Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
Humans ; CTLA-4 Antigen ; Immune Checkpoint Inhibitors/therapeutic use* ; Liver ; Prospective Studies ; Skin Neoplasms

Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.
Apoptosis Regulatory Proteins ; CTLA-4 Antigen/therapeutic use* ; Epigenesis, Genetic ; Humans ; Immunotherapy ; Neoplasms/therapy* ; Programmed Cell Death 1 Receptor/therapeutic use*

With the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.
CTLA-4 Antigen ; Diabetes Mellitus, Type 1/chemically induced* ; Humans ; Immune Checkpoint Inhibitors ; Immunologic Factors/therapeutic use* ; Immunotherapy/adverse effects* ; Neoplasms/drug therapy*

Immune checkpoint inhibitors (ICIs) have been used in treating a wide variety of cancers, but they challenge clinicians with a series of special immune related adverse events (irAEs) resulting from activated immune system. Since June 2018, when the first programmed cell death 1 (PD-1) inhibitor, nivolumab, was approved by the National Medical Products Administration (NMPA), abundant experience has been accumulated in coping with irAEs from PD-1 and PD-1 ligand 1 (PD-L1) blockade therapies. In October 2021, the first CTLA-4 inhibitor, ipilimumab, which has a different spectrum of irAEs was also approved by NMPA. The discrepancy in clinical features of pituitary irAEs is obvious between these two types of ICIs. Pituitary irAEs include hypophysitis and hypopituitarism. In this review of latest literature, we have summarized the incidence, possible mechanisms, time of onset, clinical presentations, hormone test, pituitary imaging, treatment strategies and recovery patterns of pituitary irAEs. By referring to domestic and foreign clinical guidelines, we have proposed practical suggestions for screening, diagnosing and treating pituitary irAEs.
Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Antibodies, Monoclonal/adverse effects* ; Programmed Cell Death 1 Receptor ; CTLA-4 Antigen ; Neoplasms/drug therapy*

Gastric cancer is a malignant disease with high incidence and mortality. The therapeutic methods for advanced gastric cancer, including chemotherapy and targeted therapy are very limited. Immunotherapy is a new method for cancer treatment. The immune checkpoint inhibitors developed for cancer treatment mainly target the CTLA-4 and PD-1/PD-L pathways. There have already been several inhibitors approved for the treatment of melanoma and non-small cell lung cancer by the FDA, including Ipilimumab (fully human antibody against CTLA-4), Pembrolizumab (fully human antibody against PD-1) and Nivolumab (fully human antibody against PD-1). There are also many on-going clinical trials investigating the value of immune checkpoint inhibitors in treating various malignancies, including advanced gastric cancer. In KEYNOTE-012 trial, for advanced gastric and esophagogastric junction cancer anti-PD-1 therapy seemed to be safe and effective for advanced gastric cancer with PD-L1 positivity. Moreover, studies of adoptive cell therapy and tumor vaccine in gastric cancer are underway. Here the latest developments in immunotherapy for gastric cancer will be illustrated.
Antibodies, Monoclonal ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; B7-H1 Antigen ; metabolism ; CTLA-4 Antigen ; metabolism ; Disease Progression ; Humans ; Immunotherapy ; Ipilimumab ; Programmed Cell Death 1 Receptor ; metabolism ; Stomach Neoplasms ; therapy

OBJECTIVETo investigate the immunocytodynamic changes in the livers of chronic hepatitis C patients treated with IFN alpha-2b and ribavirin and to find new bases for an effective immune regulation therapy.

METHODSForty-two chronic hepatitis C patients were treated with combined IFN alpha-2b and ribavirin and their peripheral blood and liver tissues were collected before the treatment for analyses. After the treatment, peripheral blood and liver tissue specimens were obtained from only 11 patients. All the specimens were exposed to three monoclonal antibody fluorescence dyes, and the CD45+ cells with triple colors were analyzed using flow cytometry.

RESULTSCompared to the control groups, the positive rates of CD56+, CD57+, CD161+ cells in the livers of those with chronic hepatitis C sharply decreased (Probability value less than 0.01), and CD56+T cells had decreased mildly; CD28 from the CD56+T cells decreased mildly, but the expression of CD152 increased (P<0.05); the positive rates of CD83+CD1a+ cells had decreased mildly, and the positive rates of CD80+CD11c+ and the CD86+CD11c+ cells significantly decreased (P<0.01). After the treatment, the CD56+, CD161+, CD56+T, CD161+T, CD80+CD11c+, CD86+CD11c+ cells in the responding group increased.

CONCLUSIONCombined interferon alpha-2b and ribavirin treatment can improve the suppressed cell immunity function.

