• cancer therapy
• high-throughput screening
• drug screening

• Carcinoma, Merkel Cell/drug therapy
• Carcinoma, Merkel Cell/virology
• Carcinoma, Merkel Cell/pathology
• Humans
• Animals
• Aurora Kinase B/antagonists & inhibitors
• Aurora Kinase B/metabolism
• Aurora Kinase B/genetics
• Mice
• Cell Line, Tumor
• Skin Neoplasms/drug therapy
• Skin Neoplasms/pathology
• Skin Neoplasms/virology
• Skin Neoplasms/genetics
• High-Throughput Screening Assays/methods
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Xenograft Model Antitumor Assays
• Apoptosis/drug effects
• Female
• Merkel cell polyomavirus
• Organophosphates
• Quinazolines

• HHSN261200800001C NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• ZIA AR041222 Intramural NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

• Epstein-Barr virus (EBV)
• Gastric cancer
• Immune biomarkers
• Immunotherapy
• Microsatellite instability (MSI)
• PD-L1 expression
• Predictive signatures
• Tumor mutational burden (TMB)

• Humans
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy/methods
• Microsatellite Instability
• Stomach Neoplasms/genetics
• Stomach Neoplasms/immunology
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy

• cold tumor
• hot tumor
• immunologic modulator
• immunotherapy
• therapeutic strategy
• tumor microenvironment

• Humans
• Tumor Microenvironment/immunology
• Neoplasms/immunology
• Neoplasms/therapy
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy/methods
• Animals

• Carcinoma, Merkel Cell/drug therapy
• Carcinoma, Merkel Cell/pathology
• Humans
• Skin Neoplasms/drug therapy
• Skin Neoplasms/pathology
• Skin Neoplasms/mortality
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antibodies, Monoclonal, Humanized/adverse effects
• Antibodies, Monoclonal, Humanized/administration & dosage
• Neoplasm Staging
• Antineoplastic Agents, Immunological/therapeutic use
• Antineoplastic Agents, Immunological/adverse effects
• Treatment Outcome
• Survival Rate

• tumour immunology
• immunotherapy

• Humans
• Neoplasms/therapy
• Immunotherapy
• Diet

Merkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer. Despite important progress, overall understanding of the events that drive MCC carcinogenesis remains incomplete. We discovered that the plasma membrane citrate transporter (pmCiC) is upregulated in Merkel cell carcinoma cell lines. Cancer cells import extracellular citrate via pmCiC to support their metabolism, which is critical to support proliferation and metastatic spread. In this study, we show that inhibition of pmCiC can decrease the growth rate of Merkel cell carcinoma cell lines. Targeting pmCiC and thereby the tumor metabolism should be considered further as a potential anti-cancer therapy.

Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor of the skin with a poor prognosis. The factors driving this cancer must be better understood in order to discover novel targets for more effective therapies. In the search for targets, we followed our interest in citrate as a central and critical metabolite linked to fatty acid synthesis in cancer development. A key to citrate uptake in cancer cells is the high expression of the plasma membrane citrate transporter (pmCiC), which is upregulated in the different adenocarcinoma types tested so far. In this study, we show that the pmCiC is also highly expressed in Merkel cell carcinoma cell lines by western blot and human tissues by immunohistochemistry staining. In the presence of extracellular citrate, MCC cells show an increased proliferation rate in vitro; a specific pmCiC inhibitor (Na⁺-gluconate) blocks this citrate-induced proliferation. Furthermore, the 3D in vivo Chick Chorioallantoic Membrane (CAM) model showed that the application of Na⁺-gluconate also decreases Merkel cell carcinoma growth. Based on our results, we conclude that pmCiC and extracellular citrate uptake should be considered further as a potential novel target for the treatment of Merkel cell carcinoma.

