Search

Background. Small cell lung cancer (SCLC), predominantly due to smoking, is a highly differentiated, rapidly growing epithelial cell carcinoma of high malignancy originating from bronchial neuroendocrine cells. Almost 70% of SCLC patients have metastases at the time of diagnosis, which requires the use of drug therapies, including immunotherapy. Aim. To evaluate the efficacy and safety of immune checkpoint inhibitors in patients with small cell lung cancer. Materials and methods. One hundred and twenty one patients (90 men and 31 women) aged 44 to 84 years were included in the retrospective multicentre non-randomised study. The majority (90.9%) of patients were treated in the 1st line of therapy. IT were administered in the 2nd line and subsequent lines of treatment in 9.1% of patients. Weakened (ECOG 2–3) state at the time of treatment initiation was noted in 30 (24.8%) patients. Results. Progression-free survival in patients with SCLC receiving 1st-line treatment was 5.82 (95% CI 3.92–7.72) months, and 2nd-line and beyond was 6.21 (95% CI 0.76–11.66) months. Survival in patients with small-cell lung cancer receiving 1st-line IT was 8.0 (95% CI 6.18–9.81) months, and 2nd-line or longer was 11.3 months (95% CI 4.31–18.29) months (p=0.108). Objective response was achieved in 43 (35.5%) patients, of whom 38 (34.5%) were on first-line IT and 5 (45.5%) patients were on 2nd or more. iAEs grade 3–4 was observed in only 18 (14.9%) patients. Conclusion. Immunotherapy for SCLC allows achieving high rates of objective response and disease control. This method of treatment is characterized by insignificant number of grade 3–4 immune-mediated adverse events, which indicates an acceptable safety profile.

Type 1 diabetes mellitus (DM) is one of the most common autoimmune disease that is treated with lifelong insulin therapy. Non-target indicators of glycemic control, which are observed in 71% of patients, lead to the formation and progression of diabetes complications, early disability and mortality. In this regard, the search for new approaches to the treatment and prevention of type 1 DM seems to be relevant. Various methods of immunological prophylaxis for the development of type 1 DM have been studied, in particular, the use of monoclonal antibodies. Thus, in November 2022, teplizumab was approved to slow down the clinical progression of the stage of type 1 DM. The prospects for the use of new options for islet cell transplantation are being studied — in June 2023, an allogeneic donor β-cell transplant obtained from the pancreas of donors after death was approved. Another pathogenetically substantiated method for the prevention and treatment of autoimmune diseases is high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-HSCT). HDIT-HSCT demonstrated its effectiveness and cost-effectiveness in various clinical trials. This review provides up-to-date information on modern methods of immunological prophylaxis of type 1 DM.

More than half of the world’s population is infected with the herpes simplex virus. In most cases, infection is not accompanied by symptoms, but in some people the disease occurs as a chronic infection with frequent and severe relapses. One of the most likely reasons for this may be a dysregulation of the immune system. In recent years, the role of checkpoint molecules, in particular PD-1 and Tim-3, in the regulation of the immune response and the functions of immunocompetent cells has been actively studied. Activation of PD-1 and Tim-3 on T cells has previously been shown to suppress the immune response. PD-1 and Tim-3 are also expressed on other immune cells, in particular monocytes. However, the expression of these molecules on monocytes during chronic viral infections has not been previously studied. The study was aimed at assessing the level of PD-1 and Tim-3 expression on various populations of monocytes in patients with chronic often recurrent herpesvirus infection. Twenty-six patients were recruited into the study. All patients received antiviral and immunomodulatory therapy in the immunological department. The number of classical, intermediate, and non-classical monocytes and the expression of PD-1 and Tim-3 on monocytes, were assessed by flow cytometry before and after the therapy. Monocytes were isolated from peripheral blood, and subpopulations were divided according to the level of expression of CD14 and CD16. In patients with herpes, a reduced number of monocytes was observed in comparison with healthy donors. The relative number of PD-1-positive monocytes, the mean fluorescence intensity of PD-1 and Tim-3, and the number of double-positive cells were reduced in herpes patients in all three monocyte subpopulations examined. Three months after therapy, the response to the therapy was assessed; patients who did not have a single recurrence of herpes within 3 months were considered to respond. Responding patients had a lower initial content of double-positive cells among intermediate and non-classical monocytes. The decrease in the level of PD-1 and Tim-3 positive monocytes during herpesvirus infection revealed in the present study may indicate the involvement of monocytes deficient in the expression of checkpoint molecules in the pathogenesis of the disease.

Aim. To evaluate the antitumor efficacy of our developed drug based on cytotoxic T lymphocytes genetically modified with a chimeric antigen receptor (CAR) specific to the CA125 antigen in relation to both CA125-positive and CA125negative cell cultures.Materials and methods. We performed an in vitro study on CA125-positive human ovarian cancer cells (OVCAR-3, OVKATE) and CA125 negative cells (breast cancer MCF 7, embryonic kidney HEK293). Cytotoxic effects on tumor cells were evaluated after 0, 4, 8 and 24 hours using the 3’-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) tests. We also studied the changes in the number of cells “in real time” when exposed to transfected lymphocytes using the RTCA iCELLIgence device (ACEA Biosciences, USA). Lymphokineactivated killer (LAK) cells were used as a specificity control.Results. The study demonstrated that anti-CA125 CAR-T lymphocytes exhibited a pronounced cytotoxic effect on OVCAR-3 and OVKATE cell cultures, exceeding the effect of LAK by 1.3 times. The cell population in the experimental samples decreased by 70 ± 4%, which exceeded the LAK effect by 9 ± 8.2%. With regard to the MCF-7 cell line, the cytotoxic effect of anti-CA125 CAR-T lymphocytes was minimal as evidenced by a 25.8% decrease in the relative number of live cells in comparison to the LAK cytotoxicity of 68%. Real-time monitoring of cell proliferation and viability proved a high specific cytotoxic effect of anti-CA125 CAR-T lymphocytes against tumor cultures expressing CA-125, while inferior to LAK in cultures not expressing CA125 (MCF-7, HEK293).Conclusions. The use of anti-CA125 CAR-T lymphocytes against CA125-positive tumor cell lines OVCAR-3 and OVKATE demonstrated a pronounced specific cytotoxic effect exceeding the cytotoxic effect of LAK, which was not achieved against CA125-negative MCF-7 and HEK293 cells.

Digital papillary adenocarcinoma (DPA ) is a rare malignant neoplasm of sweat glands, which was first described by Helwig in 1979 and then classified by Kao in 1987. This disease most often occurs in men aged 50–70 years and is characterized by a relatively favorable prognosis. In most cases, radical excision of the tumor leads to cure. However, 14–47 % of patients develop distant metastases with predominant lung involvement (70 %). The study of etiology and pathogenesis of this rare cancer and its molecular genetic profile seems to be interesting. Currently, there is no clear approach to the treatment of metastatic DPA , but sporadic cases of using chemotherapy have been reported. Aim of the study: to analyze current data on the pathogenesis of DPA , diagnostic features and treatment methods used, as well as to present the first clinical case of treatment of disseminated digital carcinoma with immune checkpoint inhibitors described in scientific literature. Material and Methods. A search of available literature published in Medline, Pubmed, etc. databases from 1984 to 2023 was performed, 21 sources were included in this review. Clinical Case Description. We present a rare case of metastatic digital papillary carcinoma in a 23-year-old male with disease manifestation at the age of 14 years. Lack of vigilance and awareness of oncologists and morphologists did not allow timely diagnosis of malignancy, even in case of 3 local recurrences of the disease. Only biopsy of a metastatic lung nodule with histological and IHC examination (of archival and new material) made it possible to make a correct diagnosis. This case revealed 2 potential targets that could be used for disease control: androgen receptor positive expression and PD -L1 expression with CPS =20. The use of immune response checkpoint inhibitors (ipilimumab + nivolumab) resulted in partial response followed by stable disease.

Anaplastic thyroid cancer is the rarest and the most aggressive form of thyroid cancer. It comprises 1-2 % of all cases and is characterized by rapid growth. median survival of patients with this pathology is about 5 months. Clinical manifestations of the disease are rapid deformation in the neck area, progressive respiratory distress, and dysphagia.The article describes a clinical case of a response of unresectable, BRAF-negative, PD-L1-positive (programmed death-ligand 1) anaplastic thyroid cancer to immunotherapy with pembrolizumab.

