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1.
Int J Colorectal Dis ; 39(1): 83, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38809459

ABSTRACT

BACKGROUND: Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important immune checkpoint molecules that contribute to tumor immune evasion. However, the main treatment modalities for patients with early and intermediate stage colorectal cancer (CRC) are surgery, and the role of PD-1/PD-L1 inhibitors in these patients is not yet clear. Therefore, this study aims to review the treatment progress of PD-1/PD-L1 inhibitors for early- and intermediate-stage microsatellite high-instability (MSI-H) and stable (MSS) colorectal cancer, in order to provide more options for patients with early- and intermediate-stage colorectal cancer. MATERIALS AND METHODS: A scoping review of clinical trial registries ( Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on PD-1/PD-L1 Inhibitors for early and middle-stage MSI-H and MSS CRC was done up to March 2024. RESULTS: A total of 19 trials related to early to mid-stage MSH-I or MSS CRC were included. Among them, 6 trials are in recruiting status, 3 trials are in active, not recruiting status, 3 trials are completed, 1 trial is terminated, and 1 trial is unknown. Of these, 9 trials involve MSI-H type CRC, and 10 trials involve MSS type CRC. Preclinical phase I/II trials are predominant, with only 3 clinical phase III trials. In trials related to MSI-H type CRC, 4 studies involve PD-1/PD-L1 inhibitors combined with neoadjuvant therapy, and 5 studies involve combination therapy. In trials related to MSS type CRC, 3 studies involve PD-1/PD-L1 inhibitors combined with targeted therapy, 2 studies involve PD-1/PD-L1 inhibitors combined with chemotherapy, 1 study involves PD-1/PD-L1 inhibitor combined immunotherapy, 1 study involves PD-1/PD-L1 inhibitors combined with bacterial therapy, and 3 studies involve PD-1/PD-L1 inhibitors combined with comprehensive therapy. As for primary outcome measures, 4 trials select pathological complete response rates, 3 trials select progression-free survival rate, 3 trials select objective response rate, 3 trials select overall survival rate, 4 trials select disease-free survival rate, 1 trial selects clinical complete response rate, and 1 trial selects percentage of participants with a dose-limiting toxicity. CONCLUSION: For early- and middle-stage MSI-H and MSS CRC, PD-1/PD-L1 inhibitors have shown some therapeutic efficacy, as evidenced by phase I/II studies. However, contemporary trial designs exhibit heterogeneity, with relatively few inclusion criteria, the use of various drug combinations and regimens, and significant variations in reported endpoints. Nevertheless, more double-arm, multicenter, randomized controlled trials are still needed to confirm the efficacy of immunotherapy.


Subject(s)
B7-H1 Antigen , Colorectal Neoplasms , Immune Checkpoint Inhibitors , Microsatellite Instability , Neoplasm Staging , Programmed Cell Death 1 Receptor , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , B7-H1 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/therapeutic use
2.
Front Cell Infect Microbiol ; 14: 1336619, 2024.
Article in English | MEDLINE | ID: mdl-38415009

