Exploration of Immune-Modulatory Effects of Amivantamab in Combination with Pembrolizumab in Lung and Head and Neck Squamous Cell Carcinoma.

Immune checkpoint inhibitors are effective first-line therapy for solid cancers. However, low response rate and acquired resistance over time has led to the need for additional therapeutic options. Here, we evaluated synergistic antitumor efficacy of EGFR × MET targeting bispecific antibody, amivantamab with PD-L1 immunotherapy, pembrolizumab in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma tumor-bearing humanized patient-derived xenograft (PDX) models. We demonstrated that pembrolizumab or amivantamab alone was ineffective and that combination treatment induced a significant reduction of tumor growth in both models (P < 0.0001 and P < 0.01, respectively). It appeared that combination of amivantamab and pembrolizumab significantly enhanced infiltration of granzyme B-producing CD8 T cells was in the TME of HNSCC PDX (P < 0.01) and enhanced neoantigen-associated central memory CD8 T cells in circulating immune cells. Analysis of single-cell RNA transcriptomics suggested that the tumor cells dramatically upregulated EGFR and MET in response to PD-L1 immunotherapy, potentially creating a metabolic state fit for tumor persistence in the tumor microenvironment (TME) and rendered pembrolizumab ineffective. We demonstrated that EGFRHIGHMETHIGH subcluster displayed an increased expression of genes implicated in production of lactate [SLC16A3 and lactate dehydrogenase A (LDHA)] compared to the EGFRLOWMETLOW cluster. Accumulation of lactate in the TME has been associated with immunosuppression by hindering the infiltration of tumor killing CD8 T and NK cells. This study proved that amivantamab reduced glycolytic markers in the EGFRHIGHMETHIGH subcluster including SLC16A3 and LDHA and highlighted remodeling of the TME by combination treatment, providing rationale for additional therapy of amivantamab with PD-1 immunotherapy. SIGNIFICANCE: Amivantamab in synergy with pembrolizumab effectively eradicated EGFRHIGHMETHIGH tumor subcluster in the tumor microenvironment of head and neck squamous cell carcinoma and overcame resistance against anti-PD-1 immunotherapy.

The "new" oligometastatic disease state and associated therapies in non-small cell lung cancer: A narrative review.

Patients with non-small cell lung cancer (NSCLC) at stage IV have typically been considered incurable. Nonetheless, there is growing evidence that certain patient groups with fewer metastases, or so-called oligometastatic disease, which may have a more indolent biological nature than widespread metastatic diseases, may survive longer if definitive local treatment is administered to all metastatic sites. According to several retrospective investigations, this subgroup had a better prognosis than other stage IV patients, and the eighth edition of TNM staging was revised to reflect these findings. As a result of rapidly emerging systemic therapies, such as immune checkpoint inhibitors and a growing number of targeted therapies, more patients with this uncommon clinical opportunity have been identified and have received greater clinical attention. Currently, there is no established protocol for the management of oligometastatic disease, and the majority of therapeutic decisions are made through multidisciplinary discussion. In addition to systemic treatment, the two primary local therapeutic options for oligometastatic diseases are surgery and radiotherapy. A few phase 2 trials suggest that aggressive local ablative therapy may significantly improve the prognosis of patients with oligometastatic NSCLC. This review summarizes the most recent data on the management of oligometastatic NSCLC, with a focus on the prognostic significance of local ablative therapy in these patients.

IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy.

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

Optimal Approach to Lobectomy for Non-Small Cell Lung Cancer: Systemic Review and Meta-Analysis.

OBJECTIVE: Video-assisted thoracic surgery (VATS) lobectomy was introduced over 25 years ago. More recently, the technique has been modified from a multiport video-assisted thoracic surgery (mVATS) to uniportal (uVATS) and robotic (rVATS), with proponents for each approach. Additionally most lobectomies are still performed using an open approach. We sought to provide evidence-based recommendations to help define the optimal surgical approach to lobectomy for early stage non-small cell lung cancer. METHODS: Systematic review and meta-analysis of articles searched without limits from January 2000 to January 2018 comparing open, mVATS, uVATS, and rVATS using sources Medline, Embase, and Cochrane Library were considered for inclusion. Articles were individually scrutinized by ISMICS consensus conference members, and evidence-based statements were created and consensus processes were used to determine the ensuing recommendations. The ACC/AHA Clinical Practice Guideline Recommendation Classification system was used to assess the overall quality of evidence and the strength of recommendations. RESULTS AND RECOMMENDATIONS: One hundred and forty-five studies met the predefined inclusion criteria and were included in the meta-analysis. Comparisons were analyzed between VATS and open, and between different VATS approaches looking at oncological outcomes (survival, recurrence, lymph node evaluation), safety (adverse events), function (pain, quality of life, pulmonary function), and cost-effectiveness. Fifteen statements addressing these areas achieved consensus. The highest level of evidence suggested that mVATS is preferable to open lobectomy with lower adverse events (36% versus 42%; 88,460 patients) and less pain (IIa recommendation). Our meta-analysis suggested that overall survival was better (IIb) with mVATS compared with open (71.5% versus 66.7% 5-years; 16,200 patients). Different VATS approaches were similar for most outcomes, although uVATS may be associated with less pain and analgesic requirements (IIb). CONCLUSIONS: This meta-analysis supports the role of VATS lobectomy for non-small cell lung cancer. Apart from potentially less pain and analgesic requirement with uVATS, different minimally invasive surgical approaches appear to have similar outcomes.