Human papilloma virus (HPV), primarily type 16 (less commonly type 18), is associated with oropharyngeal squamous cell carcinoma (OPSCC). According to literature data, between 25 and 70 % of all cases of this cancer are linked to HPV infection. In the USA and some countries of the European Union, HPV-associated OPSCC comprises 60-70 % of all cases of head and neck squamous cell carcinoma. HPV-associated OPSCC is characterized by more favorable prognosis and higher survival compared to HPV-negative OPSCC. These types of this pathology are differently characterized in the 8th edition Tumor, Nodus and Metastasis (TNM). Significant differences in survival and disease prognosis led to studies aimed at deintensification of standard OPSCC treatment to minimize adverse events without the loss of effectiveness. Despite more favorable clinical progression, in 15 % of patients with HPV-associated OPSCC even after standard therapy recurrences and/or regional/distant metastases are observed which lead to unfavorable prognosis. Modern treatment schemes for recurrent/metastatic head and neck squamous cell carcinoma include immunotherapy, results of which also depend on HPV-status of the tumor. While clinical trials studying effectiveness of immune drugs include patients with HPV-positive tumors, data on treatment outcomes are contradictory, and molecular mechanisms of HPV effect on the immune response are not fully understood.The article summarizes the data on the effect of positive HPV status on the effectiveness of immunotherapy in patients with progressing/metastatic head and neck squamous cell carcinoma.

Purpose of the study. To evaluate the role and possibilities of various types of immunotherapy in the treatment of skin melanoma, as well as the prospects for its use in clinical practice.Materials and methods. The literature was looked up in the PubMed database. Publication date limit was set from 2018 to 2023. The following keywords were used as search queries: "Melanoma", "Melanoma and immunotherapy", "Treatment of Metastatic Melanoma", "Immunological Factors". Full-text versions were selected. Articles that were based on the subjective opinion of the authors were excluded from the study. For each research found, the following parameters were recorded: treatment method, number of patients, follow-up period, time of relapse-free course, survival rate. No meta-analysis of the data was performed due to the high heterogeneity of the studies. Results. A sufficiently high efficiency of adjuvant therapy with inhibitors of immune response control points in the treatment of BRAF-negative patients has been noted. For this reason, the drug ipilimumab, which appeared among the first, demonstrated its effectiveness. The drug nivolumab gave, according to one of the studies, a 5‑year overall survival rate of 35 %. The use of pembrolizumab was associated with a 5‑year overall survival rate of 41 %. In the 2015 meta-analysis It has been demonstrated that the use of nivolumab, as well as pembrolizumab, provides the best overall survival, and therefore can be included in first-line therapy. The combination of these drugs makes it possible to achieve a good response to therapy in patients with BRAF-positive status (5‑year overall survival rate of 52 %).Conclusion. Melanoma immunotherapy with immune response checkpoint inhibitors is currently the most effective treatment method, especially in cases where it complements surgical resection of the tumor. The most commonly used drugs are nivolumab and ipilimumab, which work more effectively when combined. Thus, the 5‑year progression-free survival rate is 36 %, the overall survival rate is 52 %. Resistance to immunotherapy is an important problem of this type of treatment, the solution of which will help to improve the outcomes of control over the local cancer process and improve the response to therapy. It is possible to find a solution to this problem due to the fundamental study of the molecular biology of the tumor in terms of modeling tumor growth and tumor "escape" mechanisms.

The search for domestic publications on this publication was conducted in the database on the RSCI website, and foreign ones in the PubMed and Google Scholar databases in the period 2022-2023. Their analysis showed that actively studied approaches to the immunocorrection of sepsis are aimed at changing the content or activity of cytokines, growth factors, the use of immune checkpoint inhibitors, as well as myeloid suppressor cells. When modulating the action of cytokines, a variety of approaches are used, such as changing the affinity of cytokines to their receptors, extending the half-life of cytokines and «fine-tuning» the action of cytokines. For the safe and effective use of bioregulators for immunocorrection in sepsis, additional multicenter studies of their clinical effectiveness are needed, including taking into account the stratification of patients into individual endotypes and the mechanisms of action of bioregulators.

Objective: In a prospective cohort study to evaluate the clinical and immunological efficacy of differentiated targeted interferon and immunomodulatory therapies focused on identified pathological immunophenotropes and associated clinical manifestations in immunocompromised patients suffering from atypical chronic active herpes viral infections (ACA-HVI).Materials and methods: 335 patients suffering from mixed-AHA-HVI were examined. The study complex included: methods for detecting herpesviruses: serodiagnosis, PCR-RV; immunological methods: a research of subpopulation of blood lymphocytes (method of a flow cytometry), determination of the spontaneous and induced products of IFNα and IFNγ, levels of serum cytokines and immunoglobulins (IL-1β, IL-6, IL-17, TNFα and IFNα and IFNγ, Ig A, M, G) by ELISA. The study was approved by the ethics board and informed consent was obtained from all patients.Results: Integral formulas of disorders in the antiviral immune defense system were created, which made it possible to isolate 3 pathological immunophenotypes (PIF): PIF1: NG↓+ind.IFNα/IFNγ↓+CTL↓+EKK↓+IgM↑+hypecytokinemiya (IL-1β↑+IL-6↑+TNFα↑); PIF2: NG↓+ ind. IFNα/IFNγ↓ + EKK↓+ IgG↓+hypercytokinemiya (IL-1β↑+IL-6↑+TNFα↑) and PIF3: NG↓+ind.IFNα/IFNγ↓+hypercytokinemiya (IL-1β↑+IL- 6↑+TNFα↑). Taking into account the identified disorders, a program of targeted interferon and immunomodulatory therapy was developed for each PIF: local and systemic IFN therapy + hexapeptide was developed for PIF1; for PIF2- local and systemic IFN therapy + glucosaminimuramyldipeptide; for PIF3-local and systemic IFN therapy.Conclusions: High clinical efficacy was demonstrated in 100% of patients with three groups of ACA-HVI. Immunological effectiveness of targeted interferon and immunomodulatory therapy programs: 89.5% for PIF1; for PIF2-57.6% and for PIF3- 37.5% of cases.

The abscopal effect in oncology has been known for 70 years, but until recently its clinical significance was rather low. The development of immune response checkpoint inhibitors has led to an active study of this phenomenon. There is now evidence of improved survival among patients, in whom the abscopal effect has been documented, opening new perspectives for the treatment of cancers at different stages. This review presents data on the mechanisms of the abscopal effect, experimental and clinical data, current limitations and possible perspectives. The aim of the study was to investigate the current concept of the abscopal effect occurrence and to evaluate the prospects of using the abscopal effect in therapy of metastatic cancer. Material and Methods. We searched publications in Pubmed system from 2010 to 2023. Of 286 publications, 72 were used for writing the review. Results. In the era of widespread use of immune checkpoint inhibitors (ICIs) for cancer therapy, the abscopal effect appears to be an effective therapeutic approach with broad prospects of application in the treatment of patients with metastatic cancer. Conclusion. The incidence of the abscopal effect has increased with the advent of immune therapy, and the use of ICIs with radiation therapy (RT) has shown improved survival even in patients with advanced disease. More research is needed to establish standardized treatment protocols, including the optimal dose and timing of RT, as well as the efficacy and safety of combination therapy with different classes of ICIs. Further search for clinical and laboratory abscopal effect predictors, which could allow personalized treatment approaches, is required.

Clostridioides difficile is a leading cause of diarrhea and pseudomembranous colitis associated with antibiotic therapy. Hypervirulent strains of C. difficile, such as ribotype 027, have high mortality rates. Recurrent C. difficile infection is extremely difficult to treat. Symptoms of the disease are caused by two toxins, TcdA and TcdB. These toxins are targets for therapeutic antibodies. The TcdB-specific monoclonal antibody bezlotoxumab (Zinplava ©, Merck & Co. Inc., USA), approved for the prevention of recurrent C. difficile infection, has some effectiveness against a limited set of C. difficile strains. Having a lower cost compared to monoclonal antibodies, high affinity for the antigen, and unique structural and functional properties, nanoantibodies are a promising strategy for the immunotherapy of diseases associated with C. difficile.

Immunotherapy is a treatment option that is becoming more common for different types of cancer. The idea behind this therapy is to modify the patient's immune system. One type of this therapy involves blocking the binding between PD-1 and PD-L1. By doing so, it enables increased antitumor immune activity. Immune checkpoint inhibitors have shown significant efficacy with high response rates and long-term remission in various types of cancer. Glioblastoma (GBM) is a recurrent tumor characterized by immune evasion mechanisms that resist modern immunotherapy. The literature review analyzed the mechanism of tumor resistance to immune response, specifically PD-1 and PD-L1 expression in GBM. The review presented several clinical studies that showed the results of using immune checkpoint inhibitors in GBM patients. Additionally, the review described other mechanisms of tumor resistance to the activated immune system. All sources were selected using specialized scientific retrieval systems and full-text databases such as Google Scholar, eLIBRARY, PubMed, and Elsevier.