ABSTRACT

Background: Hepatitis B virus (HBV) reactivation is a common complication in hepatocellular carcinoma (HCC) patients treated with chemotherapy or immunotherapy. This study aimed to evaluate the risk of HBV reactivation and its effect on survival in HCC patients treated with HAIC and lenvatinib plus PD1s. Methods: We retrospectively collected the data of 213 HBV-related HCC patients who underwent HAIC and lenvatinib plus PD1s treatment between June 2019 to June 2022 at Sun Yat-sen University, China. The primary outcome was the risk of HBV reactivation. The secondary outcomes were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. Results: Sixteen patients (7.5%) occurred HBV reactivation in our study. The incidence of HBV reactivation was 5% in patients with antiviral prophylaxis and 21.9% in patients without antiviral prophylaxis, respectively. The logistic regression model indicated that for HBV reactivation, lack of antiviral prophylaxis (P=0.003) and tumor diameter (P=0.036) were independent risk factors. The OS and PFS were significantly shorter in the HBV reactivation group than the non-reactivation group (P=0.0023 and P=0.00073, respectively). The number of AEs was more in HBV reactivation group than the non-reactivation group, especially hepatic AEs. Conclusion: HBV reactivation may occur in HCC patients treated with HAIC and lenvatinib plus PD1s. Patients with HBV reactivation had shorter survival time compared with non-reactivation. Therefore, HBV-related HCC patients should undergo antiviral therapy and HBV-DNA monitoring before and during the combination treatment.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Phenylurea Compounds , Quinolines , Humans , Carcinoma, Hepatocellular/drug therapy , Hepatitis B virus/physiology , Liver Neoplasms/drug therapy , Retrospective Studies , Antiviral Agents/therapeutic use , Receptors, Death Domain
3.
J Cardiovasc Dev Dis ; 10(10)2023 Oct 09.
Article in English | MEDLINE | ID: mdl-37887869

ABSTRACT

Immune checkpoint inhibitors (ICIs) have emerged as a powerful and efficacious therapeutic approach for many cancer patients. Sintilimab is a fully human IgG4 monoclonal antibody that binds with programmed cell death receptor-1 (PD-1) to block its interaction with ligands, thereby enhancing the antitumor effects of T cells. However, ICIs may induce immune-related adverse events (irAEs) in various systems and organs, with fulminant myocarditis being the most severe one. We report the case of a 45-year-old female with gastric cancer who developed chest pain two weeks after chemotherapy with sintilimab; she was diagnosed with immune-associated fulminant myocarditis and experienced an Adams-Stokes syndrome attack in the hospital. Eventually, she was discharged after being treated with methylprednisolone, immunoglobulin, and an IABP.

4.
Chin Clin Oncol ; 12(4): 38, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37699603

ABSTRACT

BACKGROUND: The prognosis remains poor after standard chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. Programmed cell death receptor-1 (PD-1) inhibitors have been recommended as the first-line treatment for recurrent cervical cancer. The efficacy of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer was still uncertain. This study aimed to explore the efficacy and safety of PD-1 inhibitors combined with concurrent chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. METHODS: This retrospective study included patients with pelvic and/or para-aortic lymph node positive diseases [International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IVA] who had received PD-1 inhibitors plus chemoradiotherapy/radiotherapy between April 1, 2020, and March 31, 2022 at the Hunan Cancer Hospital. The baseline clinicopathological characteristics, treatment, and clinical outcomes were collected. The major clinical outcomes were objective response rate (ORR), progression-free survival (PFS), and treatment-related adverse events (TRAEs). RESULTS: A total of 29 patients were included. The mean age was 55.8 [standard deviation (SD): 8.8] years. Most patients had stage IIIA-IIIB disease (72.4%) and squamous cell carcinoma (93.1%). All patients had lymph node metastases, including 24 (82.8%) with multiple metastases and 11 (37.9%) with para-aortic lymph node metastases. Among the 29 patients, 18 received sintilimab and 11 received camrelizumab concurrently with chemoradiotherapy or radiotherapy. The ORR was 96.6% [95% confidence interval (CI): 0.828, 0.993] at 3 months after radiotherapy (including 15 complete responses and 13 partial responses). At the data cutoff (August 31, 2022), the median follow-up was 14 (range, 5-30) months. The median PFS was not mature. The estimated 1- and 2-year PFS rates were 85.3% (95% CI: 60.1%, 95.2%) and 76.8% (95% CI: 47.0%, 91.2%), respectively. TRAEs of any grade occurred in 27 (93.1%) patients, most commonly as a decrease in white blood counts (82.8%), anemia (58.6%), and fatigue (48.3%). TRAEs of grade 3 or greater occurred in eight (27.6%) patients. There were no treatment-related deaths. CONCLUSIONS: PD-1 inhibitor combined with concurrent chemoradiotherapy showed potential benefit in term of tumor response and PFS in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases.


