Autoimmune Cancer Research Articles

Malignant Melanoma: Autoimmunity and Supracellular Messaging as New Therapeutic Approaches.

Melanoma is one of the most aggressive forms of cancer, with a high mortality rate in the absence of a safe and curable therapy. As a consequence, several procedures have been tested over time, with the most recent (immunological and targeted) therapies proving to be effective in some patients. Unfortunately, these new treatment options continue to generate debate related to the therapeutic strategy (intended to maximize the long-term results of patients with melanoma), not only about the monotherapy configuration but also regarding association/succession between distinct therapeutic procedures. As an example, targeted therapy with BRAF inhibitors proved to be effective in advanced BRAF-mutant melanoma. However, such treatments with BRAF inhibitors lead to therapy resistance in half of patients after approximately 6months. Even if most benign nevi incorporate oncogenic BRAF mutations, they rarely become melanoma; therefore, targeted therapy with BRAF inhibitors should be viewed as an incomplete or perfectible therapy. Another example is related to the administration of immune checkpoint inhibitors/ICIs (anti-CTLA-4 antibodies, anti-PD-1/PD-L1 antibodies), which are successfully used in metastatic melanoma. It is currently believed that CTLA-4 and PD-1 blockade would favor a strong immune response against cancer cells. The main side effects of ICIs are represented by the development of immune-related adverse events, which in some cases can be lethal. These ICI side effects would thus be not only therapeutically counterproductive but also potentially dangerous. Surprisingly, a subset of immune-related adverse events (especially autoimmune toxicity) seems to be clearly correlated with better therapeutic results, perhaps due to an additional therapeutic effect (currently insufficiently studied/exploited). Contrary to the classical approach of cancer (considered until now an uncontrolled division of cells), a very recent and comprehensive theory describes malignancy as a supracellular disease. Cancerous disease would therefore be a disturbed supracellular process (embryogenesis, growth, development, regeneration, etc.), which imposes/coordinates an increased rhythm of cell division, angiogenesis, immunosuppression, etc. Melanoma is presented from such a supracellular perspective to be able to explain the beneficial role of autoimmunity in cancer (autoimmune abortion/rejection of the melanoma-embryo phenotype) and to create premises to better optimize the newly emerging therapeutic options. Finally, it is suggested that the supracellular evolution of malignancy implies complex supracellular messaging (between the cells and host organism), which would be interfaced especially by the extracellular matrix and noncoding RNA. Therefore, understanding and manipulating supracellular messaging in cancer could open new treatment perspectives in the form of digitized (supracellular) therapy.

Application progress of biotherapy in tumor therapy

Malignant tumors have become one of the major diseases endangering human health. In recent years, the incidence and mortality of cancer have been increasing. The survival rate is only about 50% for the cancer patients after common therapists, includes surgery, radiotherapy, and chemotherapy. By facing the severe challenge of choosing treatment method, the more effective cancer treatment has become the focus of clinical researches. Biotherapy is a new tumor therapy method with significant curative effect, and is a new treatment for autoimmune cancer. The application progress of biotherapeutic technologies in cancer therapy were reviewed, including non-specific immunotherapy, cytokine therapy, adoptive cell therapy, monoclonal antibody therapy and gene therapy. Key words: Biotherapy; Tumor; Cytokine therapy; Gene therapy

Abstract 5071: Application of a novel protein biomarker discovery platform to identify biomarkers for improved diagnosis of prostate cancer

Abstract The issues surrounding the use of prostate-specific antigen (PSA) in the diagnosis of prostate cancer (PCa) are well documented and the need for a molecular diagnostic test with greater discriminatory power is clear. The development of autoantibodies associated with prostate cancer has also been described. In general, the appearance of such antibodies can precede disease symptoms by many years, making them attractive as potential biomarkers for early diagnosis. We have developed a unique “functional protein” array platform which utilises correctly folded proteins and has the ability to display native, discontinuous epitopes. The reproducibility of the platform is exceptionally good, making it possible to screen statistically meaningful numbers of samples. Following on from a successful pilot study, where panels of autoantibody biomarkers exhibiting a specificity and sensitivity for PCa superior to PSA were identified using the platform1, we have validated this approach in a large-scale analytical study. The current analytical study involving approximately 1800 samples was primarily designed to identify panels of biomarkers with the ability to distinguish between PCa (n=400) and control samples from patients with benign prostatic hypertrophy (BPH, n=406). BPH can present with similar symptoms to PCa and can also result in elevated PSA levels. Additional sample cohorts included prostatitis, other cancers of various origin and non-disease/healthy controls (n=400). All samples were age, ethnicity and gender matched. The products of 1296 unique genes (1330 proteins), chosen for their association with disease, signal transduction and cancer autoimmunity, are immobilized on each array. Serum samples (n=1781) were analysed using the arrays as described previously1. Data were split into test and training sets and analyzed with several classification algorithms to identify classifiers which would successfully distinguish case from control samples. Data were repeatedly split into test and training sets and analysis cycles repeated until a stable set of classifiers was identified. At the time of writing, data is still under analysis; however, early indications are encouraging and suggest that panels of biomarkers with a performance that significantly exceeds that of PSA may be identified. Full results of the study will be presented. 1 McAndrew et al Development of a panel of biomarkers for the diagnosis of prostate cancer (2010) Molecular Diagnostics in Cancer Therapeutic Development conference Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5071. doi:10.1158/1538-7445.AM2011-5071