Esophageal cancer (EC) is one of the most aggressive malignant neoplasms, ranking sixth among oncological causes of death. According to GLOBOCAN, more than half a million people die from this disease every year, and by 2040 this indicator is expected to increase almost twice. In most patients, esophageal cancer is diagnosed at stages III–IV of the disease. Currently, the standard of treatment for inoperable patients with EC is simultaneous chemoradiotherapy.One of the main methods of treatment of patients with non-metastatic esophageal lesion remains surgical intervention in the volume of esophagectomy with radical lymph dissection, accompanied by quite frequent serious postoperative complications. However, the results of surgical treatment of locally advanced esophageal cancer alone remain unsatisfactory, and the fiveyear survival rate is less than 20 %. In order to improve the oncological results of treatment, various combinations of drug and radiation therapy are used (preoperative chemotherapy or chemoradiotherapy, independent chemoradiotherapy). To date, recommendations for the treatment of locally advanced esophageal cancer vary from country to country. Trimodal therapy (preoperative chemoradiotherapy up to TFD – 46 Gy with 5 cycles of weekly chemotherapy according to the carboplatin + paclitaxel scheme followed by surgical treatment) is the standard in operable patients with non-metastatic squamous cell carcinoma of the esophagus in our and European countries. In Asian countries, preference is given to neoadjuvant chemotherapy, based on the data of the JCOG1109 (NExT) study, in which it was shown that the addition of docetaxel to neoadjuvant therapy with cisplatin and fluorouracil is accompanied by an improvement in overall survival and acceptable toxicity, compared with the CF regimen and chemoradiotherapy. A separate issue is the place of lifesaving esophagectomy in patients who have received a course of radical chemoradiotherapy. Unfortunately, according to several researchers, recurrent or persistent esophageal cancer remains an urgent problem with a risk of relapse of the disease in up to 60 % of cases.We have studied the data of the Russian and global literature concerning the treatment of squamous cell carcinoma of the esophagus.

Aim. Compare the lytic efficiency and the kinetics of accumulation of vesicular stomatitis virus serotypes Indiana (VSV-IND) and New Jersey (VSV-NJ) on cell lines of mouse melanoma B16F10, human hepatocellular carcinoma HepG2 and human mammary adenocarcinoma MCF7.Materials and methods. The viability of mouse melanoma B16F10, human hepatocellular carcinoma HepG2 and human mammary adenocarcinoma MCF7 cell lines infected with VSV-IND and VSV-NJ viruses at different multiplicity of infection (10 MOI; 1 MOI; 0.1 MOI) was assessed after 24, 48 and 72 hours, and the half maximal inhibitory concentration (IC50) values were measured using the methyl tetrazolium test. The relationship with virus accumulation in cell culture was determined using reverse transcription – quantitative polymerase chain reaction; 50% tissue culture infectious dose (TCID50) of VSV-IND and VSV-NJ for B16F10, HepG2, MCF7 were calculated using the Reed-Muench method.Results. The most susceptible cell line for both viruses was B16F10: cell viability 72 hours after infection at 10 MOI was only 10.4% and 5.7% for VSV-IND and VSV-NJ, respectively. HepG2 cell viability at 72 hours post-infection at 10 MOI was 10.8% and 9.8% for VSV-IND and VSV-NJ, and for MCF7 adenocarcinoma it was 46.6% and 36.2%, respectively. Moreover, only in the B16F10 culture was a positive statistically significant correlation of medium strength established between the inhibition of cell viability and the accumulation of viral RNA: for VSV-IND r = 0.601 (p < 0.05); for VSV-NJ r = 0.668 (p < 0.05). HepG2 and MCF7 showed no significant correlation.Conclusion. The research results indicate the potential of using oncolytic viruses of the VSV-IND and VSV-NJ as a platform for the development of new recombinant viruses for virotherapy of solid tumors in combination with other types of treatment.

H3K27M-altered diffuse midline gliomas are the most devastating pediatric brain tumors. These tumors are characterized by lesion of central nervous system midline structures, diffuse infiltrative growth and fatal prognosis. The pathogenesis of H3K27M-altered diffuse midline glioma is based on unique epigenetic and genetic changes which are associated with histone 3 (H3) alterations. Clinical disease course usually is non-specific, that could hamper diagnosis establishment and defines high prevalence of disseminated tumor stages. Diagnostic approach includes neuroimaging, various laboratory and molecular methods, including high throughput sequencing, which allows finding potential targets for precise therapy. Despite the availability of anti-tumor technologies, including targeted therapy and immunotherapy, the standard of care for H3K27M-altered diffuse midline glioma is radiation therapy, which does not allow achieving long-term event-free survival. A dismal prognosis and absence of curative options for these tumors determine the necessity of new treatment methods search that could improve patients’ outcome. In this article we present current worldwide data of the diagnosis and treatment trends in H3K27M-altered diffuse midline glioma.

It is well known that ischemia and hypoxia in the tumor microenvironment promote tumor progression. Оxygen deficiency in tumor microenvironment polarizes cancer cell metabolism from oxidative phosphorylation to the aerobic mode (Warburg effect) and anaerobic glycolysis. This altered carbohydrate metabolism is characterized by low energy efficiency and excessive glucose consumption. Under hypoxic conditions, the antioxidant protection of malignant cells becomes weaker, thus causing a sufficient increase of their susceptibility to direct toxic effects of reactive oxygen species (ROS). In clinical practice, oxygen saturation of tumors is usually achieved by using water-soluble ozone or hyperbaric oxygen. The ROS are shown to be produced by oxidative burst, thus being able to enhance antitumor effects of chemoradiotherapy. The immune cell-derived ROS were shown to directly inhibit tumor growth. In addition, ROS provide additional immune stimulation through the induction of mutagenesis in the tumor cells and production of immunogenic neoantigens. ROS may also enhance antitumor immune defense by inducing synthesis of interferon-γ, tumor necrosis factor-α, IL-2 and IL-6 by immune cells. Moreover, ROS may exert a negative effect on antitumor immunity. In particular, they are able to: (I) favor the recruitment and accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment; (II) promote accumulation of alternatively activated (M2) macrophages and (N2) neutrophils, and, (III) impair presentation of immunogenic antigens (Ag) by dendritic cells. We suggest that the maximal clinical effect of oxygen therapy could be achieved in case of its simultaneous or sequential combination with immunotherapeutic interventions.The authors conclude that:– oxidative stress-induced reactive oxygen species may preferentially damage tumour cells without significantly affecting normal cells;– oxygen therapy may potentiate anti-tumour effects of chemoradiotherapy;– oxygen therapy could be effectively combined with immunotherapy to achieve maximal anticancer effects with minimal side effects.

Oncolytic viral therapy is a promising approach for treating tumors. Oncolytic viruses can directly lyse tumor cells and indirectly activate antitumor immunity. Alphaviruses, as oncolytic viruses, are particularly promising agents because they can selectively infect and lyse tumor cells, modulate microtumor environment, elicit immune-mediated lysis of tumor cells, and serve as a platform for transgene delivery. To ensure safety, attenuated strains of Alphaviruses are typically used for genetic engineering, and immunogenic tumor-associated antigens or cytokines are commonly chosen as transgenes. Studies evaluating both in vitro and in vivo oncolytic and immunomodulatory effects of Alphaviruses and vectors based on them have been growing exponentially. Animal models of various tumor types were used to examine the effectiveness of Alphaviruses, including Sindbis, Semliki Forest virus, Geta (strain M1), Venezuelan equine encephalitis virus, and vectors based on them. Additionally, Alphaviruses revealed enhanced antitumor activity while used in combination therapies with other oncolytic viruses. Alphavirus-like replicon particles based on attenuated Venezuelan equine encephalitis virus may serve for transgene delivery to express heterologous proteins at high levels, and induce both humoral and cellular immune responses. An alphaviral vector-based vaccine, encoding the HER2 extracellular and transmembrane domains, has demonstrated safety and efficacy in preclinical mouse models, as well as in phase I clinical trials for advanced breast cancer patients with HER2 overexpression. This vaccine is known to be safe, effective, and capable of inducing T-cell immunity. In this review, we discuss the current progress in preclinical and clinical investigations, as well as the future potential of Alphaviruses for oncolytic virotherapy.

Purpose of the study: to analyze published data on the mechanisms of action of interferon gamma (IFN-γ) in tumor growth and to evaluate the possibility of its use in the treatment of solid tumors. Material and Methods. More than 200 publications were found in the Scopus, Pubmed, eLibrary and other databases, the search keywords were: interferon gamma, tumor growth, cancer therapy. This review includes 54 papers. Results. IFN-γ is a pleiotropic cytokine with antiviral, antitumor, and immunomodulatory functions and plays an important role in coordinating the innate and adaptive immune response. The success of immuno-oncology drugs and chemotherapy in the treatment of malignant tumors depends on the stimulation of the production and adequate signaling of IFN-γ. Suppression and loss of IFN-γ receptor and downstream signaling mediators, and amplifcation of molecules that inhibit the IFN-γ signaling pathway are common mechanisms for tumor cells to escape from the immune system. The development of malignant processes is accompanied by a change, more often a decrease, in the secretion of IFN-γ, which attracts the attention of researchers to its exogenous administration. Determination of the IFN-γ signature may be a predictive marker of clinical response to anticancer drug therapy. The antitumor properties of IFN-γ are largely dose-dependent, which has been clearly shown in clinical and experimental studies. Low doses of the drug often promote tumor growth. On the contrary, the use of high doses is usually accompanied by an antitumor effect. IFN-γ or its inducers remain promising agents for cancer therapy. Combinatorial strategies involving IFN-γ may be a rational option to overcome tumor resistance to blockade of immune checkpoints. Conclusion. It is necessary to continue fundamental and applied research to study the feasibility of using interferon gamma as a therapeutic agent in tumor growth.

