Strategies to overcome tumor microenvironment immunosuppressive effect on the functioning of CAR-T cells in high-grade glioma.

Despite significant progress in the treatment of some types of cancer, high-grade gliomas (HGGs) remain a significant clinical problem. In the case of glioblastoma (GBM), the most common solid tumor of the central nervous system in adults, the average survival time from diagnosis is only 15-18 months, despite the use of intensive multimodal therapy. Chimeric antigen receptor (CAR)-expressing T cells, which have already been approved by the Food and Drug Administration for use in the treatment of certain hematologic malignancies, are a new, promising therapeutic option. However, the efficacy of CAR-T cells in solid tumors is lower due to the immunosuppressive tumor microenvironment (TME). Reprogramming the immunosuppressive TME toward a pro-inflammatory phenotype therefore seems particularly important because it may allow for increasing the effectiveness of CAR-T cells in the therapy of solid tumors. The following literature review aims to present the results of preclinical studies showing the possibilities of improving the efficacy of CAR-T in the TME of GBM by reprogramming the TME toward a pro-inflammatory phenotype. It may be achievable thanks to the use of CAR-T in a synergistic therapy in combination with oncolytic viruses, radiotherapy, or epigenetic inhibitors, as well as by supporting CAR-T cells crossing of the blood-brain barrier, normalizing impaired angiogenesis in the TME, improving CAR-T effector functions by cytokine signaling or by blocking/knocking out T-cell inhibitors, and modulating the microRNA expression. The use of CAR-T cells modified in this way in synergistic therapy could lead to the longer survival of patients with HGG by inducing an endogenous anti-tumor response.

Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects.

Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma-Recent Advances.

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20-30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy.

Incidence of bacterial and fungal infections in Polish pediatric patients with acute lymphoblastic leukemia during the pandemic.

The most common complications related to the treatment of childhood acute lymphoblastic leukemia (ALL) are infections. The aim of the study was to analyze the incidence and mortality rates among pediatric patients with ALL who were treated in 17 Polish pediatric hematology centers in 2020-2021 during the pandemic. Additionally, we compared these results with those of our previous study, which we conducted in the years 2012-2017. The retrospective analysis included 460 patients aged 1-18 years with newly diagnosed ALL. In our study, 361/460 (78.5%) children were reported to have microbiologically documented bacterial infections during chemotherapy. Ten patients (2.8%) died due to sepsis. Fungal infections were reported in 99 children (21.5%), of whom five (5.1%) died due to the infection. We especially observed an increase in bacterial infections during the pandemic period compared to the previous study. The directions of our actions should be to consider antibiotic prophylaxis, shorten the duration of hospitalization, and educate parents and medical staff about complications (mainly infections) during anticancer therapy. It is necessary to continue clinical studies evaluating infection prophylaxis to improve outcomes in childhood ALL patients.

CAR-T Cells Immunotherapies for the Treatment of Acute Myeloid Leukemia-Recent Advances.

In order to increase the effectiveness of cancer therapies and extend the long-term survival of patients, more and more often, in addition to standard treatment, oncological patients receive also targeted therapy, i.e., CAR-T cells. These cells express a chimeric receptor (CAR) that specifically binds an antigen present on tumor cells, resulting in tumor cell lysis. The use of CAR-T cells in the therapy of relapsed and refractory B-type acute lymphoblastic leukemia (ALL) resulted in complete remission in many patients, which prompted researchers to conduct tests on the use of CAR-T cells in the treatment of other hematological malignancies, including acute myeloid leukemia (AML). AML is associated with a poorer prognosis compared to ALL due to a higher risk of relapse caused by the development of resistance to standard treatment. The 5-year relative survival rate in AML patients was estimated at 31.7%. The objective of the following review is to present the mechanism of action of CAR-T cells, and discuss the latest findings on the results of anti-CD33, -CD123, -FLT3 and -CLL-1 CAR-T cell therapy, the emerging challenges as well as the prospects for the future.

Electrochemical and Optical Sensors for the Detection of Chemical Carcinogens Causing Leukemia.

The incidence and mortality due to neoplastic diseases have shown an increasing tendency over the years. Based on GLOBOCAN 2020 published by the International Agency for Research on Cancer (IARC), leukemias are the thirteenth most commonly diagnosed cancer in the world, with 78.6% of leukemia cases diagnosed in countries with a very high or high Human Development Index (HDI). Carcinogenesis is a complex process initiated by a mutation in DNA that may be caused by chemical carcinogens present in polluted environments and human diet. The IARC has identified 122 human carcinogens, e.g., benzene, formaldehyde, pentachlorophenol, and 93 probable human carcinogens, e.g., styrene, diazinone. The aim of the following review is to present the chemical carcinogens involved or likely to be involved in the pathogenesis of leukemia and to summarize the latest reports on the possibility of detecting these compounds in the environment or food with the use of electrochemical sensors.