• Ca2+
• Cryptotanshinone
• MAPKs.
• NSCLC
• Necroptosis
• RIP1/RIP3/MLKL
• ROS

• Dosing interval
• Immunotherapy
• Oncology
• Pharmacokinetics
• Therapeutic antibodies

• Animals
• Clinical Trials as Topic
• Dose-Response Relationship, Drug
• Drug Monitoring
• Humans
• Immune Checkpoint Inhibitors/administration & dosage
• Immune Checkpoint Inhibitors/adverse effects
• Immune Checkpoint Inhibitors/pharmacokinetics
• Immune Checkpoint Inhibitors/therapeutic use
• Maximum Tolerated Dose
• Neoplasms/drug therapy
• Neoplasms/immunology

Breast cancer is the most commonly diagnosed cancer in women and is one of the leading causes of death from cancer in women worldwide. Despite the significant benefits of using conventional chemotherapy in the treatment of breast cancer, one of its subtypes, the triple-negative breast cancer, is still a challenge in clinical practice. Recent studies have been investigating the role of the immune system in breast cancer and the development of immunotherapy. Although recently the use of atezolizumab, an anti-PD-L1 monoclonal antibody, combined with chemotherapy was approved, an important step in the treatment of patients with triple-negative metastatic breast cancer, the use of immunotherapy to treat breast tumors remains a major challenge. In this systematic literature review, following PRISMA guidelines, we searched for clinical trials using immunotherapy in the treatment of metastatic triple-negative breast cancer published until March 2020 in the databases EMBASE, PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), with no language restrictions. We did not contact the authors of the clinical trials to obtain additional information. Two researchers independently collected the data and assessed the quality of this study. The literature shows that immunotherapy with anti-PD-1/PD-L1 agents is emerging as a new treatment option in breast cancer. On the other hand, when compared to other types of cancer in which several agents have already been approved, the research is still in its infancy. The use of anti-PD-1/PD-L1 agents as monotherapy revealed encouraging results in the metastatic setting, especially when administered in the early course of the disease, although combination strategies with chemotherapy appear to increase its efficacy. The main limitation of this study is the approach of cancer only in advanced stages.

• PD-1
• PDL1
• Triple-negative breast cancer
• checkpoint inhibitors
• immunotherapy

Monoclonal antibodies that target the inhibitory immune checkpoint axis consisting of programmed cell death protein 1 (PD-1) and its ligand, PD-L1, have changed the immune-oncology field. We identified K2, an anti-human PD-L1 single-domain antibody fragment, that can enhance T cell activation and tumor cell killing. In this study, the potential of different K2 formats as immune checkpoint blocking medicines was evaluated using a gene-based delivery approach. We showed that 2K2 and 3K2, a bivalent and trivalent K2 format generated using a 12 GS (glycine-serine) linker, were 313- and 135-fold more potent in enhancing T cell receptor (TCR) signaling in PD-1^POS cells than was monovalent K2. We further showed that bivalent constructs generated using a 30 GS linker or disulfide bond were 169- and 35-fold less potent in enhancing TCR signaling than was 2K2. 2K2 enhanced tumor cell killing in a 3D melanoma model, albeit to a lesser extent than avelumab. Therefore, an immunoglobulin (Ig)G1 antibody-like fusion protein was generated, referred to as K2-Fc. K2-Fc was significantly better than avelumab in enhancing tumor cell killing in the 3D melanoma model. Overall, this study describes K2-based immune checkpoint medicines, and it highlights the benefit of an IgG1 Fc fusion to K2 that gains bivalency, effector functions, and efficacy.

• gene therapy
• nanobody
• programmed death-ligand 1
• single domain antibody

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasia, with high risk of recurrence and metastasis and poor survival. Immune checkpoint inhibitors, like the anti-programmed death-ligand 1 agent avelumab, were recently approved for the treatment of advanced MCC. We, herein, report the first case of advanced MCC with oligoprogression managed with avelumab and local radical treatment.

A 61-year-old man was presented to the hospital with sporadic fever and an exudative malodorous mass (10 cm of diameter), located on the right gluteal region. The final diagnosis was MCC, cT4N3M1c (AJCC, TNM staging 8^th edition, 2017), with invasion of adjacent muscle, in-transit metastasis, and bone lesions. Patient started chemotherapy (cisplatin and etoposide), and after six cycles, the main tumor increased, evidencing disease progression. Two months later, the patient started second line treatment with avelumab (under an early access program). After two cycles of treatment, the lesion started to decrease, achieving a major response. Local progression was documented after 16 cycles. However, as the tumor became resectable, salvage surgery was performed, while keeping the systemic treatment with avelumab. Since the patient developed bilateral pneumonia, immunotherapy was suspended. More than 2.5 years after surgery (last 19 mo without systemic therapy), the patient maintains complete local response and stable bone lesions.

This report highlights the efficacy and long-term response of avelumab on the management of a chemotherapy resistant advanced MCC, with evidence of oligoprogression, in combination with local radical treatment.