Recurrent and metastatic head and neck squamous cell carcinoma is a hard-to-treat pathology. median overall survival for standard chemotherapy regimens does not exceed 11 months. One of the factors decreasing treatment effectivenessis frequency of severe adverse events which are observed in every 2nd patient during standard therapy regimens. moreover, even if notable tumor regression is achieved, this effect is transient. Development of immunotherapy drugs, namely pembrolizumab, helps solve these problems. Clinical trials and real-world use of the drug show that in the 1st and 2nd therapy lines for recurrent and metastatic head and neck squamous cell carcinoma, pembrolizumab allows to achieve persistent treatment response, increase overall survival, and decrease the frequency of adverse events.

Introduction. Head and neck squamous cell carcinoma is the 6th most common malignant tumor. It is characterized by immune response evasion and drug resistance. To stimulate antitumor immune response, antibodies against such cell cycle checkpoints as programmed cell death 1 (pD-1) and programmed death-ligand 1 (pD-L1) are used. However, effectiveness of monotherapy with these checkpoint inhibitors turned out to be low, and combinations with other antitumor drugs have high risk of adverse events.Aim. To determine the most practical ways to influence epigenetic factors in treatment of head and neck squamous cell carcinoma.Materials and methods. Scientific literature published between 2011 and 2022 and indexed in the eLIBRARY, Scopus, woS, NCBI databases (398 articles, of which 76 were used) was analyzed.Results. prospects of development of epigenetic stimulation of expression of retroelements located in tumor genomes through inhibition of DNA methyltransferases, deacetylases and histone methyltransferases were considered. when retroelements are activated, their transcripts form double-stranded RNA stimulating T killers and interferon response (virus mimicry). for DNA methyltransferase inhibitors, restoration of tumor suppressor genes which are hypermethylated in squamous cell carcinoma is also observed. However, retroelement activation is a driver mechanism of carcinogenesis, and their nonspecific expression can lead to tumor progression and formation of secondary tumors. Therefore, in the virus mimicry method it is practical to use as targets microRNA complementary to retroelements which recruit epigenetic factors to their loci (RNA-directed DNA methylation), as well as antisense oligonucleotides against oncogenic microRNA associated with retroelements. These approaches allow to inhibit retroelements participating in carcinogenesis. Nonspecific method of retrotransposon activity suppression is being developed in antitumor therapy, but data show successful application of only reverse transcriptase inhibitors preventing insertions and progression of genomic instability. we have performed analysis of scientific literature on transposable elements-derived microRNA associated with head and neck squamous cell carcinoma. As a result, 31 microRNAs were identified, derived from: LINE: miR-1249, -151a, -211, -2355, -28, -31, -3144, -374a, -374b, -421, -450b, -511, -576, -577, -582, -708, -769, -887, -95; HERv: miR-1269a, -1911, -3200, -495; non-autonomous SINE: miR-335, -342, -378a, -3934, -487b; DNA transposons: miR-224, -584, -652. These microRNAs can serve as the basis for epigenetic therapy of head and neck squamous cell carcinoma.

Minor histocompatibility antigens (MiHAs) are polymorphic peptides on the cell surface derived from self-proteins that are capable to induce an immune response during allogeneic hematopoietic stem cells transplantation. Their presentation occurs in the context of the certain major histocompatibility complex (HLA – human leucocyte antigen) alleles. One of the most common HLA alleles is HLA-A*02:01. Accordingly, for a significant number of donors and recipients pairs, it is possible to use the MiHAs presented in the HLA-A*02:01 as a target for relapsed leukemia therapy. This review discusses the main known MiHAs presented in the context of HLA-A*02:01, their characteristics and approaches used for identification. The described approaches may be used to search for new MiHAs for immunotherapy.

Primary esophageal melanoma is a rare and extremely aggressive malignant neoplasm originating from mucosal melanocytes. The complex histological structure of the tumor, which in 10–25 % of cases may not contain melanin characteristic of these formations, leads to a high frequency of diagnostic errors, reaching 50 %. Immunohistochemical examination is the standard for diagnosing the disease. Primary esophageal melanoma is a tumor with a high potential for hematogenous and lymphogenous metastasis. So, when the tumor spreads to the submucosa, the frequency of locoregional metastasis reaches 54 %. Radical surgery in combination with adjuvant methods of treatment improves the results of treatment in this category of patients. Immunotherapy is a promising method of complex treatment, but requires further study.

Background: During the new COVID-19 coronavirus infection pandemic, a growing incidence of autoimmune encephalitis cases has been observed. One of the primary problems related to patients with this highly lethal pathology is its timely early diagnostics and prescription of an optimal individual course of immunotherapy. In a debut of anti-NMDA receptor (inotropic glutamate receptor, selectively binding N-methyl D-aspartate) encephalitis, mental disorders are observed, prompting the initial admission of such patients to a psychiatric hospital. Then, the clinical picture of the disease is characterized by a significant polymorphism. In such cases, it is not always possible to suspect an autoimmune lesion of the nervous system. Clinical case description: In this article, we present a clinical case of a female patient with serologically confirmed autoimmune encephalitis against the background of the new coronavirus infection (U07.1 according to ICD-10). The disease onset involved psychiatric symptoms; the patient was transferred to the Department of neurology of the VGK BSMP No. 1 Municipal Clinical Hospital of Emergency Care No.1 from the municipal psychiatric hospital, when generalized cerebral symptoms appeared. According to the diagnostic criteria, mental disorders and generalized epileptic seizures are the most significant signs in the verification of autoimmune encephalitis. Autoimmune encephalitis was suspected based on the developed neurological symptoms and generalized epileptic seizures and confirmed by the detected anti-NMDA antibodies in the blood serum. The anti-NMDA antibody analysis in the blood and cerebrospinal fluid is the most informative way of autoimmune encephalitis diagnosis. Conclusion: Autoimmune encephalitis requires vigilance of physicians of all specialties who may encounter this disease. Timely diagnostic procedures and prescription of pathogenetically justified treatment are of importance.

Gastrointestinal stromal tumors (GIST) are most common mesenchymal tumors in gastrointestinal tract which originate from interstitial cells of Cajal and characterized by the mutations in the KIT or PDGFRA tyrosine kinase receptors. Thus, the common therapeutic approach for GIST therapy (including metastatic, recurrent and non-resectable forms) is based on inhibiton of activities of receptor tyrosine kinases indicated above by corresponding receptor tyrosine kinase inhibitors, including first-line therapeutic agent imatinib mesylate – Gleevec. Despite of high efficacy of IM-based therapy, most of GIST patients acquire resistance to this receptor tyrosine kinase inhibitor, which in turn requires second-, third- and fourth-line therapies. The review also describes the common molecular and genetic variants of GIST and the mechanisms of primary and secondary GIST resistance to the targeted-based therapies. In addition, the role of immune microenvironment in GIST and its relationship with tumor’s mutational burden are discussed in detail, thereby illustrating the immunotherapy as one of the attractive future directions for GIST therapy. Lastly, the manuscript provides the information about the ongoing clinical trials of GIST immunotherapy.

In recent years, there has been a significant increase in the number of patients with malignancies treated with immune checkpoint inhibitors (ICIs), including the anti-programmed cell death protein 1 (anti–PD-1) agent pembrolizumab. One of the important aspects of conducting clinical trials with ICIs is the assessment of the risk of developing immune-related adverse events (irAEs).The aim of the study was to evaluate the safety of a pembrolizumab biosimilar (BCD-201, Pembroria) compared with a reference medicinal product using the results of a phase I clinical trial and the available medical literature.Materials and methods. A phase I double-blind, randomised, controlled clinical trial (BCD-201-1) has been conducted in patients with advanced melanoma and non-small-cell lung cancer (n=131). Patients were randomly allocated in a 1:1 ratio to receive either BCD-201 (Pembroria) or the reference medicinal product (Keytruda®), administered intravenously at a dose of 200 mg every 3 weeks for up to 24 weeks or until disease progression or unacceptable toxicity is observed. Since the trial results remain blinded at the time of this writing, treatment group data are masked.Results. The study demonstrated the equivalence of pharmacokinetics and comparable safety profiles of pembrolizumab biosimilar and reference medicinal products. Both medicinal products were well tolerated; the frequency of all-grade irAEs was comparable between treatment groups (21.2% in Group 1 vs 21.5% in Group 2). Most irAEs were mild to moderate, with the exception of a case of Grade 3 diarrhoea and immune-mediated enterocolitis in one study subject; there were no statistically significant differences in the median time to development of irAEs between treatment groups (Р=0.22, two-sided Wilcoxon test).Conclusions. The analysed period of the BCD-201-1 trial demonstrated comparable safety characteristics of Pembroria and Keytruda®, which is consistent with the published safety data on the latter. Information on the similarity of long-term safety profiles of the pembrolizumab biosimilar and the reference medicinal product will be obtained from ongoing clinical trials.

