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The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure. The molecular characterization of melanomas has shown a high mutational burden led to the identification of some recurrent genetic alterations. BRAF gene is mutated in 40–50% of melanomas and its role in melanoma development is paramount. BRAF mutations confer constitutive activation of MAPK signalling. The large majority (about 90%) of BRAF mutations occur at amino acid 600; the majority are BRAFV600E mutations and less frequently BRAFv600K, V600D and V600M. The introduction of drugs that directly target BRAF-mutant protein (BRAF inhibitors) and of agents that stimulate immune response through targeting of immune check inhibitor consistently improved the survival of melanoma BRAFV600-mutant patients with unresectable/metastatic disease. In parallel, studies in melanoma stage II-III patients with resectable disease have shown that adjuvant therapy with ICIs and/or targeted therapy improves PFS and RFS, but not OS compared to placebo; however, neoadjuvant therapy plus adjuvant therapy improved therapeutic response compared to adjuvant therapy alone. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the emerging area of the therapeutic use of antibodies and chimeric antigen receptor (CAR)-T cells in acute myeloid leukemia (AML). Through a detailed analysis of the existing literature, this paper highlights the most recent applications of antibodies, including bispecific immune cell engagers and CAR-T cells, to the therapy of relapsing/refractory AML. Furthermore, it discusses the potential mechanisms underlying sensitivity or resistance to antibody- and CAR-T cell-based therapies. Overall, this review underscores the difficulties and potentialities of antibody-guided immunotherapies in the treatment of AML patients. This review explores the emerging area of the therapeutic use of antibodies and chimeric antigen receptor (CAR)-T cells for the treatment of acute myeloid leukemia (AML). Through a detailed analysis of the existing literature, this paper highlights the different categories of AML antigens for immunotherapeutic targeting, the most recent applications on antibodies, including bispecific immune cell engagers and CAR-T cells, to the therapy of patients with refractory/relapsing AML The studies performed in AML patients using BisAbs and CAR-T cells have shown that only a limited number of AML patients show sustained responses to these therapies, thus underlying AML heterogeneity as a major challenge. Several studies have addressed the potential mechanisms underlying the resistance of AMLs to antibody-directed immunotherapies. A better understanding of the barriers hampering the successful development of AML immunotherapy is required. However, in spite of the limitations, the studies recently carried out have shown the peculiar sensitivity of some AML subtypes to immunotherapy and have provided the basis for future studies, such as multiplex antigen targeting, which hold the promise of successful development. [ABSTRACT FROM AUTHOR]

Introduction: Primary liver cancer is a major health problem being the sixth most frequent cancer in the world and the third cause of cancer-related death in the world. The most common histological type of liver cancer is hepatocellular carcinoma (HCC, 75–80%). Areas covered: Based on primary literature, this review provides an updated analysis of studies of genetic characterization of HCC at the level of gene mutation profiling, copy number alterations, and gene expression, with the definition of molecular subgroups and the identification of some molecular biomarkers and therapeutic targets. Recent therapeutic developments are also highlighted. Expert opinion: Deepening the understanding of the molecular complexity of HCC is progressively paving the way for the development of more personalized treatment approaches. Two important strategies involve the definition and validation of molecularly defined therapeutic targets in a subset of HCC patients and the identification of suitable biomarkers for approved systematic therapies (multikinase inhibitors and immunotherapies). The extensive molecular characterization of patients at the genomic and transcriptomic levels and the inclusion of detailed and relevant translational studies in clinical trials will represent a fundamental tool for improving the benefit of systemic therapies in HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the emerging area of the therapeutic use of chimeric antigen receptor (CAR)-T cells in nervous tissue tumors. Through a detailed analysis of the existing literature, this paper highlights the most recent applications of CAR-T cells to the therapy of pediatric and adult nervous system neoplasia. Furthermore, it discusses the potential mechanisms underlying sensitivity or resistance to CAR-T cell-based therapies. Overall, this review underscores the importance of CAR-T cell therapies to the treatment of some nervous system tumors. Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various types of brain tumors due to several factors that have hampered their activity, including tumor antigen heterogeneity, the limited access of CAR-T cells to brain tumor cells, limited CAR-T cell trafficking and in vivo persistence and the presence of a highly immunosuppressive tumor microenvironment. Despite these considerations, some recent studies have shown promising antitumor activity of GD2-CAR-T cells on diffuse midline gliomas and neuroblastomas and of CARv3-TEAM-E cells in glioblastomas. However, strategies are required to improve the effect of CAR-T cells in brain tumors, including advanced CAR-T cell design with multiple antigenic targeting and incorporation of combination therapies. [ABSTRACT FROM AUTHOR]