• Merkel cell carcinoma
• Unresectable tumor
• Avelumab
• Oligoprogression
• Surgery
• Chemotherapy
• Case report

Neuroendocrine cervical cancer (NECC) is a rare cervical cancer with high aggressivity that causes poor prognosis even in the early stage. Given other neuroendocrine carcinomas and other types of cervical cancer have been proved to have expression of programmed cell death protein 1 ligand 1(PD‐L1) and poly ADP‐ribose polymerase‐1(PARP1), we would measure and analyze these proteins in this invasive cancer. The purpose of this study is to investigate the application value of PD‐1/PD‐L1 and PARP1 inhibitors in NECC.

The NECC cases in our center with formalin‐fixed paraffin‐embedded tissue blocks were collected, and immunohistochemical (IHC) staining of PD‐L1, PARP1, Mismatch repair proteins (MMRs), and P53 was performed. Chi‐square test was used to analyze associations between various protein expressions. We analyzed the efficacy of immunotherapy in a recent patient with secondary recurrence after two courses of chemotherapy.

After rigorous screening, 20 cases were finally included. Three cases did not undergo surgical treatment because of their advanced stage. Twelve (60%) developed distant metastases or relapsed within five years, and most of them within two years. The positive rate of PD‐L1 and PARP1 were 70% and 75% respectively. Among all the cases, microsatellite instability (MSI) was seen in six cases (30%) and abnormal p53 expression was in 15 patients (75%). PD‐L1 was associated with PARP1 expression in the MSI subgroup. The patient treated with chemotherapy + VEGF inhibitor (VEGFi) + programmed cell death protein 1(PD‐1) inhibitor had an excellent improvement in clinical symptoms, tumor markers, and mass size.

The IHC results of PD‐L1, PARP1, and MMRs suggested that NECC was the target of immunotargeted therapy. Our case confirmed that immune checkpoint therapy was effective in patients with PD‐L1 positive and MMRs loss. Considering the clinical practicability, more cases should be collected, and effective biomarkers still need to be further searched.

• PARP1
• PD-L1
• immunotherapy
• mismatch repair proteins
• neuroendocrine cervical cancer
• targeted therapy

• Avelumab
• Immune checkpoint inhibitors
• Multimorbid patient
• Programmed cell death-ligand 1 inhibitor
• Skin cancer

• Avelumab
• anti-angiogenesis
• antibody-dependent cytotoxicity
• chemotherapy
• immune checkpoint inhibition
• immunomodulation
• programmed death ligand-1

Merkel cell carcinoma (MCC) is a rare aggressive form of skin cancer originating in neuroendocrine cells. The antiprogrammed death ligand 1 (PD-L1) monoclonal antibody (mAb) avelumab has been approved for treatment of MCC, but options are limited, should it be ineffective as a monotherapy. Combined therapy with low/moderate dose nab-paclitaxel and an interleukin 15 (IL-15)-based therapeutic such as the IL-15 ‘superagonist’ N-803 may increase response by activation of the immune system. The case of a 71-year-old man diagnosed with MCC who achieved and maintained a complete response (CR) by treatment with the anti-PD-L1 mAb avelumab in combination with IL-15 superagonist N-803 and nab-paclitaxel (Abraxane) is presented. Avelumab treatment alone resulted in a response in a para-aortic lesion, but not the other tumor masses. N-803 was added, followed by nab-paclitaxel; CT showed a decrease in the size of the abdominal mass at 1 month, near resolution at 3 months and CR at 5 months. Abraxane was discontinued after the first CR on CT, and the patient continues on avelumab/N-803 treatment and maintains a CR. Combination of avelumab with low/moderate-dose chemotherapy and an immune enhancer such as N-803 may offer a viable treatment option for MCC patients for whom avelumab therapy alone was not effective.

• CD8-positive T-lymphocytes
• T-lymphocytes
• case reports
• drug therapy, combination
• immunotherapy

PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.

• PD-1
• PD-L1
• adverse events
• clinical trials
• immune checkpoint inhibitors
• monoclonal antibody

• biomarkers
• cancer
• liquid biopsy
• melanoma
• merkel cell carcinoma
• skin cancers

• Checkpoint inhibitor
• Cutaneous melanoma
• Immunotherapy
• Mucosal melanoma
• Uveal melanoma