Subject(s)
Uterine Cervical Neoplasms , Female , Pregnancy , Humans , Middle Aged , Uterine Cervical Neoplasms/drug therapy , Immune Checkpoint Inhibitors , Retrospective Studies , Lymphatic Metastasis , Neoplasm Recurrence, Local , Chemoradiotherapy
5.
J Int Med Res ; 51(9): 3000605231202140, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37773731

ABSTRACT

Various immunity-related adverse events have been reported to be associated with the inhibition of programmed cell death receptor 1. We report a rare case of a relapse of lupus nephritis (LN), involving rapidly progressive glomerulonephritis, which was induced by nivolumab treatment in a patient with oral cancer. The patient had a history of systemic lupus erythematosus and underwent treatment with steroids, rituximab, and plasmapheresis. However, her renal function did not improve, and she died of multiple organ failure. To our knowledge, this is the first description of severe LN induced by nivolumab.


Subject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Mouth Neoplasms , Humans , Female , Aged, 80 and over , Lupus Nephritis/drug therapy , Nivolumab/adverse effects , Neoplasm Recurrence, Local/drug therapy , Lupus Erythematosus, Systemic/complications , Chronic Disease
6.
Clin Exp Med ; 23(7): 3189-3204, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37322134

ABSTRACT

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. As the diagnosis of early gastric cancer is difficult, most patients are at a late stage of cancer progression when diagnosed. The current therapeutic approaches based on surgical or endoscopic resection and chemotherapy indeed improve patients' outcomes. Immunotherapy based on immune checkpoint inhibitors has opened a new era for cancer treatment, and the immune system of the host is reshaped to combat tumor cells and the strategy differs according to the patient's immune system. Thus, an in-depth understanding of the roles of various immune cells in the progression of gastric cancer is beneficial to application for immunotherapy and the discovery of new therapeutic targets. This review describes the functions of different immune cells in gastric cancer development, mainly focusing on T cells, B cells, macrophages, natural killer cells, dendritic cells, neutrophils as well as chemokines or cytokines secreted by tumor cells. And this review also discusses the latest advances in immune-related therapeutic approaches such as immune checkpoint inhibitors, CAR-T or vaccine, to reveal potential and promising strategies for gastric cancer treatment.


Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/therapy , Immune Checkpoint Inhibitors , Immunotherapy , T-Lymphocytes , Tumor Microenvironment
7.
Int J Gen Med ; 16: 1513-1525, 2023.
Article in English | MEDLINE | ID: mdl-37128473

ABSTRACT

Purpose: The study aimed to investigate the relationship between the expression of PD-1 and CTLA-4 on the surface of peripheral blood T lymphocyte subsets in patients with sepsis and the severity and prognosis of the disease. Patients and Methods: The study included patients with sepsis who were admitted to the intensive care unit. The expression of PD-1 and CTLA-4 on T lymphocyte subsets was detected by flow cytometry, and the severity of sepsis was assessed using the SOFA score. Results: The expression of PD-1 on CD4+T cells, PD-1 on Tregs, and CTLA-4 on Tregs increased with the severity of the disease (P<0.05). Multivariate logistic regression analysis showed that PD-1 expression on CD4+T cells, CTLA-4 expression on Tregs, and the SOFA score were independent risk factors for 28-day mortality in patients with sepsis (P<0.05). The area under the curve of the SOFA score combined with the expression of PD-1 on CD4+T cells and CTLA-4 on Treg cells was significantly higher than any single indicator (P<0.05). Patients with high expression of PD-1 on CD4+T cells (>31.25%) and CTLA-4 on Tregs (>12.64%) had a lower 28-day survival rate (P<0.05). Conclusion: The increased expression of PD-1 and CTLA-4 on CD4+T cells and Tregs is significantly associated with the severity and prognosis of sepsis patients. The combination of the SOFA score and the expression of PD-1 on CD4+T cells and CTLA-4 on Tregs can further improve the prognostic predictive value. These findings may be promising biomarkers for prognostic assessment, risk stratification, and identification of immunosuppression in patients with sepsis.

