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Neuroblastoma is the most common extracranial solid tumor found in childhood and is responsible for 15% of deaths among children with cancer. Although multimodal therapies focused on surgery, chemotherapy, radiotherapy, and stem cell transplants have favorable results in many cases, the use of conventional therapies has probably reached the limit their possibility. Almost half of the patients with neuroblastoma belong to the high-risk group. Patients in this group require a combination of several therapeutic approaches. It has been shown that various immunotherapies combined with conventional methods can work synergistically. Due to the development of such therapeutic methods, we present combinations and forms of combining immunotherapy, focusing on their mechanisms and benefits but also their limitations and potential side effects.

Infant acute lymphoblastic leukemia (Infant ALL) is a kind of pediatric ALL, diagnosed in children under 1 year of age and accounts for less than 5% of pediatric ALL. In the infant ALL group, two subtypes can be distinguished: KMT2A -rearranged ALL, known as a more difficult to cure form and KMT2A - non-rearranged ALL with better survival outcomes. As infants with ALL have lesser treatment outcomes compared to older children, it is pivotal to provide novel treatment approaches. Progress in the development of molecularly targeted therapies and immunotherapy presents exciting opportunities for potential improvement. This comprehensive review synthesizes the current literature on the epidemiology, clinical presentation, molecular genetics, and therapeutic approaches specific to ALL in the infant population.

Pediatric cancers predominantly constitute lymphomas and leukemias. Recently, our knowledge and awareness about genetic diversities, and their consequences in these diseases, have greatly expanded. Modern solutions are focused on mobilizing and impacting a patient's immune system. Strategies to stimulate the immune system, to prime an antitumor response, are of intense interest. Amid those types of therapies are chimeric antigen receptor T (CAR-T) cells, bispecific antibodies, and antibody-drug conjugates (ADC), which have already been approved in the treatment of acute lymphoblastic leukemia (ALL)/acute myeloid leukemia (AML). In addition, immune checkpoint inhibitors (ICIs), the pattern recognition receptors (PRRs), i.e., NOD-like receptors (NLRs), Toll-like receptors (TLRs), and several kinds of therapy antibodies are well on their way to showing significant benefits for patients with these diseases. This review summarizes the current knowledge of modern methods used in selected pediatric malignancies and presents therapies that may hold promise for the future.

Targeted therapy has revolutionized the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) with specific genetic abnormalities. It is still being described as a new landmark therapeutic approach. The main purpose of the use of molecularly targeted drugs and immunotherapy in the treatment of ALL is to improve the treatment outcomes and reduce the doses of conventional chemotherapy, while maintaining the effectiveness of the therapy. Despite promising treatment results, there is limited clinical research on the effect of target cell therapy on the potential toxic events in children and adolescents. The recent development of highly specific molecular methods has led to an improvement in the identification of numerous unique expression profiles of acute lymphoblastic leukemia. The detection of specific genetic mutations determines patients' risk groups, which allows for patient stratification and for an adjustment of the directed and personalized target therapies that are focused on particular molecular alteration. This review summarizes the knowledge concerning the toxicity of molecular-targeted drugs and immunotherapies applied in childhood ALL.

