Role of Cardiac Biomarkers in Cancer Patients

In patients with cancer—and especially some specific subtypes—the heart can be pathologically affected due to the direct action of the tumor or its secretion products or due to the toxicity of some oncological treatments. Cardiac biomarkers have been investigated as inexpensive and easily accessible tools for prediction, early diagnosis, monitoring, or prognosis of various forms of cancer-related cardiac diseases. However, their clinical usefulness was not always clearly demonstrated in every area of cardioncology. For the identification of anthracycline related cardiotoxicity in the very early stages troponins proved to be more efficient detectors than imaging methods. Nevertheless, the lack of a standardized dosage methodology and of cardiotoxicity specific thresholds, do not yet allow to outline the precise way to employ them in clinical routine and to incorporate them into appropriate diagnostic or managing algorithms. Cardiac biomarkers proved also effective in patients with primary cardiac amyloidosis, in which both troponins and natriuretic peptides were able to predict adverse outcome, and carcinoid heart disease, where a precise diagnostic cut-off for N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was identified to screen patients with valvular involvement. Likewise, NT-proBNP proved to be an excellent predictor of postoperative atrial fibrillation (POAF). On the contrary, evidence is still not sufficient to promote the routine use of cardiac biomarkers to early diagnose myocarditis due to immune check points inhibitors (ICIs), radiotherapy induced cardiotoxicity and cardiac complications related to androgenetic deprivation. In this review we present all the evidence gathered so far regarding the usefulness and limitations of these relatively inexpensive diagnostic tools in the field of cardio-oncology.

The use of immunotherapy for the treatment of refractory forms of Hodgkin lymphoma in real clinical practice.

With a frequency of 2.2 cases per 100,000 population in Russia, Hodgkin's lymphoma (HL) is one of the most common malignant neoplasms in young people. In connection with the predominant spread of HL among young people, the issue of effective treatment of various forms of HL remains relevant. Currently, 70-90 % of patients with HL who have received standard chemotherapy or chemoradiotherapy have a long period of remission. However, 10 % of patients with progressive course, can`t achieve a response, and 30 % of patients subsequently recur. The standard approach of treating recurrent and/or refractory HL after initial treatment is “salvage therapy” followed by consolidation with high-dose chemotherapy and stem cell transplantation. Although there is a model for treating these patients, recent research has focused on improving the effectiveness and tolerability of rescue therapy. The use of anti- PD-1 drugs opens up new possibilities for the treatment of recurrent/refractory HL. The article describes the results of using checkpoint inhibitors for patients with a history of multi- course chemotherapy. Inhibitors of immune check points were supplemented in the 3rd and subsequent lines of ChT. A clinical case with immunotherapy supplementation in a patient with severe comorbidity is also presented.

Boosting innate immunity during SARS-CoV-2 clearance

: Currently, humanity is suffering from a highly contagious and infectious novel coronavirus disease. Due to the unavailability of any specifically approved therapy to eradicate this pathogenic virus, day by day, it is claiming more and more life of the humans. By observing the current scenario, human civilization seems to be in dangerous situations, and the development of a potential vaccine against this invisible enemy may take some more time. It was observed that the individual immune system plays an important role in the fighting against the novel coronavirus. Additionally, the innate immune system of the host acts as the first line of defense against invading pathogenic viruses. The host innate immune cells can to detect and detoxify the evading viruses. Thus, boosting the innate immune response via targeting activator or inhibitory immune check points pathways for enhancing T-cell immune response that may potentially help the patients to fight against this deadly virus. The aim of this editorial is to discuss in brief about pathogenesis of COVID-19, role of innate immunity and autophagy during viral clearance.

ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected with Schistosoma japonicum

BackgroundHumoral immune responses play an important role in mediating liver granulomatous inflammation and fibrosis in schistosomiasis. Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on inducible T cell costimulator (ICOS) signaling, but the underlying molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis.Methodology/Principal FindingsWe used a strain of ICOS-transgenic (Tg) mice to test the degrees of liver granulomatous inflammation and fibrosis, the frequency of splenic Tfh cells and soluble egg antigen-specific cytokine responses longitudinally in mice following Schistosoma japonicum (S. japonicum) infection. In comparison with that in wide-type (WT) mice, significantly severer liver granulomatous inflammation and fibrosis and higher mortality were observed in ICOS-Tg mice. Significantly higher frequency of splenic Tfh cells was accompanied by significantly higher levels of Bcl-6 and CXCR5 expression in the livers of ICOS-Tg mice. Furthermore, significantly higher levels of SEA-specific IL-4, IL-6, IL-10, IL-13, IL-17A, IL-21 and TGF-β1 responses, but lower levels of IFN-γ responses were detected in ICOS-Tg mice, which were abrogated by treatment with ICOS blockers in vitro. In addition, significantly higher levels of serum anti-SEA IgG were detected in ICOS-Tg mice.Conclusions/SignificanceThe ICOS-related signaling may promote the pathogenesis of murine schistosomiasis by polarizing Tfh cells, which may be immune check points for the prevention and intervention of schistosomiasis.Author summaryGranulomatous inflammation and fibrosis in the liver are the major pathogenic characteristics of schistosomiasis. ICOS is crucial for the development of Tfh cells, which are the key modulators of B cell activation and humoral immunity. However, the underlying molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis. Here, our results showed that the ICOS over-expression would significantly induce severer liver inflammation and fibrosis, higher frequency of splenic Tfh, higher levels of anti-SEA IgG as well as imbalanced SEA-specific cytokine responses in ICOS-Tg mice. The findings suggested that ICOS signaling may promote the pathogenesis of murine schistosoma-related liver inflammation and fibrosis by polarizing Tfh cells. Potentially, ICOS signaling and Tfh cells may be immune check points for the prevention and intervention of schistosomiasis.

Current advances in kidney cancer immunotherapy

In Russia, among tumors of the genitourinary system, renal cell carcinoma takes the 2nd place after prostate cancer. In 25 % of patients at the time of diagnosis, metastases are detected. Treatment of advanced stages of renal cell carcinoma is often not effective enough. The introduction into clinical practice of modern immunotherapeutic drugs based on inhibition of immune check points has changed the prognosis of the disease for many patients with various malignant neoplasms, including kidney cancer. In this article, we described the results of recent clinical trials on the use of immunotherapy in the treatment of kidney cancer. The most effective is combination of drugs that inhibit different immune check points, and a combination of a check point inhibitor with a targeted drug. This approach is likely to be a major one in the treatment of renal cell carcinoma in the short term. Combinations of control point inhibitors with radiation therapy and immunomodulatory drugs, the role of miRNAs in the regulation of expression of immune control points, the significance and characteristics of the microbiome in connection with the success of immunotherapy for kidney cancer, gene expression profiles as biomarkers of the immune response, and other biomarkers are considered. A better understanding of the mechanisms that limit the effectiveness of immune control point inhibitors will improve future treatment.

