Perspectives for the Use of Fucoidans in Clinical Oncology.

Fucoidans are natural sulfated polysaccharides that have a wide range of biological functions and are regarded as promising antitumor agents. The activity of various fucoidans and their derivatives has been demonstrated in vitro on tumor cells of different histogenesis and in experiments on mice with grafted tumors. However, these experimental models showed low levels of antitumor activity and clinical trials did not prove that this class of compounds could serve as antitumor drugs. Nevertheless, the anti-inflammatory, antiangiogenic, immunostimulating, and anticoagulant properties of fucoidans, as well as their ability to stimulate hematopoiesis during cytostatic-based antitumor therapy, suggest that effective fucoidan-based drugs could be designed for the supportive care and symptomatic therapy of cancer patients. The use of fucoidans in cancer patients after chemotherapy and radiation therapy might promote the rapid improvement of hematopoiesis, while their anti-inflammatory, immunomodulatory, and anticoagulant effects have the potential to improve the quality of life of patients with advanced cancer.

An algorithm for drug discovery based on deep learning with an example of developing a drug for the treatment of lung cancer.

In this study, we present an algorithmic framework integrated within the created software platform tailored for the discovery of novel small-molecule anti-tumor agents. Our approach was exemplified in the context of combatting lung cancer. In the initial phase, target identification for therapeutic intervention was accomplished. Leveraging deep learning, we scrutinized gene expression profiles, focusing on those associated with adverse clinical outcomes in lung cancer patients. Augmenting this, generative adversarial neural (GAN) networks were employed to amass additional patient data. This effort yielded a subset of genes definitively linked to unfavorable prognoses. We further employed deep learning to delineate genes capable of discriminating between normal and tumor tissues based on expression patterns. The remaining genes were earmarked as potential targets for precision lung cancer therapy. Subsequently, a dedicated module was formulated to predict the interactions between inhibitors and proteins. To achieve this, protein amino acid sequences and chemical compound formulations engaged in protein interactions were encoded into vectorized representations. Additionally, a deep learning-based component was developed to forecast IC50 values through experimentation on cell lines. Virtual pre-clinical trials employing these inhibitors facilitated the selection of pertinent cell lines for subsequent laboratory assays. In summary, our study culminated in the derivation of several small-molecule formulas projected to bind selectively to specific proteins. This algorithmic platform holds promise in accelerating the identification and design of anti-tumor compounds, a critical pursuit in advancing targeted cancer therapies.

Spontaneous regression of a metastatic carcinoma transmitted by a kidney graft.

Transmission of a malignancy from a donor's organ to the recipient of the graft is a rare event, though it is a severe complication that can result in a poor outcome. Usually, immunosuppressive therapy is discontinued and the allograft is removed. However, treatment of patients with the disseminated cancers implies that after the graft removal and cessation of the immunosuppression, radiotherapy, chemotherapy, or immunotherapy with alpha-interferon (INF-α) or interleukin-2 (IL-2) are required. The case report presents a clinical case of a transmitted kidney graft with multiple metastases (MTS) in a 31-year-old woman with the spontaneous regression of the metastatic cancer after transplantectomy and cancellation of the immunosuppressive therapy. Obviously, the determining factor is the recognition of the tumor by the effectors of the antitumor immunity due to the human leukocyte antigen (HLA) mismatch between the donor and the recipient. Therefore, cancellation of the immunosuppressive therapy in cases of transferal of a malignancy with a transplanted organ allows the effectors of the immune system to distinguish the tumor as a foreign tissue and effectively eliminate this neoplasm.

Transplantable Murine Tumors in the Studies of Peptide Antitumor Vaccines.

Numerous studies have shown that antitumor vaccines based on synthetic peptides are safe and can induce both CD8+ and CD4+ tumor-specific T cell responses. However, clinical results are still scarce, and such approach to antitumor treatment has not gained a wide implication, yet. Recently, particular advances have been achieved due to tumor sequencing and the search for immunogenic neoantigens caused by mutations. One of the most important issues for peptide vaccines, along with the choice of optimal adjuvants and vaccination regimens, is the search for effective target antigens. Extensive studies of peptide vaccines, including those on murine models, are required to reveal the effective vaccine constructs. The review presents transplantable murine tumors with the detected peptides that showed antitumor efficacy as a vaccine compound.

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 expression in a wide range of normal tissues. Thus, side effects are caused by CAR lymphocyte "on-target off-tumor" reactions. We aimed to develop safer HER2-targeting CAR-based therapy. CAR constructs against HER2 tumor-associated antigen (TAA) for transient expression were delivered into target T and natural killer (NK) cells by an effective and safe non-viral transfection method via nucleofection, excluding the risk of mutations associated with viral transduction. Different in vitro end-point and real-time assays of the CAR lymphocyte antitumor cytotoxicity and in vivo human HER2-positive tumor xenograft mice model proved potent cytotoxic activity of the generated CAR-T-NK cells. Our data suggest transient expression of anti-HER2 CARs in plasmid vectors by human lymphocytes as a safer treatment for HER2-positive human cancers. We also conducted preliminary investigations to elucidate if fucosylated chondroitin sulfate may be used as a possible agent to decrease excessive cytokine production without negative impact on the CAR lymphocyte antitumor effect.

Osteoconductive, Osteogenic, and Antipathogenic Plasma Electrolytic Oxidation Coatings on Titanium Implants with BMP-2.

