Combined immune checkpoint inhibitors of CTLA4 and PD-1 for hepatic melanoma of unknown primary origin: A case report

BACKGROUND Melanoma is uncommonly found in lymph nodes,subcutaneous tissue,or visceral organs without a primary lesion,where it is identified as metastatic melanoma with unknown primary(MUP).Hepatic MUP is extremely rare and has a poor prognosis.There is limited information on its pathogenesis,clinical and imaging features,and pathological findings.There are no guidelines for the use of immune checkpoint inhibitors(ICIs)in hepatic MUP,and the treatment outcome has rarely been reported.CASE SUMMARY A 42-year-old woman presented to our hospital with hepatic tumors found incidentally during a routine check-up.Contrast-enhanced abdominal computerized tomography showed multiple mass lesions in the liver.Pathological results revealed melanoma,which was confirmed by immunohistochemical staining for HMB-45(+),Melan-A(+),S-100(+),and SOX10(+).There was no evidence of primary cutaneous,ocular,gastrointestinal,or anal lesion on a comprehensive examination.The patient was diagnosed with hepatic MUP.She received combined antibodies against cytotoxic T-lymphocyte-associated antigen 4(CTLA-4,ipilimumab)and programmed death protein-1(PD-1,nivolumab).She died of hepatic failure 9 mo after hepatic MUP was diagnosed.This the first case of hepatic MUP treated with combined ipilimumab and nivolumab,who showed better outcome than previous cases.CONCLUSIONCombined ICIs of PD-1 and CTLA-4 may be considered as the first-line therapyfor patients with hepatic MUP.

Advances in immunotherapy for treatment of lung cancer

Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 （PD-1） and its ligand （PD-L1）, on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab~ another anti PD-1 antibod）5 has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer （NSCLC）, supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.

Specific CD8^+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.

Immune checkpoint inhibitor-mediated colitis in gastrointestinal malignancies and inflammatory bowel disease

Immune checkpoint inhibitors(ICI)have markedly changed the landscape of cancer therapy.By re-invigorating the immune system against tumors,ICI provide novel therapeutic options for a broad variety of malignancies,including many gastrointestinal(GI)cancers.However,these therapies can also induce autoimmune-like side effects in healthy tissue across the body.One of the most common of these side effects is ICI-mediated colitis and diarrhea(IMC).Here,we review the incidence and risk of IMC in ICI therapy,with a focus on what is known regarding IMC in patients with GI malignancies.We also discuss data available on the use of ICI and risk of IMC in patients with pre-existing inflammatory bowel disease,as these patients may have increased risk of IMC due to their underlying intestinal pathology.

Faecal microbiota transplantation enhances efficacy of immune checkpoint inhibitors therapy against cancer

Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microbiota.Additionally,faecal microbiota transplantation may enhance efficacy of ICIs.Nevertheless,the data available in this field are insufficient,and relevant scientific work has just commenced.As a result,the current work reviewed the latest research on the association of gut microbiota with ICI treatments based on anti-programmed cell death protein 1 antibody and anti-cytotoxic T-lymphocyte-associated protein 4 antibody and explored the therapeutic potential of faecal microbiota transplantation in combination with ICI therapy in the future.

Immunotherapies for well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors:A new category in the World Health Organization classification

According to the 2019 World Health Organization(WHO)classification,welldifferentiated grade 3(G3)gastroenteropancreatic(GEP)neuroendocrine tumors(NETs)are a new category of cancer of the digestive system.G3 GEP-NET research and treatment are not as robust as those of lower grade(G1/2)NETs and poorly differentiated neuroendocrine carcinomas(NECs).Previously,the management of high-grade NETs was mainly based on NEC therapies,as highgrade NETs were classified as NECs under the previous WHO classification.Despite this,G3 GEP-NETs are significantly less responsive to platinum-based chemotherapy regimens than NECs,due to their distinct molecular pathogenesis and course of pathological grade transition.Patients with advanced G3 GEPNETs,who have progressed or are intolerant to chemotherapy regimens such as capecitabine plus temozolomide,have limited treatment choices.Immunotherapy has helped patients with a variety of cancers attain long-term survival through the use of immune checkpoint inhibitors.Immunotherapies,either alone or in combination with other therapies,do not have a clear function in the treatment of G3 GEP-NETs.Currently,the majority of immunotherapy studies,both prospective and retrospective,do not reliably differentiate G3 GEP-NETs from NECs.By contrast,a significant number of studies include non-GEP neuroendocrine neoplasms(NENs).Therefore,there is an urgent need to summarize and evaluate these data to provide more effective therapeutic approaches for patients with this rare tumor.The purpose of this mini-review was to screen and summarize information on G3 GEP-NETs from all studies on NENs immunotherapy.

Costimulatory blockade:A novel approach to the treatment of glomerular disease?