Construction of plasmids expressing recombinant B cell epitopes of PD1

Latar Belakang: Pengobatan kanker di Indonesia umumnya menggunakan pengobatan dengan kemoterapi atau dengan operasi. Efek samping dari pengobatan ini antara lain adalah kerontokan rambut, mual dan penurunan berat badan. Saat ini sedang berkembang alternatif terapi kanker dengan menggunakan immunoterapi. Kemampuan sel kanker untuk menghindar dari sistem imun disebabkan adanya protein PD-1 pada sel T yang berikatan dengan ligannya PD-L1. Metode: Penelitian ini merupakan penelitian awal yaitu pembuatan rekombinan PQE PD-1 dan menggunakan bagian soluble dari PD-1 yang disebut dengan EP2PD1 yang akan digunakan untuk pembuatan antibodi monoklonal dan sistem pendeteksi antibodi monoklonal. Metode pembuatan rekombinan PD-1 dan EP2PD1 dengan cara penentuan sekuens epitop sel B yang paling imunogenik dilanjutkan dengan amplifikasi sekuen tersebut dengan PCR dan diligasi ke vektor pengekspresi PQE80. Hasil: Telah terbentuk konstruksi rekombinan PQE80 PD-1 dan PQEEP2PD1 yang diverifikasi menggunakan PCR koloni, pemotongan enzimatik dan sekuensing. Hasil penelitian menunjukkan bahwa epitop PD1 telah terklona ke PQE 80 dan tidak ditemukan mutasi dalam urutan asam amino. Kesimpulan: Konstruksi yang dibuat tidak mempunya mutasi dan dapat dilanjutkan untuk pembuatan antibodi monoklonal. Kata Kunci: PD1, Epitop, Kanker, Immunotherapy Abstract Background: Medications on cancer to date in Indonesia is mostly by surgical or chemotherapy, this type of medications is not always curing the patients. The side effect of the chemotherapy drugs sometimes more challenging such as hair loss, nausea and lost weight. One of the promising targets for cancer is using immune therapy. Cancer cells can avoid immune response by surprising immunity through activation of specific inhibitory signalling pathways, referred to as immune checkpoints. Immune check points like PD-1, PD-L1 are breakthrough therapies in oncology and this monoclonal antibody have been approved by the FDA for treatment. In this research we develop full PD-1 and part of PD1 sequence as an insert then we construct with plasmid PQE80L. This recombinant called PQE PD-1 and PQEEP2PD1. The aim of this study is to make recombinant which would be used to detect PD1 full clone monoclonal antibodies. Methods: In this study, we designed our recombinants using Indonesian HLA and others using in silico models, this prototype will not only cover Indonesian patients but also other country. Results: The result showed that the epitope sequence of PD1 has been clone to PQE 80 wt and verified using colony PCR, Enzyme Digestion and Sanger Sequencing. The Clone than will be expressed and injected to animal model to produce antibody. Conclusion: Construction of recombinant PQE PD-1 and PQE EP2PD1 are constructed without any mutation in the sequence, this recombinant can be used in the next study for protein expression of PQE PD-1 and PQE EP2PD1. Keywords: PD1, Epitope , Cancer, Immunotherapy

PD-1/PD-L1 immune check points blockade to attenuate growth of metastatic colon cancer in the CBP/β-catenin inhibited liver.

556 Background: Immune check points blockade with specific antibodies can accelerate anti-tumor immunity, resulting in a clinical response in patients with various types of cancer. Thus, a wide variety of treatment combinations based on PD-L1/ PD-1 pathway blockage are under development to enhance the therapeutic effect. Here, the effects of the combination treatment of PRI-724, a selective inhibitor of the CBP/β-catenin, with anti-PD-L1 antibody were examined in a mouse model of the liver metastasis of colon cancer. Methods: Mice were inoculated with SL4 colon cancer cells into the spleen to produce metastatic liver tumors. The animals were intraperitoneally injected with or without PRI-724 and/or anti-PD-L1 antibody (10F.9G2) 3 times a week. A part of mice treated with PRI-724 and anti-PD-L1 antibody was administrated with anti-mouse CD4 or CD8 antibody 3 times a week. First, to evaluate anti-tumor effect in those mice, we analyzed liver histology and survival rates after treatment. Next, to examine immune response in the liver, intrahepatic lymphocytes were analyzed by FACS for CD8 memory phenotype, Treg cells, macrophages, and dendritic cells, and the cytokine production from these cells (TNFa, IFNg etc.). Furthermore, inflammatory cytokines and chemokines mRNAs levels and PCR array concerned to Wnt signaling in the liver and serum cytokines levels were also analyzed. Results: The combination of the treatments resulted in regression of tumor growth, whereas monotherapy of each treatment did not show any anti-tumor activity. PRI-724 increased T lymphocytes recruitment, including CD8+ T cells, in the tumor, which may have been induced by inflammatory chemokines and a change of the macrophage property to the cytotoxic phenotype in the liver. Anti-PD-L1 antibody induced CD69+-activated T lymphocytes in the PRI-724-treated livers of mice inoculated with SL4. Administration of anti-CD8 antibody canceled the anti-tumor effects of the combination treatments of PRI-724 and anti-PD-L1 antibody. Conclusions: Targeting CBP/β-catenin combined with PD-1/PD-L1 immune check points blockade shows potential as a new therapeutic strategy for treating the liver metastasis of colon cancer.