NK cells are innate lymphocytes that are able to eliminate altered cells, which makes them promising for the immunotherapy of viral diseases and tumors. The NK cell population is characterized by high phenotypic and functional diversity. In particular, in the pool of highly differentiated NK cells in the presence of cytomegalovirus (HCMV), a population of adaptive cells can be formed, characterized by a high lifespan and high cytotoxicity. However, in order to carry out a cytotoxic reaction, a NK cell must undergo a licensing process, during which it acquires the expression of NKG2A and KIRs. Currently, there are many effective methods of NK cell accumulation for subsequent use in therapy, one of them is the stimulation with IL-2 and K562-mbIL21 feeder cells. Highly differentiated adaptive-like NK cells are able to expand in respond to such stimulation. However, the phenotype of actively expanding NK cells dynamically changes. Loss of inhibitory KIR expression during intense proliferation of NK cells may adversely affect their cytotoxic potential. This work shows that highly differentiated CD56dimNKG2C+ NK cells from HCMV-seropositive individuals have a high proportion of KIR2DL2/3+ cells. This may indicate a high stability of KIR receptor expression in this population. We have shown that CD56dimNKG2C+ clonal cultures obtained by stimulation with IL-2 and K562- mbIL21 are characterized by high stability of KIR2DL2/3 expression compared to NKG2C-negative and less differentiated CD56brightNKG2C+. Also, in heterogeneous cultures of adaptive NK cells precursors CD57- CD56dimNKG2C+, a higher expression level of KIR2DL2/3 was observed in comparison with NKG2C-negative cultures of CD57-CD56dimNKG2C-. Thus, the accumulation of NK cells upon stimulation with IL-2 and K562- mbIL2 feeder cells can lead to loss of expression of KIR receptors and a decrease in their functional activity. However, cultures of highly differentiated NK cells of HCMV-seropositive individuals CD56dimNKG2C+, as well as cultures of precursors of adaptive NK cells CD57-CD56dimNKG2C+, are characterized by a greater stability of KIR2DL2/3 expression. As a result, stimulation with IL-2 and K562-mbIL21 feeder cells can be used to accumulate adaptive-like cells and their progenitors with stable inhibitory KIR expression and high cytotoxic potential.

According to modern ideas, changes in the functioning of the immune system affect the immune processes in the nervous system, contributing to the development of neuro-immuno-inflammation and thereby indirectly affect the rate of progression of neurodegenerative processes. The aim of our study was to investigate the prevalence of post-viral chronic fatigue syndrome and cognitive impairment (aMCI) among patients with atypical, chronic active herpesvirus infections (ACA-HVI).Under our supervision were 126 patients of both sexes aged 18 to 60 years with ACA-HVI.It was established that mono-EBV infection affects 27.7%; mixed EBV infection is observed in 72.3% of patients. When assessing cognitive functioning using CGI, MMSE scales, the incidence of aMCI was found to be 68.3%: with mixed HVI — 87.4%, with mono HVI — 38.8%. During the study, significant limitations were identified in the use of standard scales due to the impossibility of conducting a comprehensive assessment of clinical status parameters and cognitive dysfunctions, as well as correlation of these parameters and assessment of dynamics of the immunocorrection. To achieve this goal the Scale of assessment of the criterion clinical symptoms of patients with ACA-HVI with CFS was used. It was shown that in mixed-HVI, the severity of symptoms exceeded the severity of symptoms of patients with mono-HVI and was 52.7 (43.1-62.2) and 38.0 (31.9-42.8) points, respectively (p > 0.05). Thus, it was found that patients suffering from mixed HVI have more pronounced, severe manifestations of CFS and aMCI, which are 1.5 times higher than similar manifestations in patients with mono-HVI, significantly reducing the quality of life of these patients, worsening their social adaptation.Prolonged persistence of herpes viruses in immune-compromised people creates conditions for constant antigenic stimulation and immune imbalance with the onset of secondary immunodeficiency or clinical manifestation of existing primary disorders in the immune system, which creates the prerequisites for the development of neuro-immuno-inflammatory changes in nervous system, followed by the formation of clinical manifestations of ME/CFS with different cognitive impairments that may be classified as aMCI.

Autoimmune Limbic Encephalitis is a rare disease occurring with a frequency of approximately 13.7/100,000 people, mainly among middle-aged women. The disease is caused by autoantibodies, either synthesised due to the presence of a tumour or having an idiopathic nature. Depending on the type of autoantibodies detected, the disease is divided into subtypes, which differ in the frequency of specific clinical symptoms (most commonly psychosis, mood changes, memory problems, cognitive impairment and seizures) and can direct to detection of a specific type of cancer. Making a prompt diagnosis and initiating treatment is crucial as it ensures a reduction in clinical symptoms and improves survival rate. Broad immunotherapy is used - intravenous immunoglobulin, corticosteroids, azathioprine, rituximab, cyclophosphamide, anti-epileptic drugs and plasmapheresis. The efficacy is high - 80% of patients recover, and relapses occur in only 10% of cases. If a patient is diagnosed with cancer, effective oncological treatment is necessary to achieve complete remission.

In the structure of the incidence of skin tumors, melanoma accounts for a relatively smaller percentage, but that disease is associated with higher risk of an adverse outcome compared with many other malignancies. The study of innovative clinical developments in drug therapy for resectable melanoma, presented at the American Society of Clinical Oncology Annual Meeting June 2022. The best clinical developments in drug treatment of patients with resectable melanoma were selected for analysis: 1) phase 3 study KEYNOTE-716; 2) PRADO; 3) Neo Trio; 4) SWOG 1512. The presented developments bring extremely promising results for melanoma therapy workflows. The use of cutting-edge anti-cancer therapeutics acting on various molecular targets drastically improves the tumor response as well as straitens the appearance of treatment-related adverse events.

Aim of the study: to evaluate prognostic value of baseline lung immune prognostic index (LIPI) and its modification (mLIPI) for metastatic non-small cell lung cancer (mNSCLC) patients treated with immune checkpoint inhibitors (ICI).Material and methods. Baseline neutrophil-to-lymphocyte ratio, lactate dehydrogenase, hemoglobin, platelets, and fibrinogen level were collected from 133 patients treated with ICI in monotherapy or combination between July 2015 and July 2022 in N.N. Blokhin NMRCO. According to evaluating factors patients were divided into three groups of “good” (LIPI 0/mLIPI 0–1), “intermediate” (LIPI 1/mLIPI 2–3) and “poor” prognosis (LIPI 2/mLIPI 4–5). The primary endpoint was progression free survival (PFS).Results. The median PFS for the LIPI groups were 9.7 months (1.4–17.9; 95 % CI), 7.9 months (5.9–9.9; CI 95 %) and 6.0 months (4.07–7.93; 95 % CI) in the “good”, “intermediate” and “poor” prognosis groups, respectively; the hazard ratio (HR) for patients in the “poor” prognosis group (17 patients) was 2.02 (1.06–3.84; 95 % CI) compared with the “good” LIPI group (p=0.03). The median PFS for mLIPI groups were 9.0 months (4.53–13.47; 95 % CI), 8.0 months (5.4–10.6; CI 95 %) and 2.0 months. (1.33–2.67; 95 % CI) in the “good”, “intermediate” and “poor” prognosis groups, respectively. The HR for patients in the “poor” prognosis group (n=12) was 3.12 (1.51–6.46; 95 % CI) compared with the “good” mLIPI group (p=0.002).Conclusion. Baseline LIPI and mLIPI predicts potential resistance to ICI treatment in mNSCLC patients.