8.
Front Vet Sci ; 10: 1144869, 2023.
Article in English | MEDLINE | ID: mdl-37252387

ABSTRACT

Monoclonal antibody targeting programmed cell death-1 (PD-1) is one of the most promising treatment therapies for human cancers. Canine PD-1 antibodies used in clinical trials have also shown efficacy in treating canine cancers. An 11-year-old male intact border collie presented to us for evaluation of left cervical mass. Computed tomography (CT) examination revealed an irregular pharyngeal mass invading the surrounding soft tissue. Histological and immunohistochemical results were consistent with a diagnosis of adenocarcinoma, most likely originating from the minor salivary gland. An anti-canine PD-1 monoclonal antibody was administered. Two months after the initial treatment, the tumor reached partial remission and maintained as such for 6 months. Finally, the patient was euthanized due to reasons unrelated to cancer, with a survival time of 316 days. To our knowledge, this is the first report of response to PD-1 blockade treatment in canine adenocarcinoma.

9.
Ann Transl Med ; 10(22): 1256, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36544678

ABSTRACT

Background: Nivolumab is the first programmed cell death receptor 1 (PD-1) inhibitor approved in China. Compared with chemotherapy, nivolumab has shown advantages of good efficacy and safety in the treatment of a variety of tumors. However, due to its short time of use in China and lack of safety experience, clinical understanding of its adverse reactions has not been sufficiently elucidated. In recent years, cases of diabetic ketoacidosis caused by nivolumab have been reported in the emergency department, which has aroused our concern. Case Description: Here we present a serious case of diabetic ketoacidosis in a 69-year-old woman with invasive mucinous adenocarcinoma of the lung, which occurred following therapy with the PD-1 inhibitor nivolumab and dendritic cell/cytokine-induced killer cell (DC/CIK) immunotherapy. She presented with diabetic ketoacidosis 5 days after the second cycle of nivolumab administration. The patient presented with dry mouth symptoms, a maximum blood glucose of 511.2 mg/dL, hemoglobin A1c (HbA1c) level of 7.4%, urine ketone body value of 3+, and extracellular fluid residual alkali level of -3.8 mmol/L. Normal saline and insulin was initiated. The patient had no history of obesity or family history of diabetes. She received a single dose of 3.75 mg of dexamethasone treatment during this period of time which resulted in cough improvement, but did not explain the onset of the diabetes. She was treated with insulin, sitagliptin phosphate tablets and acarbose tablets. Diabetic ketoacidosis was considered an immune-related toxicity caused by nivolumab, and consequently, treatment with nivolumab was suspended. Patient was maintained under insulin treatment with a blood glucose levels normalization. Conclusions: The incubation period of nivolumab-induced diabetic ketoacidosis is dispersive and the clinical risk is high. Patients need life-long insulin therapy. Blood glucose and HbA1c should be monitored routinely before and during nivolumab immunotherapy to avoid the occurrence of diabetic ketoacidosis. After the occurrence of diabetic ketoacidosis, insulin should be used to actively control blood glucose and do a good job in medication education to ensure long-term compliance of patients. Nivolumab should only be initiated if the patient has a clinical benefit under stable glucose control.

