this is a simple and minimally invasive strategy to analyze the pharmacological effect of PD-1-blocking antibodies in cancer patients.

Lipid nanoparticles of Type-A CpG D35 suppress tumor growth by changing tumor immune-microenvironment and activate CD8 T cells in mice.

Type-A CpG oligodeoxynucleotides (ODNs), which have a natural phosphodiester backbone, is one of the highest IFN-α inducer from plasmacytoid dendritic cells (pDC) via Toll-like receptor 9 (TLR9)-dependent signaling. However, the in vivo application of Type-A CpG has been limited because the rapid degradation in vivo results in relatively weak biological effect compared to other Type-B, -C, and -P CpG ODNs, which have nuclease-resistant phosphorothioate backbones. To overcome this limitation, we developed lipid nanoparticles formulation containing a Type-A CpG ODN, D35 (D35LNP). When tested in a mouse tumor model, intratumoral and intravenous D35LNP administration significantly suppressed tumor growth in a CD8 T cell-dependent manner, whereas original D35 showed no efficacy. Tumor suppression was associated with Th1-related gene induction and activation of CD8 T cells in the tumor. The combination of D35LNP and an anti-PD-1 antibody increased the therapeutic efficacy. Importantly, the therapeutic schedule and dose of intravenous D35LNP did not induce apparent liver toxicity. These results suggested that D35LNP is a safe and effective immunostimulatory drug formulation for cancer immunotherapy.

Monitoring antibody binding to T cells in a pembrolizumab-treated patient with lung adenocarcinoma on hemodialysis.

Recent clinical trials have demonstrated that anti-PD-1 blocking antibodies showed remarkable clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Clinical trials usually exclude patients with renal dysfunction who are receiving hemodialysis (HD). Therefore, it is unclear whether these patients can be safely and effectively treated with pembrolizumab. Here, we present a non-small cell lung cancer patient on HD who achieved complete remission after one dose of pembrolizumab without severe adverse events. We assessed pembrolizumab binding to peripheral blood T cells in this patient using a method that we recently developed. This is the first report to visualize pembrolizumab binding to T cells in a patient on HD during and after pembrolizumab treatment. The pharmacokinetics of pembrolizumab in this case were similar to those in patients with normal renal function, suggesting that severe renal dysfunction has little influence on the metabolism of pembrolizumab, and is not a contraindication for anti-PD-1 treatment. Immune checkpoint inhibitors, including pembrolizumab, may be a vital therapeutic option for lung cancer patients on HD.

Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells.

Although responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) are initially positive, 30%-40% of patients with EGFR-mutant tumors do not respond well to EGFR-TKIs, and most lung cancer patients harboring EGFR mutations experience relapse with resistance. Therefore, it is necessary to identify not only the mechanisms underlying EGFR-TKI resistance, but also potentially novel therapeutic targets and/or predictive biomarkers for EGFR-mutant lung adenocarcinoma. We found that the GPI-anchored protein semaphorin 7A (SEMA7A) is highly induced by the EGFR pathway, via mTOR signaling, and that expression levels of SEMA7A in human lung adenocarcinoma specimens were correlated with mTOR activation. Investigations using cell culture and animal models demonstrated that loss or overexpression of SEMA7A made cells less or more resistant to EGFR-TKIs, respectively. The resistance was due to the inhibition of apoptosis by aberrant activation of ERK. The ERK signal was suppressed by knockdown of integrin ß1 (ITGB1). Furthermore, in patients with EGFR mutant tumors, higher SEMA7A expression in clinical samples predicted poorer response to EGFR-TKI treatment. Collectively, these data show that the SEMA7A-ITGB1 axis plays pivotal roles in EGFR-TKI resistance mediated by ERK activation and apoptosis inhibition. Moreover, our results reveal the potential utility of SEMA7A not only as a predictive biomarker, but also as a potentially novel therapeutic target in EGFR-mutant lung adenocarcinoma.

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients.

BACKGROUND: The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events. METHODS: To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up. RESULTS: Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response. CONCLUSIONS: Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623. FUNDING: This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).

Trastuzumab emtansine suppresses the growth of HER2-positive small-cell lung cancer in preclinical models.