Objective. To conduct a systematic analysis of data on the results of studies published in scientific journals on the pro-carcinogenic and anticarcinogenic role of microbiota, as well as on the therapeutic potential of microorganisms in oncogenesis.Material and Methods. The articles were searched using the Web of Science, Scopus, PubMed, Medline, and eLIBRARY databases. More than 150 sources dedicated to the study of the carcinogenic function of the microbiota and the possible influence of its species and quantitative composition on the efficacy and toxicity of antitumor therapy were found. Data from 71 articles were included in the review.Results. The relationship between the gut microbiota and cancer is multifactorial and bilateral: pro-carcinogenic on the one hand and anti-carcinogenic on the other hand. Microorganisms can induce tumor growth and cancer development through DNA damage and induction of mutagenesis, trigger oncogenic signals, disruption of barrier function, as well as immune response system disruption. Depletion of microbiota, the development of dysbiosis and induction of chronic inflammatory state are negative factors in the development of cancer. The anticancer effect of microorganisms is presumably based on the production of tumor-suppressive metabolites that function through multiple immune reactions. Maintenance of barrier function, competitive exclusion of pathogenic bacteria, and direct action on immune cells to prevent inflammation are also important protective factors. The presence of intratumor microorganisms in various tumors has been noted. Changes in species and quantitative composition of cancer patients’ microbiota are influenced by diet, taking antibacterial drugs, chemo-, immuno- and radiation therapy. In turn, the microbiota can affect the ongoing treatment. Numerous studies on the influence of the gut microbiota on the efficacy of immunotherapy, particularly in disseminated melanoma, have been conducted. It has been suggested that primary resistance to immunotherapy may be related to the abnormal composition of the gut microbiota. The level of gut microfora composition diversity and the number of Faecalibacterium or Bacteroidales in the fecal microbiota have been suggested to be the predictor of response to anti-PD-1 therapy. To change the composition and activity of the gut microbiota, several therapeutic methods, such as the administration of prebiotics, probiotics, synbiotics, postbiotics, fecal microbiota transplantation, as well as the change in the microbiota composition through a specific diet, are available.

Deficient DNA mismatch repair (dMMR) is a rare molecular disorder found in 20-30 % of endometrial tumors. Laboratory identification of dMMR/microsatellite instability (MSI) has a high diagnostic value, since these impairments are considered as biomarkers of endometrial adenocarcinoma. They help to identify patients at high risk of Lynch syndrome, evaluate the disease prognosis, and estimate the efficacy of immune checkpoint inhibitors and their combinations. This review details current concepts of MSI diagnostics and discusses its predictive value in patients with endometrial cancer. It also describes a new diagnostic algorithm for the detection of dMMR and MSI.

Chronic bacterial prostatitis reduces the reproductive function of men and worsens the quality of life. Impairment of the immune system in chronic bacterial prostatitis requires immunocorrection and use of additional immunomodulatory therapy. The objective of this multicenter, double-blind, randomized, placebo-controlled clinical trial was to prove the efficacy and safety of the recombinant interferon alpha-2b preparation and highly active antioxidants (vitamins E and C) in complex therapy in patients with chronic bacterial prostatitis. Men aged 18 to 50 years with a diagnosis of chronic bacterial prostatitis of category II or IIIA (N = 140) were randomized into two groups. Patients in the main group (N = 70) received interferon alpha-2b, rectal suppositories 1,000,000 IU (20 days bid), and patients in the comparison group (N = 70) received placebo as described above. All patients received levofloxacin (500 mg/day, 28 days) as antibiotic therapy. The efficacy of treatment was assessed by clinical questionnaires, bacteriological and microscopic analyses, frequency of chronic bacterial prostatitis relapses within 6 months from the start of treatment, and by ultrasound and urodynamic testing. The efficacy was evaluated at the end of additional therapy, at the end of antibiotic therapy and six months after the start of treatment. Clinical symptoms of chronic bacterial prostatitis decreased in both groups within 20 days after the start of treatment. However, interferon alpha-2b therapy reduced the average number of leukocytes in the prostate secretion/third urine specimen by 2.6 (95% CI: 1.6-4.4) times by the end of interferon therapy, by 4.2 (95% CI: 2.4-7.2) times by the end of antibiotic therapy and by 5.4 (95% CI: 3.4-8.3) times by the end of follow-up period compared to placebo (p < 0.001). The proportion of patients with prostate secretion microbiota was 20% lower in interferon alpha-2b compared to Placebo group (p = 0.013). Thus, complex interferon alpha-2b therapy improved chronic bacterial prostatitis resolution by accelerating the elimination of bacteria and reducing inflammatory and proliferative processes in the prostate. Interferon alpha-2b had no safety concerns and was well tolerated by patients.

According to the common concept of immune editing, the interaction of malignant tumor cells and immune system is a complex multifactorial process, which may result in both antitumor effector activity and development of suppressor mechanisms that promote tumor growth. Accumulation of scientific knowledge in the field of studying the antitumor immune response and tolerance has led to emergence of many research and therapeutic approaches that use different components of the immune system to combat neoplastic processes. Along with currently available approaches, there are strategies that use the potential of antigen-specific T lymphocytes, the main effectors of adaptive immunity, in order to fight malignant neoplasms which appeared more than a century ago and have built the scientific basis of cancer immunotherapy. One line of evidence of the significant antitumor potential of T cells in immunotherapeutic schemes for the cancer treatment was presented by successful therapy of hemato-oncological diseases, achieved at the end of the past decade. At the same time, however, the therapy of solid malignant neoplasms still faces significant difficulties that limit the efficiency of treatment. In this regard, the main objective of the review is to accumulate up-to-date information on the successes and limitations of T cell immunotherapy in the patients with solid tumors. To date, the phenotype and functionality of T cells is being investigated and modulated both towards enhancing antitumor cytotoxicity, increasing viability and proliferative activity of T cells, and in overcoming the immunosuppressive effect of the tumor and its tolerogenic microenvironment upon T cells, as well as ensuring targeted migration of the effector T cells to the malignant tissues. This review discusses immunotherapeutic approaches exploiting the potential of effector T lymphocytes, e.g., current clinical trials or applied therapeutic regimens for the treatment of solid malignant neoplasms. Antigen-independent approaches aimed at nonspecific enhancement of the T cell responses, i.e., therapy with recombinant cytokines and inhibition of immune checkpoint molecules. Antigendependent, or antigen-specific approaches such as adoptive T cell therapy with endogenous T lymphocytes are also discussed as well as trials on T cells with modified antigen-recognition receptor (CAR-Tcells, TCR-Tcells), like as usage of bispecific antibodies as T cell engagers. The review describes the benefits and disadvantages of these approaches in monotherapy, as well as current results and prospects for their mutual combinations.

Glioblastoma (GBM) is the most malignant and the most common primary tumor of the central nervous system. During the last several years GBM has been classified and managed according to the World Health Organization (WHO) criteria which subdivide it into primary and secondary GBM. As it is suggested, GBM originates from glial cells and has a diffuse growth pattern, but its etiology and pathophysiology are poorly investigated up to date. Its rapid progression and anatomical location in the brain often limits the effectiveness of therapeutic interventions. Despite all scientific and technological advances, GBM remains an incurable disease with a median survival of approximately 18 months. Standard treatment options involving maximal safe resection of the tumor followed with radiotherapy and chemotherapy do not provide satisfactory Results.Better understanding of the molecular pathology of GBM and its associated signaling pathways has opened up possibilities for new treatments for newly diagnosed and relapsing tumors. A multitargeted therapeutic approach using compounds capable of inhibiting more than one specific molecular target is a promising alternative to conventional therapies.Currently, specialists study such innovative treatment options as small molecule inhibitors aimed at signaling pathway disruptions, immunotherapy, including checkpoint inhibitors, oncolytic vaccines, CAR T-cell therapy, and drug delivery systems. In terms of an innovative approach, the elaboration of targeted drug delivery systems is of particular interest, since this strategy looks the most promising due to its ability to increase the bioavailability and effectiveness of both standard and newly tested agents. This review discusses results of preclinical and clinical studies of innovative therapeutic approaches, their advantages and disadvantages. An interdisciplinary approach is expected to be able to combine the results of cutting-edge research in this area and to provide novel promising therapeutic strategies for patients with GBM.

Objective. To present the available data regarding the tolerance of immune checkpoint inhibitors (ICIs) in cancer patients with concurrent HIV.Material and Methods. A literature search was conducted in the electronic databases PubMed, Cochrane Library and UpToDate up to February 2022.Results. The article outlines the background and experience of using ICIs for the treatment of malignant tumors in patients with concomitant HIV infection.Conclusions. Until recently, the presence of chronic infections, including HIV infection, was one of the key contraindications for prescribing immunotherapy. However, the recent scientific publications demonstrate the efficacy and good tolerability of ICIs in cancer patients with concurrent HIV. Future prospective clinical trials will help to predetermine the potential of immunotherapy in clinical practice in this patients.

Purpose. To reflect the current understanding of the frequency, molecular mechanisms, and means of overcoming alopecia in cancer patients, taking into account the fundamental data of recent years on the physiology of the hair follicle and the pharmacological profile of the toxicity of anticancer drugs.Material and Methods. A literature search using Medline, Pubmed, etc. databases was carried out. More than 200 publications devoted to the study of alopecia were found, of which 42 were included in this review.Results. Chemotherapy-induced hair loss is a common adverse effect in cancer patients undergoing treatment. The frequency and molecular mechanism of the development of alopecia are related to the pharmacological features of the drug-based treatments, initial nutritional premorbid status, and predisposing polymorphisms of genes involved in drug conversion and excretion. Focal or diffuse alopecia may be the first sign of malignant growth within the paraneoplastic syndrome, primary or metastatic malignancies of the scalp, or be a manifestation of nutritional insufficiency. Baldness negatively affects the psycho-emotional state of patients, exacerbating depressive disorders, anxiety, reducing self-esteem and adherence to treatment. Thus, prevention or rapid overcoming of alopecia can significantly improve the quality of life of cancer patients. The use of scalp cooling or ‘cold caps’ is proven to be an effective way of combating chemotherapy-induced hair loss.Conclusion. Further studies are needed to prevent and treat alopecia in cancer patients.