We report a one-pot plasma electrolytic oxidation (PEO) strategy for forming a multi-element oxide layer on the titanium surface using complex electrolytes containing Na2HPO4, Ca(OH)2, (NH2)2CO, Na2SiO3, CuSO4, and KOH compounds. For even better bone implant ingrowth, PEO coatings were additionally loaded with bone morphogenetic protein-2 (BMP-2). The samples were tested in vivo in a mouse craniotomy model. Tests for bactericidal and fungicidal activity were carried out using clinically isolated multi-drug-resistant Escherichia coli (E. coli) K261, E. coli U20, methicillin-resistant Staphylococcus aureus (S. aureus) CSA154 bacterial strains, and Neurospora crassa (N. crassa) and Candida albicans (C. albicans) D2528/20 fungi. The PEO-Cu coating effectively inactivated both Gram-positive and Gram-negative bacteria at low concentrations of Cu2+ ions: minimal bactericidal concentration for E. coli and N. crassa (99.9999%) and minimal inhibitory concentration (99.0%) for S. aureus were 5 ppm. For all studied bacterial and fungal strains, PEO-Cu coating completely prevented the formation of bacterial and fungal biofilms. PEO and PEO-Cu coatings demonstrated bone remodeling and moderate osteoconductivity in vivo, while BMP-2 significantly enhanced osteoconduction and osteogenesis. The obtained results are encouraging and indicate that Ti-based materials with PEO coatings loaded with BMP-2 can be widely used in customized medicine as implants for orthopedics and cranio-maxillofacial surgery.

Real-World Experience with Targeted Therapy in BRAF Mutant Advanced Melanoma Patients: Results from a Multicenter Retrospective Observational Study Advanced Melanoma in Russia (Experience) (ADMIRE).

Clinical trials of targeted therapy (TT) and immunotherapy (IT) for highly aggressive advanced melanoma have shown marked improvements in response and survival rates. However, real-world data on treatment patterns and clinical outcomes for patients with advanced BRAF V600 mutant melanoma are ultimately scarce. The study was designed as an observational retrospective chart review study, which included 382 patients with advanced BRAF V600 mutant melanoma, who received TT in a real-world setting and were not involved in clinical trials. The data were collected from twelve medical centers in Russia. The objective response rates (ORRs) to combined BRAFi plus MEKi and to BRAFi mono-therapy were 57.4% and 39.8%, respectively. The median progression-free survival (PFS) and median overall survival (OS) were 9.2 months and 22.6 months, respectively, for the combined first-line therapy; 9.4 months and 16.1 months, respectively, for the combined second-line therapy; and 7.4 months and 17.1 months, respectively, for the combined third- or higher-line therapy. Analysis of treatment patterns demonstrated the effectiveness of the combined TT with BRAF plus MEK inhibitors in patients with brain metastases, rare types of BRAF mutations, and across lines of therapy, as well as a well-tolerated and manageable safety profile.

Insights Into Mechanisms of Tumor and Immune System Interaction: Association With Wound Healing.

A large number of studies have presented a great deal of information about tumor and immune system interaction. Nevertheless, the problem of tumor evasion from the immune reaction is still difficult to resolve. Understanding the ways in which immunosuppressive tumor microenvironment develops and maintains its potential is of utmost importance to ensure the best use of the suppressed immune functions. The study presents a review covering the data on tumor-associated antigens, mechanisms of tumor evasion from the immune reactions, and search for common immunosuppressive processes of tumor growth and normal wound healing. The study discusses the important role of monocytes/macrophages in the regulation of immune system reactions. We suggest that the simultaneous actions of growth factors and pro-inflammatory cytokines may result in the suppression of the immune system. The study describes intracellular signaling molecules that take part in the regulation of the myeloid cell functions. If the hypothesis is proved correct, the indicated interaction of cytokines could be regarded as a prospective target for antitumor therapy.

Immunological monitoring for prediction of clinical response to antitumor vaccine therapy.

Immunotherapy has shown promising results in a variety of cancers, including melanoma. However, the responses to therapy are usually heterogeneous, and understanding the factors affecting clinical outcome is still not achieved. Here, we show that immunological monitoring of the vaccine therapy for melanoma patients may help to predict the clinical course of the disease. We studied cytokine profile of cellular Th1 (IL-2, IL-12, IFN-γ) and humoral Th2 (IL-4, IL-10) immune response, vascular endothelial growth factor (VEGFA), transforming growth factor-ß 2 (TGF-ß 2), S100 protein (S100A1B and S100BB), adhesion molecule CD44 and serum cytokines ß2-microglobulin to analyze different peripheral blood mononuclear cell subpopuations of patients treated with dendritic vaccines and/or cyclophosphamide in melanoma patients in the course of adjuvant treatment. The obtained data indicate predominance of cellular immunity in the first adjuvant group of patients with durable time to progression and shift to humoral with low cellular immunity in patients with short-term period to progression (increased levels of IL-4 and IL- 10). Beta-2 microglobulin was differentially expressed in adjuvant subgroups: its higher levels correlated with shorter progression-free survival and the total follow-up time. Immunoregulatory index was overall higher in patients with disease progression compared to the group of patients with no signs of disease progression.

Update on the challenges and recent advances in cancer immunotherapy.

This overview provides an analysis of some of the immunotherapies currently in use and under investigation, with a special focus on the tumor microenvironment, which we believe is a major factor responsible for the general failure of immunotherapy to date. It is our expectation that combining immunotherapy with methods of altering the tumor microenvironment and targeting regulatory T cells and myeloid cells will yield favorable results.