10.
J Med Cases ; 13(9): 449-455, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36258702

ABSTRACT

Nivolumab is a humanized monoclonal anti-programmed cell death receptor-1 (PD-1) antibody that has been authorized for use in the treatment of advanced malignancies. Cutaneous reactions are the most common immune-related adverse events reported with anti-PD-1 agents, and they range broadly from mild localized reactions to rarely severe or life-threatening systemic dermatoses. The occurrence of Steven-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) with nivolumab use is an exceedingly rare phenomenon that was only documented in a handful of cases in the current literature, but it deserves careful attention as SJS/TEN may be associated with fatal outcomes. We present a case of nivolumab-induced SJS/TEN in a middle-aged female patient with metastatic gastric adenocarcinoma that was successfully treated with immunosuppressive therapy and supportive care. Prompt recognition of SJS/TEN with discontinuation of nivolumab is warranted when SJS/TEN is suspected clinically. Multidisciplinary management in a specialized burn unit is the key to improving outcomes of SJS/TEN.

11.
Front Immunol ; 13: 995121, 2022.
Article in English | MEDLINE | ID: mdl-36091070

ABSTRACT

Immune checkpoint inhibitor-associated adverse reactions (irAEs) are a clinical treatment issue that requires additional attention when ICIs have significant survival benefits in patients with advanced hepatocellular carcinoma (HCC). Among them, ICIs-associated myocarditis (ICIAM) is a kind of severe irAE with a high mortality rate (17%-50%). Despite its low incidence (PD1/PD-L1 related: 0.41%-0.8%), ICIAM can significantly disturb the decision making of therapeutic schemes and even the survival outcomes of patients. ICIAM induced by sintilimab has not been reported in any complete clinical studies yet and understanding the clinical characteristics involved may inform better practices for the management. Here, we reported a 78 y/o patient with advanced HCC, who experienced ICIAM induced by sintilimab within a short course from treatment onset and found that adequate baseline examination before the implementation of the therapeutic scheme, regular monitoring of myocardial enzymonram and cardiac imaging were measures for the early detection, while glucocorticoid pulse therapy is still the best choice with timely and sufficient application. Simultaneously, the combination of other immunosuppressants may lead to better results. New-predictive markers and examination methods are still required to facilitate the early detection.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Myocarditis , Antibodies, Monoclonal, Humanized/adverse effects , Carcinoma, Hepatocellular/drug therapy , Humans , Liver Neoplasms/drug therapy
12.
Cancer Treat Rev ; 109: 102428, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35753157

ABSTRACT

IMPORTANCE: Anti-programmed cell death receptor-1 (PD-1) therapy is standard of care for incurable recurrent or metastatic non-nasopharyngeal head and neck cancer. In contrast, there are no regulatory agency-approved anti-PD-1 agents indicated for the treatment of recurrent or metastatic nasopharyngeal carcinomas (RM-NPC) in the Western hemisphere, and no standard treatment option exists beyond first-line chemotherapy for RM-NPC. The pace of development of novel systemic therapy regimens for RM-NPC has been slow compared to many other advanced tumor types, leaving an unmet clinical need for these patients with a poor prognosis. OBSERVATIONS: Recent clinical trials have documented the clinical activity of anti-PD-1 therapy in RM-NPC. In particular, randomized clinical trials in the first-line setting have demonstrated significant improvements in progression-free survival (PFS) with the addition of anti-PD-1 therapy to standard chemotherapy. Whether the observed PFS benefits require combination chemoimmunotherapy or can be achieved with chemotherapy followed by crossover to immunotherapy upon progression remains unknown. Ongoing clinical trials are exploring novel anti-PD-1 therapy-based combinations, which may further solidify a role for these agents in RM-NPC. CONCLUSIONS AND RELEVANCE: Among patients with RM-NPC, anti-PD-1 therapy added to first-line standard-of-care gemcitabine plus cisplatin provides significantly better efficacy outcomes compared to chemotherapy alone, and anti-PD-1 monotherapy appears to have comparable clinical activity and better tolerability than chemotherapy in previously treated disease. Thus, anti-PD-1 therapy is poised to advance standard of care for the treatment of RM-NPC.


