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CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel), with an ORR ranging from 58% to 82%. More recently, axi-cel and liso-cel were approved as second-line treatments for patients with R/R disease up to 12 months after the completion of first-line chemo-immunotherapy. The safety profile was acceptable with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome being the two most frequent acute adverse events. Potential long-term toxicities of CD19-targeting CAR T-cells have also been described. Overall, 30% to 40% of patients are cured with a single infusion of CAR T-cells. However, 60% to 70% of patients relapse after being treated with CAR T-cells and have a dismal prognosis. The advent of bispecific antibodies (BsAb) offers an additional treatment modality for patients with R/R LBCL. The aim of this review is to describe the clinical efficacy of the three CAR T-cells, as well as their safety profile. We also compare these three CAR T-cells in terms of their efficacy and safety profile as well as evaluating the place of CAR T-cells and BsAb in the treatment arsenal of patients with R/R LBCL. [ABSTRACT FROM AUTHOR]

The advent of targeted therapies such as monoclonal antibodies, adoptive T-cell therapies, and antibody–drug conjugates (ADCs) dramatically changed the treatment landscape of diffuse large B-cell lymphoma (DLBCL) over the last two decades. Rituximab was the first one approved. Chimeric antigen receptor T-cells are currently approved as second-line treatment in patients with DLBCL refractory to first-line chemo-immunotherapy. Polatuzumab, a CD79b-targeting ADC, is approved as first-line treatment in high-risk patients in combination with chemo-immunotherapy. Bispecific antibodies (BsAbs) are a novel category of drugs that are also changing the treatment paradigm of patients with DLBCL. They are engineered to bind to two different targets at the same time. To date, two BsAbs (glofitamab and epcoritamab) are approved as monotherapy in third-line treatment in DLBCL. Combination strategies with chemotherapy, immunotherapy, and ADCs are currently under investigation with encouraging results in first-line or subsequent lines of treatment. In the following review, we focus on the structure of BsAbs, the mechanism of action, clinical efficacy, and the mechanisms of resistance to BsAbs. [ABSTRACT FROM AUTHOR]

B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of acute leukemia in the pediatric population. The prognosis and treatment of B-ALL have dramatically improved over the past decade with the adoption of intensive and prolonged combination chemotherapy regimens. The advent of novel immunologic agents such as blinatumomab and inotuzumab has changed the treatment landscape of B-ALL. However, patients have continued to relapse, raising the need for novel therapies. Chimeric antigen receptor (CAR) T-cells have achieved a milestone in the treatment of B-ALL. Two CD19-targeting CAR T-cells were approved by the Food and Drug Administration and the European Medicines Agency for the treatment of relapsed and/or refractory B-ALL. In this review, we review the available data regarding CD19-targeting CAR T-cells with their safety profile as well as the mechanism of resistance to these agents and the way to overcome this resistance. [ABSTRACT FROM AUTHOR]

One of the most important steps forward in the management of cancer was the discovery of immunotherapy. It has become an essential pillar in the treatment paradigm of cancer patients. Unfortunately, despite the various options presented with immune checkpoint inhibitors (ICIs), the benefit is still limited to select patients and the vast majority of these patients gain either minimal benefit or eventually progress, leaving an unmet need for the development of novel therapeutic agents and strategies. Lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor protein, is a molecule found on the surface of activated T-cells. It plays a major role in negatively regulating T-cell function thereby providing tumors with an immune escape in the tumor microenvironment (TME). Given its importance in regulating the immune system, LAG-3 has been considered as a promising target in oncology and precision medicine. To date, two LAG-3-directed agents (eftilagimod alpha and relatlimab) have been approved in combination with programmed death-1 (PD-1) inhibitors in the setting of advanced solid tumors. In this review, we discuss the structure of LAG-3, its mechanism of action, and its interaction with its ligands. We also shed light on the emerging treatments targeting LAG-3 for the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific antibodies, and innovative T-cell therapy. Antibody-drug conjugates (ADCs) have also revolutionized the treatment of cancer. Several ADCs have already been approved in hematology and clinical oncology, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. The efficacy of ADCs is limited by the emergence of resistance due to different mechanisms, such as antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. In this review, we summarize the clinical data that contributed to the approval of T-DM1, T-DXd, SG, and EV. We also discuss the different mechanisms of resistance to ADCs, as well as the ways to overcome this resistance, such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors or tyrosine-kinase inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: Mantle cell lymphoma (MCL) is associated with poor response to anthracycline-based chemotherapy, and high-dose cytarabine offers a durable response. Recently, multiple targeted therapies have been approved for the treatment of MCL, highlighting the role of the tumor microenvironment (TME) in the expansion and resistance of the disease. We review herein the TME in MCL and the different therapeutic strategies of treatment. Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) dramatically improved during the past 20 years with the advent of tyrosine kinase inhibitors and monoclonal antibodies. Their great efficacy in young and fit patients led to question our reliance on chemotherapy and allogeneic hematopoietic stem cell transplantation. Moreover, these well-tolerated treatments can be safely administrated even in the elderly that represent the majority of Ph+ ALL patient. This review will focus on the recent changes of paradigm in the management of Ph+ ALL patients and the development of novel therapeutic strategies. Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is the most common subtype of B-ALL in adults and its incidence increases with age. It is characterized by the presence of BCR-ABL oncoprotein that plays a central role in the leukemogenesis of Ph+ ALL. Ph+ ALL patients traditionally had dismal prognosis and long-term survivors were only observed among patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). However, feasibility of allo-HSCT is limited in this elderly population. Fortunately, development of increasingly powerful tyrosine kinase inhibitors (TKIs) from the beginning of the 2000′s dramatically improved the prognosis of Ph+ ALL patients with complete response rates above 90%, deep molecular responses and prolonged survival, altogether with good tolerance. TKIs became the keystone of Ph+ ALL management and their great efficacy led to develop reduced-intensity chemotherapy backbones. Subsequent introduction of blinatumomab allowed going further with development of chemo free strategies. This review will focus on these amazing recent advances as well as novel therapeutic strategies in adult Ph+ ALL. [ABSTRACT FROM AUTHOR]