Blinatumomab, a CD19-CD3 bispecific T cell engager (BiTE), has two recombinant single-chain variable fragments that temporarily link CD3+ T cells and CD19+ B cells, leading to the T cell-mediated lysis of neoplastic B cells. Improved minimal residual disease (MRD)-negative response rates and long-term overall survival have been observed in B-ALL patients who received this drug. These therapeutic successes have led to FDA approval for refractory/relapsed and MRD-positive B-ALL patients. Furthermore, recent studies in newly diagnosed B-ALL patients have led in Philadelphia chromosome-positive patients to the development of chemotherapy-free regimens based on tyrosine kinase inhibitors plus Blinatumomab and in Philadelphia chromosome-negative patients to improvement in outcomes using chemotherapy regimens that have incorporated Blinatumomab in the consolidation phase of treatment. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a disorder of the monoclonal plasma cells and is the second most common hematologic malignancy. MM initiation and progression are dependent upon complex genomic abnormalities. The current pathogenic model of MM includes two types of primary events, represented by chromosome translocations or chromosome number alterations resulting in hyperdiploidy. These primary molecular events are observed both in MM and in monoclonal gammopathy, its premalignant precursor. Subsequent genetic events allow the progression of monoclonal gammopathy to MM and, together with primary events, contribute to the genetic complexity and heterogeneity of MM. Newer therapies have considerably improved patient outcomes; however, MM remains an incurable disease and most patients experience multiple relapses. The dramatic progresses achieved in the analysis of the heterogeneous molecular features of different MM patients allowed a comprehensive molecular classification of MM and the definition of an individualized prognostic model to predict an individual MM patient's response to different therapeutic options. Despite these progresses, prognostic models fail to identify a significant proportion of patients destined to early relapse. Treatment strategies are increasingly. Based on disease biology, trials are enriched for high-risk MMs, whose careful definition and categorization requires DNA sequencing studies. [ABSTRACT FROM AUTHOR]

In the last ten years, a consistent number of clinical studies have evaluated different gene approaches for the treatment of patients with sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). Initial studies of gene therapy for hemoglobinopathies involved the use of lentiviral vectors to add functional copies of the gene encoding β-globin in defective CD34 cells; more recently, gene editing techniques have been used involving either CRISPR-Cas9, transcription activation-like effector protein nuclease, zinc finger nuclease, and base editing to either induce fetal hemoglobin production at therapeutic levels or to genetically repair the underlying molecular defect causing the disease. Here, we review recent gene editing studies that have started the development of a new era in the treatment of hemoglobinopathies and, in general, monoallelic hereditary diseases. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM), characterized by abnormal proliferation of clonal plasma cells, is an incurable hematological malignancy. Various immunotherapy strategies have emerged as an efficacious approach for the treatment of MM, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cells. Anti-B-cell maturation antigen (BCMA) CAR-T cells have revolutionized the treatment of MM patients with relapsed/refractory disease and their clinical use was approved for the treatment of these patients. Despite this progress, the efficacy of CAR-T cells in MM is limited by the responsiveness of only a part of the treated patients, the relapse of other patients, the cost of the treatment and the diminished response in patients with prior exposure to anti-BCMA targeting agents. Ongoing clinical trials are evaluating the use of CAR-T cells at an earlier stage of MM disease and the use of CAR-T cells targeting other membrane antigens expressed on malignant plasma cells. [ABSTRACT FROM AUTHOR]