Subject(s)
Head and Neck Neoplasms , Nasopharyngeal Neoplasms , B7-H1 Antigen , Cisplatin , Humans , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology
13.
Asia Pac J Clin Oncol ; 18(5): e268-e274, 2022 Oct.
Article in English | MEDLINE | ID: mdl-34581488

ABSTRACT

AIMS: Programmed death receptor ligand-1 (PD-L1) expression has been identified as the main predictor of responsiveness to programmed death receptor-1 (PD-1)-targeted immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). In this retrospective study, we explored the inter- and intratumoral PD-L1 heterogeneity in patients who received two separate pathologically verified NSCLC diagnoses at Shandong Provincial Hospital Affiliated to Shandong First Medical University and Linyi People's Hospital. METHODS: Patients were classified into four groups according to the type of intra- and intertumoral heterogeneity: Group 1 included patients in whom primary tumor heterogeneity was observed between biopsy and surgical specimens; in Group 2, heterogeneity was observed between primary tumors and paired dissected regional lymph nodes; in Group 3, heterogeneity was observed between resected primary tumors and distant metastases or recurrent disease; in Group 4, heterogeneity was observed before and after microwave ablation. Of the 221 enrolled patients, 97, 36, 57, and 31 were allocated to groups 1, 2, 3, and 4, respectively. RESULTS: Significant heterogeneity was observed among all patients (P = 0.026) and within Group 1 (P = 0.022) when using a PD-L1 tumor proportion score (TPS) cut-off of 5%. However, no heterogeneity was observed in the other groups or with a PD-L1 TPS cut-off value of 1%. CONCLUSIONS: Intratumoral PD-L1 expression heterogeneity between the biopsy and surgical specimens of primary tumors was more frequently detected than intertumoral heterogeneity in advanced NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Ligands , Lung Neoplasms/metabolism , Programmed Cell Death 1 Receptor , Receptors, Death Domain , Retrospective Studies
14.
Cancer Chemother Pharmacol ; 89(1): 93-103, 2022 01.
Article in English | MEDLINE | ID: mdl-34750637

ABSTRACT

PURPOSE: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. METHODS: Part 1 featured a 3 + 3 weight-based dose-escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death. RESULTS: The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. CONCLUSIONS: Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacokinetics , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/pharmacokinetics , Neoplasms/drug therapy , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacology , Area Under Curve , Body Weight , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/pharmacology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/pathology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Treatment Outcome
16.
Front Immunol ; 12: 753890, 2021.
Article in English | MEDLINE | ID: mdl-34804039

ABSTRACT

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the "adaptive" NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation.


Subject(s)
Adoptive Transfer , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/therapy , Immune Checkpoint Inhibitors/therapeutic use , Killer Cells, Natural/immunology , Lymphocyte Transfusion , Salvage Therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Differentiation , Cytomegalovirus Infections/complications , Disease-Free Survival , Feasibility Studies , Female , Hodgkin Disease/complications , Hodgkin Disease/drug therapy , Humans , Male , Middle Aged , Nivolumab/therapeutic use , Recurrence , Transplantation, Autologous , Young Adult
18.
Clin Immunol ; 229: 108742, 2021 08.
Article in English | MEDLINE | ID: mdl-33905818

ABSTRACT

Sepsis is characterized by high mortality and poor prognosis and is one of the leading causes of death among patients in the intensive care unit (ICU). In the past, drugs that block early inflammatory responses have done little to reverse the progression of sepsis. Programmed cell death receptor 1 (PD-1) and its two ligands, programmed cell death receptor ligand 1(PD-L1) and programmed cell death receptor ligand 2 (PD-L2), are negative regulatory factors of the immune response of the body. Recently, the role of the PD-1 signaling pathway in sepsis has been widely studied. Studies showed that the PD-1 signaling pathways are closely related to the mortality and prognosis of sepsis patients. In the immunotherapy of sepsis, whether in animal experiments or clinical trials, anti-PD-1/PD-L1 antibodies have shown good promise. In this review, firstly, we focus on the immunosuppressive mechanism of sepsis and the structure and function of the PD-1 signaling pathway. The variety of the PD-1 signaling pathways in sepsis is introduced. Then, the relationship between the PD-1 signaling pathway and immune cells and organ dysfunction and the regulatory factors of the PD-1 signaling pathway in sepsis is discussed. Finally, the application of the PD-1 signaling pathway in sepsis is specifically emphasized.