Overcoming chemoresistance is essential for achieving better prognoses in SCLC. Previously, we reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated ADCC. However, irinotecan-resistant SCLC cells, such as SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we examined the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC. Treatment with T-DM1 significantly suppressed the growth of SBC-3/SN-38 xenografts in mice compared with trastuzumab (P < 0.05). Histological analysis of xenografts was performed to evaluate the therapeutic effect on apoptosis, proliferation and tumor vasculature. T-DM1 monotherapy induced apoptosis in SBC-3/SN-38 xenografts to a greater extent than trastuzumab monotherapy with the apoptotic index of 3.71 ± 1.56% vs. 0.60 ± 0.32% (P < 0.05), and also inhibited the proliferation of tumor cells compared with trastuzumab with the proliferative index of 74.30 ± 5.54% vs. 80.12 ± 4.81% (P < 0.05). On the other hand, no significant difference in micro vessel density was observed between the treatment groups. In vivo imaging using fluorescence-labeled T-DM1 showed that intravenously administered T-DM1 was rapidly delivered to xenografts and continued to accumulate for several days in a HER2-selective fashion. From these findings, delivery of the cytotoxic agent DM1 into cells via HER2-mediated internalization is expected to exert antitumor effect in such ADCC-lacking SCLC cells. Collectively, T-DM1 will be a promising option for overcoming trastuzumab-resistance in HER2-upregulated SCLC.

Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade.

INTRODUCTION: Proinflammatory cytokine interleukin-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a protumorigenic inflammatory phenotype and inhibits antitumor immune responses. METHODS: We generated bitransgenic mice expressing a conditional IL-17A allele along with conditional KrasG12D and performed immune phenotyping of mouse lungs, a survival analysis, and treatment studies with antibodies either blocking programmed cell death 1 (PD-1) or IL-6 or depleting neutrophils. To support the preclinical findings, we analyzed human gene expression data sets and immune profiled patient lung tumors. RESULTS: Tumors in IL-17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared with that of KrasG12D mice. IL-6, granulocyte colony-stimulating factor (G-CSF), milk fat globule-EGF factor 8 protein, and C-X-C motif chemokine ligand 1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that levels of tumor-associated neutrophils were significantly increased, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared with in KrasG12D mice. In therapeutic studies PD-1 blockade was not effective in treating IL-17:KrasG12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T-cell activation. In tumors from patients with lung cancer with KRAS mutation we found a correlation between higher levels of IL-17A and colony- stimulating factor 3 and a significant correlation among high neutrophil and lower T-cell numbers. CONCLUSIONS: Here we have shown that an increase in a single cytokine, IL-17A, without additional mutations can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine and neutrophil depletion.

Successful treatment with gefitinib after Stevens-Johnson syndrome associated with afatinib therapy in a patient with adenocarcinoma of the lung.

We report a case of a 65-year-old woman with stage IV lung adenocarcinoma who experienced Stevens-Johnson syndrome (SJS) during afatinib therapy. The patient received afatinib as the first-line therapy after the confirmation of harboring an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene. The patient presented with multiple erythematous papules mainly on the body trunk and thigh 32 days after afatinib administration. Subsequently, diffuse erosions of oral mucosa and purpuric macules with flat atypical targets emerged. Skin biopsy specimen showed the histology compatible with epidermal necrosis and the patient was diagnosed as having SJS. The symptoms of SJS were recovered by systemic steroid and immunoglobulin treatment. Gefitinib was administered as the third-line therapy after the second-line therapy with carboplatin plus pemetrexed had failed. Tumor shrinkage was obtained shortly and has been maintained without the recurrence of SJS. Rechallenge of tyrosine kinase inhibitor by gefitinib could be an alternative treatment option in patients who experienced SJS by afatinib.

A Rare Case of Pleomorphic Carcinoma of the Lung Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement.

Molecular testing for anomalies, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase (ALK) rearrangement, is part of the current standard of care for non-small cell lung cancer, particularly adenocarcinoma. ALK rearrangement occurs most frequently in adenocarcinoma cells and rarely in non-adenocarcinoma cells. We herein report a rare case of pleomorphic lung carcinoma with ALK rearrangement in both its adenocarcinoma and spindle cell components. This case suggests the possibility of ALK rearrangement in pleomorphic carcinoma.

Nanoparticle Albumin-bound Paclitaxel+Carboplatin Therapy for Small Cell Lung Cancer Combined with Squamous Cell Carcinoma and Interstitial Lung Disease.

It has recently been shown that nanoparticle albumin-bound paclitaxel (nab-PAC)+carboplatin (CBDCA) provides a favorable overall response rate in non-small cell lung cancer. This is the first case report of nab-PAC+CBDCA therapy in small cell lung cancer (SCLC). Our patient was a 72-year-old man with stage IV SCLC combined with squamous cell carcinoma and interstitial lung disease (ILD). We administered nab-PAC+CBDCA as a second-line chemotherapy. A partial response was evident after two cycles of chemotherapy, and no serious side effects occurred. The progression-free survival was 15 weeks. Second-line chemotherapy using nab-PAC+CBDCA was effective and well tolerated in an SCLC patient with ILD.