Given the increased morbidity and mortality in patients with type 1 diabetes mellitus (T1DM), as well as the burden posed by the disease, the search for methods to prevent the destruction of beta cells is of paramount importance. Until recently, no attempts of immunotherapeutic interventions have achieved significant success, allowing at best reducing the rate of destruction of beta cells without stopping the immune process and not allowing normalization of glycemia. In November 2022, the U.S. Food and Drug Administration (FDA) approved the drug teplizumab to delay clinical diagnosis of T1DM. The purpose of the publication is to evaluate the results of teplizumab treatment in high-risk participants with the second (preclinical) stage of T1DM, as well as to consider further prospects for this treatment.

Introduction. The tactics of managing and treating patients with chronic recurrent bacterial prostatitis (CRBP) in some cases is a difficult-to-treat condition for a practicing urologist. This circumstance occurs because the disease has several predisposing factors, a complex and multifaceted pathogenesis, and certain difficulties in diagnosis and treatment.Objective. To study the effectiveness of recombinant interferon α-2b medications in post-COVID-19 patients with chronic recurrent prostatitis against the background of antibiotic multi-drug resistance of microorganisms verified in prostate secretion.Materials and methods. The treatment of 52 post-COVID-19 patients with CRBP was analyzed, divided into three therapy-dependent groups. Group 1 patients (n = 18) received antibiotic therapy (ABT): Levofloxacin 500 mg q.d. PO for 28 days. Group 2 patients (n = 18) underwent combined therapy: ABT supplemented with recombinant interferon α-2b with an antioxidant complex of vitamins E and C (“Viferon®” rectal suppositories) 3.000.000 IU b.i.d. PR q12h for 28 days. Group 3 patients (n = 16) received monotherapy with recombinant interferon α-2b with an antioxidant complex of vitamins E and C (“Viferon®”rectal suppositories) 3.000.000 IU b.i.d. PR q12h for 28 days. The follow-up period was 6 months with monitoring of clinical and laboratory parameters assessed before treatment, after 1, 3 and 6 months from the start of therapy.Results. Based on the monitoring of the clinical picture and laboratory parameters, after 1 follow-up month, there was a significant decrease in the symptoms of the disease in all study groups. However, after 3 and 6 follow-up months, this trend was observed only in patients of groups 2 and 3 receiving recombinant interferon alfa-2b with an antioxidant complex (vitamins E and C).Conclusions. Strengthening the standard CRBP-therapy with recombinant interferon α-2b with an antioxidant complex of vitamins E and C makes it possible to normalize both clinical and laboratory parameters in most patients.

The sum of the effects of all negative factors on the human body is manifested, including in the form of an imbalance in the work of the immune system, which leads to a violation of the recognition and elimination of foreign substances of the most diverse origin. This is manifested in an increase in the frequency of development of inflammatory processes, the risk of their chronicity and the development of complications, the identification of opportunistic or conditionally pathogenic flora as a pathogen, including those with atypical biological properties and antibiotic resistance. The use of etiotropic chemotherapy alone in the treatment does not allow achieving sufficient control over many infectious diseases. The purpose of this review was to investigate additional, alternative approaches to influencing anti-infective immunity. An analysis of the strategy based on the use of modulation of the immune response in the treatment of patients was carried out and its advantages over traditional antimicrobial treatment were determined. The concept of «immunotherapy» is discussed, which implies a variety of effects on the immune system in order to stop the pathological process. The review highlights the main types of immunotherapy - local, general, combined and monoimmunotherapy, as well as active and passive, specific and nonspecific. The review provides convincing data on the need for immunomodulators to meet a number of requirements, analyzes various ways of classifying them and their areas of application. The necessity of using immunotropic drugs on the basis of a comprehensive examination is emphasized, taking into account the correspondence between the nature of clinical manifestations and the severity of changes in immunological parameters. The analyzed data allow us to conclude that immunomodulatory therapy can be used to restore the function of the immune system to the physiological norm after a severe inflammatory process at the stage of immunorehabilitation.

Intercellular relationships are the basis of the physiological and pathological biochemical processes in the organism, and recent advances in exosome (Exo) research helped to reveal the mechanism of intercellular exchange of information. Furthermore, the functional properties of extracellular vesicles are being actively investigated nowadays, this opens up great perspectives for their using in clinical practice. Numerous investigations demonstrated the applicability of exosomes for targeted drug delivery. Exosomes play an important role in cancer and they contain the genetic material not only of normal cells of the organism, but also of tumor cells. Therefore, the analysis of exosomes from peripheral blood may be more efficient and specific for the non-invasive diagnosing of cancer. Moreover, exosomes from immune cells possess the immunomodulating activity and can be used in antitumor immunotherapy.

Purpose of the study. To substantiate the expediency of cellular immunotherapy in the treatment of patients with relapses of high-grade gliomas and evaluate the safety of injecting allogeneic cells directly into the cerebrospinal fluid.Materials and methods. Our study included 5 patients, median age 7,6 years (2–16). Three patients had anaplastic astrocytoma (AA) (1st recurrence – 1 patient, 2nd recurrence – 2 patients), 1 patient had glioblastoma multiforme (GBM) (3rd recurrence) and 1 had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), to the second one was 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogenic immunocompetent cells (alloIC) for at least 2 years.Results. Two of 3 patients with AA experienced a progression-free interval of 67 and 71 months One patient with 3rd GBM relapse is alive without any therapy 13.3 years after immunotherapy start. The median time of follow-up was 67 months with the 2‑years overall survival was 58 %. Two patients died from disease progression within 6 and 7 months from the start of immunotherapy. Over the period of treatment the patients received a median of 20 (8 to 60) alloIC injections and 18 (8 to 44) DV administrations. No serious side-effect was observed.Conclusion. Immunotherapy could be an attractive option for treating patients with high-grade malignant gliomas irresponsible to conventional therapy and is worthy of further investigation.

Aim.The objective is to optimize the diagnosis and management of the atrophic variant of the vulvar lichen sclerosus (LS). Materials and methods. We examined 58 female patients from 20 to 70 years old with the atrophic variant of the vulvar LS. The control group included 30 deemed healthy females 2070 years old. The atrophic variant of LS was diagnosed based on symptoms (dryness and discomfort in the vulva, superficial vulvodynia and dyspareunia, mild itching) and signs (marked atrophy of the external genitalia tissue up to aplasia of the labia minora and clitoris, vaginal stenosis, minimal hypopigmentation, absence of sclerosis). In addition, the following cytokines were measured in the peripheral blood of patients: interleukin (IL)-20, 23, 10, tumor necrosis factor-, and interferon-. The measurements were performed before and after immunotherapy with sodium deoxyribonucleate. Results. In all patients, there was a rapid shrinkage of the labia minora and clitoris, thinning and easy traumatization of the dermis and epidermis, contributing to secondary infection and synechiae formation up to complete vaginal occlusion. An increase in IL-23 (19.01 [18.0; 38.5] vs. 16.6 [12.98; 20.71] in the control group), 2.7-fold (p0.03) decrease in tumor necrosis factor-, interferon- and IL-20 are common for the atrophic variant of LS. The immunomodulatory and clinical efficacy of sodium deoxyribonucleate was demonstrated. Severe vulvodynia before treatment was noted in 29 (50%) patients and no patient (0%) after therapy; 44 (75.8%) patients reported complete reversal of superficial vulvodynia after treatment, and there were no patients without vulvodynia before treatment (0%). Mild itching before treatment was noted by 20 (40%) patients and 2 (3.4%) patients after treatment. Considering the cytokine levels, topical glucocorticoids in atrophic LS are inappropriate and can lead to atrophy and immunosuppression aggravation, contributing to the secondary infection. Conclusion. The observed differences in cytokine levels in patients with atrophic vulvar LS confirm the relevance of LS clinical classification by variants, support their use for LS diagnosis and immunotherapy efficacy control, and also suggest a differentiated approach to the treatment of different LS variants considering the effect of the drugs used on cytokine status.