Subject(s)
Programmed Cell Death 1 Receptor/immunology , Sepsis/immunology , Adaptive Immunity , Animals , B-Lymphocytes/immunology , B7-H1 Antigen/immunology , Dendritic Cells/immunology , Humans , Immune Tolerance , Immunity, Innate , Immunotherapy , Macrophages/immunology , Models, Immunological , Monocytes/immunology , Neutrophils/immunology , Prognosis , Programmed Cell Death 1 Ligand 2 Protein/immunology , Sepsis/therapy , Signal Transduction/immunology , T-Lymphocytes/immunology
19.
Neurosurg Clin N Am ; 32(2): 235-248, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33781505

ABSTRACT

The glioblastoma tumor microenvironment is highly immunosuppressed. This immunosuppressive state is engineered by inhibitory molecules secreted by tumor cells that limit activation of immune effector cells, drive T-cell exhaustion, and enhance the immunosuppressive action of tumor-associated myeloid cells. Immunotherapeutic approaches have sought to combat glioblastoma microenvironment immunosuppression with agents such as immune checkpoint inhibitors. Although immune checkpoint blockade in glioblastoma has yielded disappointing results thus far, there is significant interest in the combination of immune checkpoint blockade with other approaches to enhance response.


Subject(s)
Glioblastoma , Glioblastoma/drug therapy , Humans , Immune Checkpoint Inhibitors , Programmed Cell Death 1 Receptor/therapeutic use , Tumor Microenvironment
20.
Recent Pat Anticancer Drug Discov ; 16(3): 312-332, 2021.
Article in English | MEDLINE | ID: mdl-33563158

ABSTRACT

BACKGROUND: Camrelizumab, which was launched in China on May 29, 2019, is a humanized anti-programmed cell death-1 (PD-1) antibody. It is used for the treatment of complicated or refractory classic Hodgkin's lymphoma with at least second-line chemotherapy. On March 4, 2020, camrelizumab was approved as a second-line drug in China for the treatment of advanced hepatocellular carcinoma. Currently, camrelizumab is undergoing clinical research for advanced solid tumors such as liver cancer, gastric cancer, esophageal cancer, and lung cancer, and all have shown clinical efficacy. OBJECTIVE: This review describes preclinical studies on camrelizumab and its efficacy and safety in clinical studies in various tumors. METHODS: A literature search was conducted on basic research and clinical trials of camrelizumab determined its pharmacology, toxicology, pharmacokinetic properties, and current clinical research status. We also analyzed the difference between camrelizumab and other PD-1 antibodies. RESULTS: The results of preclinical studies show that camrelizumab binds to the PD-1 receptor and has stable anti-tumor activity in a dose-dependent manner. Clinical studies show that camrelizumab has therapeutic effects on a variety of tumors. The incidence of adverse reactions with camrelizumab is low, with most being mild, reversible, and predictable. CONCLUSION: This review summarizes the current status of preclinical and clinical studies on camrelizumab. Current research confirms that camrelizumab alone or in combination with other drugs shows significant anti-cancer activity and a low incidence of adverse reactions. However, further studies are needed to verify the application potential of camrelizumab in a variety of tumors.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Carcinoma, Hepatocellular/drug therapy , Drug Evaluation, Preclinical , Esophageal Neoplasms/drug therapy , Hodgkin Disease/drug therapy , Humans , Immune Checkpoint Inhibitors/pharmacology , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Stomach Neoplasms/drug therapy
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