Proteomics-based Identification of Human Acute Leukemia Antigens That Induce Humoral Immune Response

The identification of panels of tumor antigens that elicit an antibody response may have utility in cancer screening, diagnosis, and establishing prognosis. Until now, autoimmunity in cancer has been mainly revealed in solid tumors. The aim of this study was to apply the proteomic approach to the identification of proteins that commonly elicit a humoral response in acute leukemia (AL). Sera from 21 newly diagnosed patients with AL, 20 patients with solid tumors, and 22 noncancer controls were analyzed for antibody-based reactivity against AL proteins resolved by two-dimensional electrophoresis. As a result, autoantibody against a protein identified by mass spectrometry as Rho GDP dissociation inhibitor 2 was detected in sera from 15 of 21 patients with AL (71%). By contrast, such antibody was detected in sera from one of 20 patients with solid tumors (5%) and one of 22 noncancer controls (4.5%). Five other protein autoantibodies were also found in AL patients with a high frequency and constituted the major target antigens of the AL autoimmune response. The findings of autoantibodies against Rho GDP dissociation inhibitor 2 and other proteins in sera of patients with AL suggest that the proteomic approach we have implemented may have utility for the development of a serum-based assay for AL screening and diagnosis.

Diversity of antinucelar antibody responses in hepatocellular carcinoma

Background/Aims: The development of antinuclear antibodies (ANA) in malignancies has been described but its mechanism is still not understood. The aim of this study was to examine ANA specificities in hepatocellular carcinoma to further understand autoimmunity in cancer. Methods: Two hundred and four hepatocellular carcinoma patients were compared with 68 chronic hepatitis C, with 126 chronic hepatitis B and with 30 alcoholic liver cirrhosis patients, as well as with 87 healthy donors. Indirect immunofluorescence, immunoblotting, and immunoprecipitation were used to study ANA reactivities. Results: Hepatocellular carcinoma had a significantly higher frequency of ANA using HEp-2 cells as substrate (31%) than chronic hepatitis C (10%), chronic hepatitis B (9.5%), alcoholic liver cirrhosis (10%) or healthy donors (4.5%). A great diversity of ANA specificities was found in hepatocellular carcinoma. Three hepatoma sera had antibodies that co-localized with non-snRNP splicing factor SC35, suggesting that the antigenic targets might be involved in mRNA splicing. We identified antibodies to two known nuclear autoantigens: fibrillarin and p330 d/CENP-F. These autoantigens are involved in the 5′ processing of precursor ribosomal RNA transcripts and in mitotic functions, respectively. Conclusions: Diversity was found in the autoantibody specificity, in contrast to the specific subsets of auto-antibodies seen in several systemic rheumatic autoimmune diseases. Our data suggest that immune response in hepatocellular carcinoma targets important proteins involved in cellular biosynthetic or proliferative functions.

Molecular biology in medicine.

Part 1 Molecular biology at the centre of human disease: haemophilia A. Part 2 Workings of the human genome: DNA, RNA and proteins analyzing human genes and their products the control of human gene expression medical genetics. Part 3 Inherited disorders of the human genome: monogenic diseases inherited cancer polygenic diseases. Part 4 Somatic mutation of the human genome: immune diversity autoimmunity cancer. Part 5 Diagnostic and therapeutic applications of molecular biology: bacterial infections viral infections recombinant products pre-natal diagnosis gene therapy ethics.

The Relation Of the Immune Reaction To Cancer

Publisher Summary The chapter attempts to organize and correlate all the research reports and discussions based on the relevance of immunology to cancer. The chapter begins with the very dynamic processes involved in tumor transplantation. Immunity to transplanted tumors depends on genetic and, therefore, antigenic differences between the tumor and host. The then chapter moves on to the highly technical fields of serology. The effects of various sera and antisera have been investigated in an attempt to evaluate the degree of protection. The chapter discusses immunochemical pattern of tumor related antigens. Immunological method is refined enough to show qualitative discrimination between two given tissue antigens. The concept of auto immunity in cancer and viral oncogenesis has been explained with the help of significant virus work and various aspects of immunity during the tumorous state is also summarized. The chapter also presents theoretical implications of the phenomena observed in tumor autoimmunity.