Adult ; Aged ; Antigens, CD ; metabolism ; Antiviral Agents ; therapeutic use ; CTLA-4 Antigen ; Female ; Hepatitis C, Chronic ; drug therapy ; immunology ; Humans ; Interferon-alpha ; therapeutic use ; Killer Cells, Natural ; immunology ; Liver ; immunology ; Male ; Middle Aged ; Recombinant Proteins ; Ribavirin ; therapeutic use

OBJECTIVETo study on treating organ transplant rejection with low doses of CsA and CTLA4-Ig.

METHODSWe set up a rat's cardiac transplant rejection model by Ono's way. The experimental rats were divided into four groups: group A: without any treatment; group B: intraperitoneal injection of CsA at 10 mg / (-1) / (-1) 1 - 7 days; after operation group C: intraperitoneal injection of 100 microgram CTLA4-Ig after 2nd operative day; group D: intraperitoneal injection of CsA 2 mg / (-1) / (-1) 1- 7 days after operation. 50 microgram CTLA4-Ig was given intraperitoneally on the 2nd day postoperation. The survival days of allograft, serum concentration of IL-2, and histological changes were tested.

RESULTSThe allograft survival time of the four groups was 7.2 +/- 0.7 (group A), 19.4 +/- 2.07 (group B), 31.6 +/- 1.8 (group C) and 24.6 +/- 2.07 (group D) respectively. There were significantly differences among the groups (P < 0.05). The survival time in group D was more prolonged than that in group B (P < 0.05). The concentration of IL-2 was significantly decreased after operation. Significant difference was observed between the control group and each treated group (P < 0.01). In group A, B, C and D allograft rejection was graded IV, II, I and I respectively.

CONCLUSIONCTLA4-Ig had a stronger immunosuppression than did CsA. The low doses of CsA and CTLA4-Ig had show a synergistic immunosuppression in allograft transplantation.

Abatacept ; Animals ; Antigens, CD ; Antigens, Differentiation ; therapeutic use ; CTLA-4 Antigen ; Cyclosporine ; therapeutic use ; Disease Models, Animal ; Drug Therapy, Combination ; Graft Rejection ; drug therapy ; Immunoconjugates ; Immunosuppressive Agents ; therapeutic use ; Male ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Transplantation, Homologous ; Transplants

Cancer immunotherapy is increasingly popular in the field of cancer treatment, and related research is emerging. For patients with non-small cell lung cancer (NSCLC), in recent years, immune checkpoint inhibitors (ICIs) represented by programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunosuppressants, have become one of the most promising treatments for malignant tumors. Immune checkpoint blockade therapy includes anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) mAb, anti-PD-1 mAb and anti-PD-L1 mAb, with the best-known number of PD-L1 immunotherapy. At present, ICIs have achieved very good therapeutic results in clinical treatment, but with less effective efficiency, so we hope to obtain higher therapeutic efficiency. In recent years, exosomal PD-L1 has played an important role in the progress of immunotherapy for NSCLC. This paper reviews the effects of tumor exosomal PD-L1 protein on the tumor microenvironment, the effect prediction of immunotherapy, and as novel therapeutic strategies for immunotherapy in NSCLC.
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B7-H1 Antigen ; CTLA-4 Antigen ; Carcinoma, Non-Small-Cell Lung/pathology* ; Exosomes/pathology* ; Humans ; Immune Checkpoint Inhibitors ; Immunosuppressive Agents/therapeutic use* ; Immunotherapy/methods* ; Ligands ; Lung Neoplasms/pathology* ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment

Despite impressive survival benefits with immunotherapy in patients with various solid tumors, the full potential of these agents in prostate cancer has yet to be realized. Sipuleucel-T demonstrated a survival benefit in this population, indicating that prostate cancer is an immunoresponsive disease; however, these results have not been matched by other agents. A large trial with ipilimumab in prostate cancer failed to meet its primary objective, and small trials with PD-1/PD-L1 inhibitors did not yield a significant improvement in overall response. However, several late-stage clinical trials are underway with other vaccines in prostate cancer. Reports of clinical benefit with immunotherapies, particularly when used in combination or a select population, have provided the framework to develop sound clinical trials. Understanding immunogenic modulation, antigen spread, biomarkers, and DNA-repair defects will also help mold future strategies. Through rational patient selection and evidence-based combination approaches, patients with prostate cancer may soon derive durable survival benefits with immunotherapies.
Animals ; Antineoplastic Agents, Immunological/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; B7-H1 Antigen/antagonists & inhibitors* ; Benzamides ; CTLA-4 Antigen/antagonists & inhibitors* ; Cancer Vaccines/therapeutic use* ; Humans ; Immunotherapy ; Ipilimumab/therapeutic use* ; Male ; Nitriles ; Phenylthiohydantoin/analogs & derivatives* ; Programmed Cell Death 1 Receptor/antagonists & inhibitors* ; Prostatic Neoplasms/drug therapy* ; Tissue Extracts/administration & dosage*