The purpose of the study was to conduct a systematic literature review of high-technology methods in breast cancer treatment. Material and methods. To select information sources, a global search was used using the Web of Science, Scopus, PubMed, and RSCI databases. The search included the analysis of metadata by keywords, and relevant publications were used for full-text search. The review used 55 publications from 2001 to 2021. Most of the articles were published over the past 7 years. Results. Modern literature data presented in this review prove that long-term studies based on histological and immunological features of tumor development are very important for improving survival in breast cancer. Clinical treatment protocols that were based primarily on the anatomical characteristics of the disease are now switching to the biological mechanisms underlying carcinogenesis. Drugs targeting estrogen receptors play an important role in systemic therapy and make it possible to correct the mechanisms responsible for endocrine resistance. Targeted therapy targeting the HER2 receptor, especially in an antibody-drug conjugate combination, has associated cytotoxic therapy with anti-HER2 antibodies. Modern methods of biological therapy and cell engineering make it possible to develop methods for treating triple-negative breast cancer based on the regulation of the microenvironment, mechanisms of repair, immunosuppression, and the creation of a target from a larger repertoire of both surface and intracellular antigens. Conclusion. Promising strategies based on the use of signaling and metabolic pathways, cell surface molecules, and cell engineering increase the effectiveness of treatment and improve the progression-free and overall survival in breast cancer patients.

Background. The development of unique immune-related adverse events (irAEs) is a known hallmark of immunotherapy. Generally, such complications occur during the first 3–6 months of immunotherapy, however, the experience with immune checkpoint inhibitors (ICIs) shows that irAEs can also occur after completion of ICI therapy, as well as during other anticancer treatment regimens. Description of the clinical case. We present a clinical case of a patient with metastatic cutaneous melanoma, who had recurrent events of grade 2 immune-mediated diarrhea during the 2ndline of therapy. After completion of the course of immunosuppressive therapy with systemic glucocorticoids, irAE resumed, and mesalazine and budesonide (local steroid) with subsequent dose reduction were prescribed. Maintenance anti-inflammatory therapy and re-induction of targeted therapy with BRAF- and MEK-inhibitors due to the progression of the disease resulted in the reactivation of immune-mediated colitis. The complication was successfully managed by increasing dose of local steroid to full dose. Anticancer therapy was continued at the same regime without recurrent episodes of irAEs. Conclusion. When changing the anticancer treatment regimen, the recurrence of irAEs dictates careful monitoring of toxicity and the importance of timely selection of the optimal treatment algorithm to improve the quality and longevity of cancer patients.

Objective: to describe musculoskeletal immune-mediated adverse events (iAEs) associated with the therapy of solid tumors with immune checkpoint inhibitors (ICIs, inhibitors of the PD-1/PD-L1 pathway).Patients and methods. 13 patients receiving ICIs therapy with musculoskeletal iAEs were examined. The average age of patients was 59±10 years. All cases had a histologically verified diagnosis of a malignant solid neoplasm: melanoma (n=5), kidney cancer (n=3), bladder cancer (n=2), non-small cell lung cancer (n=1), breast cancer (n=1), cervical cancer (n=1). All patients were prescribed inhibitors of the PD-1/PD-L1 signaling pathway: nivolumab (n=6), pembrolizumab (n=3), atezolizumab (n=3), prolgolimab (n=1). In 7 (54%) patients, in addition to musculoskeletal disorders, other AEs were also detected: thyroiditis (n=3), neuropathy (n=2), rash (n=1), dry syndrome (n=1), hepatitis (n=1). The median time from the start of antitumor immunotherapy (IT) to the onset of musculoskeletal pathology was 20 [9; 48] weeks.Results and discussion. Clinical manifestations of musculoskeletal pathology included: synovitis in 9 (69%) patients, tenosynovitis in 11 (85%), enthesitis in 4 (31%), morning stiffness in the joints for more than 30 minutes in 4 (31%). In 11 cases, musculoskeletal pathology was persistent (in 9 patients with arthritis and 2 with periarthritis) and in 2 – transient. The knee (77%), shoulder (69%) and hand (54%) joints were most frequently affected, with bilateral involvement in 9 (69%) patients. Inflammatory changes in the joints were represented by mono- (n=1), oligo- (n=3) and polyarthritis (n=5), including those involving the small joints of the hands and/or feet (n=5) and predominantly affecting the joints of the lower limbs (n=3). In 3 patients with arthritis, periarticular changes dominated in clinical picture (in 2 patients with symmetrical polyarthritis and severe tenosynovitis, in another 1 patient – with RS3PE syndrome). The severity of musculoskeletal pathology was assessed using the CTCAE v5.0 toxicity criteria: grade 1 was documented in 2 (15.5%), grade 2 in 9 (69%), and grade 3 in 2 (15, 5%) patients. Laboratory workup revealed elevation of ESR ≥30 mm/h (median – 34 [14; 42] mm/h) in 7 out of 12 (58%) patients, elevation of CRP level >5 mg/l (median – 7.2 [4.6; 12.9] mg/l) – in 7 out of 10 (70%). In 7 out of 10 patients, antinuclear antibodies (Hep2) were detected in titers: 1:160 (n=2), 1:320 (n=3), 1:640 (n=2). Rheumatoid factor and antibodies to cyclic citrullinated peptide were not detected in any case. Therapy for musculoskeletal AEs included non-steroidal anti-inflammatory drugs (n=10), oral systemic glucocorticoids – GC (n=5), methotrexate – MT (n=1) and hydroxychloroquine (n=5), intra-articular administration of GC (n=1). Five patients with arthritis required long-term therapy (median duration – 12 [3; 12] months), in 1 patient with polyarthritis and severe tenosynovitis, antitumor IT was interrupted for the duration of the course of MTX treatment.Conclusion. It has been shown that musculoskeletal iAEs have heterogeneous manifestations and may require long-term treatment and in rare cases, anticancer therapy interruption. Additional studies and close cooperation between rheumatologists and oncologists are needed to obtain a more complete understanding of the nature and spectrum of musculoskeletal AEs, to identify their clinical, laboratory and instrumental features, and to develop an management of patients algorithm.

Recent advances in cancer immunotherapy have steadily increased the effectiveness of standard antitumor therapy methods. Due to their low toxicity and simple production process, personalized therapeutic vaccines based on dendritic cells are of particular clinical interest. A striking fact is that the first attempts to use such vaccines in clinical practice were discouraging. However, their scope and effectiveness were subsequently greatly enhanced by the development of new approaches to activating and loading dendritic cells with tumor-associated antigens, as well as by their use as an adjuvant in combination with other therapeutic methods for cancer treatment. This review considers new techniques and the latest achievements in the development of dendritic vaccines that ensure their clinical success.

Introduction and purpose Breast cancer (BC) management includes local therapies surgery, radiotherapy and systemic – hormonotherapy, chemotherapy, targeted and immunotherapy. However, some adverse events of these treatment strategies limit their wide administration in BC therapy. The aim of the study was to present adverse effects in the management of BC, prevention and treatment of them. State of the knowledge Surgery of the breast leads to lymphedema, pain, and anatomical changes. The most characteristic adverse event of radiotherapy is radiation dermatitis which is more probable among obese, older patients, females, and smokers. Other side effects are pneumonia, cardiac and pulmonary injury. Chemotherapeutics lead to complications such as anthracyclines-induced cardiotoxicity. As a consequence of endocrine therapy, patients are affected by vasomotor, musculoskeletal, and vulvovaginal symptoms. Immune checkpoint inhibitors may cause immune-related adverse events (irAEs), which are usually mild. When severe irAEs occur, immunosuppressive drugs are used. Depending on stage, toxicities of the therapies can lead to interrupting the treatment of BC. Moreover, drug resistance is an important therapeutic obstacle in BC treatment. Conclusion The application of a diversity of drugs in the treatment of breast cancer is associated with adverse effects which limit its efficacy. It is vital to develop novel, targeted therapeutic methods to optimize outcomes of patients. Given the adverse effects of breast cancer therapies and drug resistance, it is vital to develop novel, targeted therapeutic methods.

Gastric cancer (GC) is the fifth most common malignant neoplasm in the world among all malignant tumors. Currently, the “gold” standard of treatment for patients with non‑metastatic cancer of the stomach and esophageal–gastric junction is surgical treatment, which is complemented by perioperative chemotherapy according to the FLOT scheme, which includes four courses of therapy before surgery and four after. However, according to statistics, less than half of patients complete all adjuvant courses of FLOT chemotherapy due to the high toxicity of the regimen and a decrease in the functional status of patients in the postoperative period. In this regard, studies are being conducted to study the tolerability of total neoadjuvant chemotherapy, when all courses are held at the preoperative stage in order to carry out all stages of treatment in full. International studies have shown the results of the use of targeted (ramucirumab, trastuzumab, pertuzumab), immune drugs (pembrolizumab, nivolumab, ipilimumab), S‑1 in combination with chemotherapy as part of the combined treatment of gastric and esophageal‑ gastric junction cancer. The emergence of new therapeutic agents previously studied in metastatic GC may change approaches to the treatment of localized and locally advanced GC.The review presents the features of perioperative therapy regimens in patients with resectable gastric and esophageal‑ gastric junction cancer in order to reduce the frequency of local and long‑term relapses and improve further prognosis.