Prevalence of chronic obstructive pulmonary disease in Korea: the fourth Korean National Health and Nutrition Examination Survey, 2008.

BACKGROUND AND OBJECTIVE: Because the mortality and social burden associated with COPD is increasing, repeated surveys of the prevalence of COPD have been used to assess risk factors, detect potential patients, and establish early diagnoses and management protocols. We report the prevalence of spirometrically detected COPD in Korea in 2008, using data from the fourth Korean National Health and Nutrition Survey. METHODS: Using nationwide stratified random sampling, based on the Korean Statistical Office census, 6840 subjects aged ≥19years underwent spirometry, which was performed by four trained technicians, during 2008. The place of residence, levels of education and income and smoking status, as well as other results from a COPD survey questionnaire were also assessed. RESULTS: Airflow obstruction (FEV(1) /FVC<0.7) was detected in 8.8% of subjects aged ≥19years (11.6% of men and 5.9% of women) and COPD was detected in 13.4% of subjects aged ≥40years (19.4% of men and 7.9% of women). Of the 6840 subjects, 27.3% were current smokers and 17.2% were former smokers, and the prevalence of COPD was higher in current and former smokers than in never smokers. Approximately 94% of patients with COPD had mild-to-moderate disease, without apparent symptoms; only 2.4% had been diagnosed by a physician and only 2.1% of patients had been treated. The independent risk factors for COPD were smoking, advanced age and male gender. CONCLUSIONS: Although the prevalence of COPD in Korea is high, the disease is underdiagnosed and most COPD patients are under-treated.

Association of insulin resistance with anti-Mullerian hormone levels in women without polycystic ovary syndrome (PCOS).

OBJECTIVE: To explore the relationship of insulin resistance (IR) and adipokines (leptin, adiponectin, RBP4) to anti-Mullerian hormone (AMH) levels in women without polycystic ovary syndrome (PCOS). DESIGN/PATIENTS/MEASUREMENTS: We recruited 120 healthy, reproductive age women without PCOS. An overnight fasting blood draw, anthropometric measurements, analyses of serum levels of AMH, adipokines (leptin, adiponectin and RBP4) and total testosterone, a homeostasis model assessment for insulin resistance (HOMA-IR) and a transvaginal ultrasound scan were performed between the third and fifth day of their spontaneous menstrual cycles. RESULTS: Higher HOMA-IR levels were associated with lower levels of AMH. After adjustment for age, serum AMH levels negatively correlated with insulin, fasting glucose, HOMA-IR and RBP4. However, a positive correlation was identified between serum AMH and adiponectin. A final multiple stepwise linear regression demonstrated that HOMA-IR was independently associated with AMH. CONCLUSION: An independent relationship exists between HOMA-IR and AMH in women without PCOS, possibly due to the effect of abnormal insulin action on AMH secretion by granulosa cells.

Feasibility to generate monocyte-derived dendritic cell from coculture with melanoma tumor cells in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-4.

OBJECTIVE: We investigated how melanoma cells and membrane-bound granulocyte/macrophage colony stimulating factor (mbGM-CSF) melanoma cell lines affect the differentiation of dendritic cells (DC) from CD14+ monocytes. METHOD OF STUDY: The malignant melanoma cell lines (Conley and Jorp) and mbGM-CSF-positive cell lines (Conley B-F8 and Jorp C-E6) were cultured and cell-free supernatants were collected from each cell line cultures to assess the GM-CSF level. Adherent monocytes were cocultured for 6-7 days with irradiated mbGM-CSF and wild type melanoma cells (50 Gy) at each 1:1 and 0.1:1 ratio in six-well culture plates in ex vivo culture medium containing interleukin (IL)-4. Immunophenotyping was performed by triple color immunofluorescence staining with flow cytometry analysis. RESULTS: GM-CSF was detected at low levels in the culture supernatants of Conley B-F8 (0.48 ng/10(6) cells/24 hr), whereas there was no detectable GM-CSF in that of Conley melanoma cell line. Monocytes cultured with GM-CSF/IL-4 generated the expression of high levels of HLA DR, CD1a and CD86, while the expression of CD14 and CD83 were in low amounts. However, the addition of GM-CSF to these cultures resulted in an increased expression of these markers and decreased that of CD14. Monocytes cocultured with Jorp C-E6 illustrated similar expression pattern of CD1a, HLA DR and CD14 in the presence or absence of GM-CSF as Conley B-F8 melanoma cell line. Monocytes cocultured with Conley B-F8 melanoma cells at 1:1 and 0.1:1 ratio showed no significant difference in expression of CD1a, CD14 and CD83 between the two ratios. CONCLUSION: Our results illustrate the feasibility to generate monocyte-derived DC from coculture with melanoma tumor cells in the presence of GM-CSF and IL-4. However, mbGM-CSF tumor cells did not significantly enhance the DC differentiation through juxtacrine stimulation unless soluble GM-CSF was added in the culture media.