Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various tissues and organs. LCH is often characterized by activating mutations of the mitogen-activated protein kinase (MAPK) pathway with BRAF^V600E being the most recurrent mutation. Although this discovery has greatly helped in understanding the disease and in developing better investigational tools, the process of malignant transformation and the cell of origin are still not fully understood. In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential.

For many years disappointing results have been generated by many investigations which have utilized a variety of immunologic strategies to enhance the ability of a patient’s immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient’s immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA)-specific monoclonal antibodies (mAbs), T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs) T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include the off-target toxicity and mechanisms of cancer immune evasion which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (FcCRs)-based strategy. Like CARs, FcCRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor  chain. In contrast, the extracellular CAR single chain variable fragment (scFv), which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcRIIIA (CD16). FcCR T cells have a few intriguing features. First, given in combination with mAbs, FcCR T cells mediate anti-cancer activity in vitro and in vivo by an antibody-mediated-cellular-cytotoxicity (ADCC) mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available. Third, the off-target effect of CD16-CR T cells may be controlled by withdrawing the mAb administration. The goal of this manuscript was three fold. First, we review the current state-of-the-art of pre-clinical CD16-CR T cell technology. Second, we describe its in vitro and in vivo anti-tumor activity. Lastly, we compare the advantages and limitations of the CD16-CR T cell technology with those of CAR T cell methodology.

Bone morphogenetic proteins (BMPs) are potent signaling molecules initially described as osteopromoting proteins. BMPs represent one of the members of the larger TGFβ family and today are recognized for their important role in numerous processes. Among the wide array of functions recently attributed to them, BMPs were also described to be involved in the regulation of components of the innate and adaptive immune response. This review focuses on the signaling pathway of BMPs and highlights the effects of BMP signaling on the differentiation, activation, and function of the main cell types of the immune system.

Acute lymphoblastic leukemia (ALL) is a blood cancer that primarily affects children but also adults. It is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. ALL is divided into B cell (85%) and T cell lineages (10 to 15%); rare cases are associated with the natural killer (NK) cell lineage (<1%). To date, the survival rate in children with ALL is excellent while in adults continues to be poor. Despite the therapeutic progress, there are subsets of patients that still have high relapse rates after chemotherapy or hematopoietic stem cell transplantation (HSCT) and an unsatisfactory cure rate. Hence, the identification of more effective and safer therapy choices represents a primary issue. In this review, we will discuss novel therapeutic options including bispecific antibodies, antibody–drug conjugates, chimeric antigen receptor (CAR)-based therapies, and other promising treatments for both pediatric and adult patients.

KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)‐specific monoclonal antibodies cetuximab and panitumumab‐based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS‐mutated cancer cell growth in vitro by natural killer (NK) cell‐mediated antibody‐dependent cellular cytotoxicity (ADCC), KRAS‐mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS‐mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fcγ‐CR constructs including CD16^158F‐CR, CD16^158V‐CR, CD32^131H‐CR, and CD32^131R‐CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32^131H‐CR (83.5 ± 9.5) and CD32^131R‐CR (77.7 ± 13.2) were significantly higher than those expressing with CD16^158F‐CR (30.3 ± 10.2) and CD16^158V‐CR (51.7 ± 13.7) (p < 0.003). CD32^131R‐CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16^158V‐CR T cells released high levels of interferon gamma (IFNγ = 1,145.5 pg/ml ±16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNFα = 614 pg/ml ± 21 pg/ml, p < 0.001) upon incubation with cetuximab‐opsonized HCT116 cells. Moreover, only CD16^158V‐CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS‐mutated cells in vitro. CD16^158V‐CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17‐SCID mice in vivo. Thus, CD16^158V‐CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS‐mutated CRC immunotherapies.