Costimulatory pathways(Cluster of differentiation 28,tumor necrosis factor-related,adhesion and T Cell Ig-and mucin-domain molecules) regulating the interactions between receptors on the T cells andtheir ligands expressed on several cell types,have a key role in controlling many immunological and non immunological processes.Indeed,accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions,such as allograft rejection,atherosclerosis,rheumatoid arthritis,psoriasis and renal diseases,including glomerulonephritis.Primary or secondary(i.e.,associated with infections,drugs or systemic diseases,such as systemic lupus erythematosus,diabetes,etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic mechanisms.Since costimulatory molecules,in particular CD80 and CD40,have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis,costimulation has been thought as a new therapeutic target for patients with glomerular diseases.However,although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases,clinical trials reported contrasting results.So,at this moment,there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary glomerulonephritis.Here,we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach.

Why natural killer cells in triple negative breast cancer?

The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.

Expression of E2A in Mid-secretory Endometrium of Women Suffering from Recurrent Miscarriage

E2A is involved in promoting forkhead box P3（FOXP3） and retinoid-related orphan receptor gamma t（RORγt） gene transcription, which are pivotal transcription factors of T regulatory cells and Th17 cells, respectively. Little is known about the involvement of E2 A in pregnancy process. This study aimed to investigate the expression of E2 A, cytotoxic T-lymphocyte-associated protein 4（CTLA-4）, and Foxp3 in luteal phase endometrium of women suffering recurrent miscarriage（RM）（n=21） and control group（n=11） by immunohistochemistry, with the Vectra？ automated quantitative pathology imaging system for analysis. The percentage of E2 A＋ cells and CTLA-4＋ cells was significantly higher in the endometrium of women with RM than in the controls. There was positive correlation between E2 A and CTLA-4（r=0.523, P=0.002）, E2 A and FOXP3（r=0.380, P=0.032）, and FOXP3 and CTLA-4（r=0.625, P=0.000） in the mid-secretory phase of endometrium for all subjects. It was concluded that the abnormal expression of endometrial E2 A existed in mid-secretory endometrium of women with RM, and there was a positive correlation between E2 A and FOXP3, and E2 A and CTLA-4, suggesting the possible regulation role of E2 A involved in regulating endometrium receptivity.

Blood and Histopathological Biomarkers of Immune-related Adverse Effects of Treatment with Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have been a recent major breakthrough in the management of tumors.They have broadened the scope of management in medical oncology,which has been heavily dependent on chemotherapy.Immune checkpoint inhibitors have renewed the hope of many patients for a more effective treatment.However,Immune checkpoint inhibitors are also associated with a variety of adverse effects,most commonly immunerelated adverse events,and these are often different from the known chemotherapy-induced toxicities.Hence,there is a need to identify specific biomarkers which are able to predict or diagnose these immune-related adverse events.

Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febrile or infectious episode.Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon,and it is recognized that immunosuppression is associated with a higher cancer risk.The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment.Effective immunity against cancer involves complex interactions between the tumor,the host,and the environment.Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer,since attention has become more focused on the“biologic passport”of the individual tumor rather than the site of origin of the tumor.The different types of cancer immunotherapies discussed here include biologic modifiers,such as cytokines and vaccines,adoptive cell therapies,oncolytic viruses,and antibodies against immune checkpoint inhibitors,such as the co-inhibitory T-cell receptor PD-1 and one of its ligands,programmed death-ligand 1.

Up-regulation of indoleamine 2,3-dioxygenase 1(IDO1)expression and catalytic activity is associated with immunosuppression and poor prognosis in penile squamous cell carcinoma patients

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan (Trp)catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penilesquamous cell carcinoma (PSCC) and explored their clinical significance.Methods: IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn)were examined in 114 PSCC patients by immunohistonchemistry and solid-phaseextraction-liquid chromatography-tandem mass spectrometry. The survival was analyzed using Kaplan-Meier method and the log-rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were definedby principal component analysis. The correlativity was assessed by Pearson’s correlation analysis.Results: The expression level of IDO1 in PSCC cells was positively correlatedwith serum Kyn concentration and Kyn/Trp radio (KTR;both P < 0.001) but negatively correlated with serum Trp concentration (P = 0.001). Additionally, IDO1 upregulation in cancer cells and the increase of serum KTR were significantly associated with advanced N stage (both P < 0.001) and high pathologic grade (P = 0.008and 0.032, respectively). High expression level of IDO1 in cancer cells and serumKTR were associated with short disease-specific survival (both P < 0.001). However, besides N stage (hazard radio [HR], 6.926;95% confidence interval [CI],2.458-19.068;P < 0.001) and pathologic grade (HR, 2.194;95% CI, 1.021-4.529;P = 0.038), only serum KTR (HR, 2.780;95% CI, 1.066-7.215;P = 0.036) was anindependent predictor for PSCC prognosis. IDO1 expression was positively correlated with the expression of interferon-𝛾 (IFN𝛾, P < 0.001) and immunosuppressivemarkers (programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 and 2;all P < 0.05), and the infiltration ofimmune cells (including cytotoxic T lymphocytes, regulatory T lymphocytes, tumorassociated macrophages, and myeloid-derived suppressor cells;all P < 0.001) inPSCC tissues. Furthermore, the expression of IDO1 was induced by IFN𝛾 in a dosedependent manner in PSCC cells.Conclusions: IFN𝛾-induced IDO1 plays a crucial role in immunoediting andimmunosuppression in PSCC. Additionally, serum KTR, an indicator of IDO1catabolic activity, can be utilized as an independent prognostic factor for PSCC.