Relationship between progression-free survival and overall survival in patients with advanced non-small cell lung cancer treated with anticancer agents after first-line treatment failure.

AIM: The hazard ratio of progression-free survival (PFS-HR) generally does not reflect that of overall survival (OS-HR) in advanced non-small cell lung cancer (NSCLC) patients treated with first-line therapy. Short survival post-progression (SPP) better reflects the PFS-HR and OS-HR in simulations. We aimed to evaluate whether the PFS-HR reflects the OS-HR in NSCLC clinical trials for post-first-line treatments. METHOD: We reviewed clinical studies of post-first-line anticancer agents for NSCLC. We examined the sample size of the experimental arm (EA), median PFS (mPFS) or median time to progression in the EA, median overall survival (mOS) in the EA, the PFS-HR and the OS-HR. SPP was defined as the difference between mOS and mPFS. The association between mPFS and SPP, mPFS and mOS, and the PFS-HR and OS-HR was tested. We sought for the optimal point of correlation of PFS-HR and OS-HR by every 1 month of SPP. RESULTS: We identified 32 trials (34 arms). mPFS and mOS were weakly correlated (correlation coefficient [r] = 0.376; P = 0.0286). The PFS-HR and OS-HR were also moderately correlated (r = 0.415; P = 0.015). The maximum r value was 0.770 (SPP < 6 months; P < 0.0001) when we tested the associations between the PFS-HR and OS-HR for SPP using 1-month increments. The estimated regression equation at this point was OS-HR = 0.679 × (PFS-HR) + 0.349. CONCLUSION: The PFS-HR and OS-HR were strongly correlated in advanced NSCLC patients treated with post-first-line anticancer agents, with a SPP of less than 6 months.

[Denosumab for bone metastasis of thoracic tumors-preparation of a practice manual and evaluation of its effectiveness].

The anti-receptor activator of nuclear factor-kB ligand (RANKL) antibody denosumab is thought to be useful in the improvement of the quality of life of patients with bone metastasis from thoracic tumors, given the ease of its subcutaneous administration. However, attention has to paid to the onset of hypocalcemia when determining the optimal dosage, especially since data and methods on its prevention are limited. Our project team monitored serum calcium levels in patients receiving denosumab treatment, evaluated methods to supplement calcium and vitamin D in cases of hypocalcemia, and developed an evidence-based common manual. Subsequently, denosumab administration and hypocalcemia were evaluated as per the manual. Grade 3 hypocalcemia was observed in 2 cases before the preparation, with no new cases seen since adopting the new protocol in the manual. We conclude that the development of severe hypocalcemia associated with denosumab treatment can be avoided by prompt management of this condition in the early stages and by adopting measures listed in the practice manual.

Stratification of malignant pleural mesothelioma prognosis using recursive partitioning analysis.

PURPOSE: Prognostic factors and complicated prognostic models have been proposed for malignant pleural mesothelioma (MPM). This study was designed to stratify MPM prognosis by using a simple model. METHODS: Patients diagnosed with MPM in the past 10 years (n = 122) were examined retrospectively. Data on the presence of chest pain, performance status (PS), asbestos exposure, smoking status, white blood cell count (WBC), haemoglobin (Hb) concentration, platelet count (PLT), lactate dehydronate (LD), histology, stage, and date of death or censored status were collected. After the factors were examined in the univariate analysis, recursive partitioning analysis was performed. RESULTS: Statistically significant factors related to survival were the type of histology, stage, PS, WBC, PLT, Hb concentration, and LD. Histology, stage, PS, and Hb concentration were used in multivariate analysis. Stage and Hb concentration showed good statistical significance, whereas PS was borderline significant. The survival analyses were stratified into five groups by PS, stage, Hb concentration, and chest pain using recursive partitioning analysis. Group A comprised patients showing the most favourable prognoses (PS 0-2 and Hb concentration >12.1 g dL(-1) or PS 0-2 and Hb concentration ≤12.1 g dL(-1) without pain), and group B comprised the remaining patients. The median overall survival in groups A and B was 563 days (95 % confidence interval [CI] 502-779) and 157 days (95 % CI 115-224), respectively (hazard ratio of 5.44 [3.46-8.53, P < 0.0001]). CONCLUSIONS: The MPM patients with PS 0-2 and Hb concentration >12.1 or ≤12.1 g dL(-1) without chest pain had favourable prognoses.