Non-Hodgkin lymphomas (NHL) are a group of cancers that originate in the lymphatic system, especially from progenitor or mature B-cells, T-cells, or natural killer (NK) cells. NHL is the most common hematological malignancy worldwide and also the fourth most frequent type of cancer among pediatric patients. This cancer can occur in children of any age, but it is quite rare under the age of 5 years. In recent decades, available medicines and therapies have significantly improved the prognosis of patients with this cancer. However, some cases of NHL are treatment resistant. For this reason, immunotherapy, as a more targeted and personalized treatment strategy, is becoming increasingly important in the treatment of NHL in pediatric patients. The objective of the following review is to gather the latest available research results, conducted among pediatric and/or adult patients with NHL, regarding one immunotherapy method, i.e., chimeric antigen receptor (CAR) T cell therapy. We focus on assessing the effectiveness of CAR-T cell therapy, which mainly targets B cell markers, CD19, CD20, and CD22, their connections with one another, sequential treatment, or connections with co-stimulatory molecules. In addition, we also evaluate the safety, aftermath (especially neurotoxicities) and limitations of CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite intensive standard treatment, acute myeloid leukemia (AML) continues to be associated with a poor prognosis due to treatment resistance and a high risk of relapse. For this reason, it is necessary to develop new therapeutic strategies, which, when used in combination with standard treatment, can increase the chances of patient survival. One of them might be the use of CAR-T cells. In the following review, we present the latest reports on the use of anti-CD33, -CD123, -FLT3 or -CLL-1 CAR-T cells in (pre-)clinical trials, as well as the emerging challenges of the proposed therapy. The use of CAR-T cells in common clinical practice in the treatment of AML will only be possible after further research, the focus of which should be the myeloablative effect of CAR-T cells, the eradication of cells in the immunosuppressive environment of the tumor, and their life span in the body. 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. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs—oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive effect of therapy with TRL agonists on the course of hemato-oncological diseases. Ligands impact activation of antigen-presenting cells which results in production of cytokines, transfer of mentioned cells to the lymphoid tissue and co-stimulatory surface molecules expression required for T-cell activation. Toll-like receptor agonists have already been used in oncology especially in the treatment of dermatological neoplastic lesions. The usage of these substances in the treatment of solid tumors is being investigated. The present review discusses the direct and indirect influence that TLR7/8 agonists, such as imiquimod, imidazoquinolines and resiquimod have on neoplastic cells and their promising role as adjuvants in anticancer vaccines. [ABSTRACT FROM AUTHOR]

Immunotherapy is a milestone in the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) and is expected to improve treatment outcomes and reduce doses of conventional chemotherapy without compromising the effectiveness of the therapy. However, both chemotherapy and immunotherapy cause side effects, including neurological ones. Acute neurological complications occur in 3.6–11% of children treated for ALL. The most neurotoxical chemotherapeutics are L-asparaginase (L-ASP), methotrexate (MTX), vincristine (VCR), and nelarabine (Ara-G). Neurotoxicity associated with methotrexate (MTX-NT) occurs in 3–7% of children treated for ALL and is characterized by seizures, stroke-like symptoms, speech disturbances, and encephalopathy. Recent studies indicate that specific polymorphisms in genes related to neurogenesis may have a predisposition to MTX toxicity. One of the most common complications associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS). Mechanisms of neurotoxicity in CAR T-cell therapy are still unknown and may be due to disruption of the blood–brain barrier and the effects of elevated cytokine levels on the central nervous system (CNS). In this review, we present an analysis of the current knowledge on the mechanisms of neurotoxicity of standard chemotherapy and the targeted therapy in children with ALL. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute lymphoblastic leukemia is the most common blood cancer in pediatric patients. Despite the enormous progress in ALL treatment, which is reflected by a high 5-year overall survival rate that reaches up to 96% in the most recent studies, there are still patients that cannot be saved. Treatment of ALL is based on conventional methods, including chemotherapy and radiotherapy. These methods carry with them the risk of very high toxicities. Severe complications related to conventional therapies decrease their effectiveness and can sometimes lead to death. Therefore, currently, numerous studies are being carried out on novel forms of treatment. In this work, classical methods of treatment have been summarized. Furthermore, novel treatment methods and the possibility of combining them with chemotherapy have been incorporated into the present work. Targeted treatment, CAR-T-cell therapy, and immunotherapy for ALL have been described. Treatment options for the relapse/chemoresistance ALL have been presented. Acute lymphoblastic leukemia is the most common blood cancer in pediatric patients. There has been enormous progress in ALL treatment in recent years, which is reflected by the increase in the 5-year OS from 57% in the 1970s to up to 96% in the most recent studies. ALL treatment is based primarily on conventional methods, which include chemotherapy and radiotherapy. Their main weakness is severe toxicity, which prompts dose reduction, decreases the effectiveness of the treatment, and, in some cases, can lead to death. Currently, numerous modifications in treatment regimens are applied in order to limit toxicities emerging from conventional approaches and improve outcomes. Hematological treatment of pediatric patients is reaching for more novel treatment options, such as targeted treatment, CAR-T-cells therapy, and immunotherapy. These methods are currently used in conjunction with chemotherapy. Nevertheless, the swift progress in their development and increasing efficacity can lead to applying those novel therapies as standalone therapeutic options for pediatric ALL. [ABSTRACT FROM AUTHOR]