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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]

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]

Purpose: In patients with indolent B‐cell non‐Hodgkin's lymphoma (B‐NHL), one course of low‐dose radiotherapy (LD‐RT) 2 × 2 Gy is emerging as new option of therapy in palliative setting. Efficacy of LD‐RT when repeated remains to be determinate. This study aims to assess the efficacy of repeated LD‐RT given in patients with indolent B‐NHL. Materials and Methods: All consecutive adult patients who received two or more courses of LD‐RT 2 × 2 Gy for indolent B‐NHL at Gustave Roussy institution, during the period 1990‐2015 were retrospectively investigated. Results: Thirty‐three patients received two or more courses of LD‐RT for indolent B‐NHL during the study period. The median age was 57 (range 37‐80) years, histological types were distributed among follicular lymphoma (n = 24 pts; 73%), marginal‐zone lymphoma (n = 6 pts; 18%), and primary cutaneous follicle center lymphoma (n = 3 pts; 9%). The median number of low‐dose radiation therapy courses given per patients was 2 (range 2‐6). The overall response rates following the first and the second course of LD‐RT were 96% and 88%, respectively (P =.31). The 1‐ and 2‐years local control rates following the first courses of LD‐RT were 94% (CI 95: 86‐100) and 94% (CI 95: 86‐98); and were 91% (CI 95: 82‐100) and 88% (CI 95: 77‐100) following the second course of LD‐RT (P =.39). Conclusion: The repeated courses of LD‐RT offered similar efficacy compare with the first course in patients with indolent B‐NHL. LD‐RT repeated is a simple, easy to give, and non‐toxic asset that could be investigated as treatment option in patients with indolent B‐NHL. [ABSTRACT FROM AUTHOR]

Background: High‐dose cyclophosphamide to treat solid refractory tumors demonstrated meaningful activity, while data to treat lymphoma remain scarce. This study aims to assess high‐dose cyclophosphamide to treat relapsed or refractory lymphoma. Methods: A phase II study included adult patients with relapsed or refractory B‐cell non‐Hodgkin's lymphoma, previously treated by ≥2 prior lines with no other available option of therapy. High‐dose cyclophosphamide was given intravenously 3 g/m2 over two consecutive days and repeated once at 28 days in responding patients. Rituximab 375 mg/m2 intravenously was added in patients not refractory to anti‐CD20 antibody. Results: Forty‐two patients with median age 65 [56‐70] years were included. Patients had previously received a median of four lines of therapies. Tumor types were diffuse large B‐cell lymphoma (n = 26; 62%), indolent B‐cell non‐Hodgkin lymphoma (n = 10; 24%), or mantle lymphoma (n = 6; 14%). Hematologic and non‐hematologic grade 3‐5 toxicities occurred in 42 (100%) and 18 (43%) of patients, respectively. The overall response rate was 45%. Conclusion: One to two cycles of high‐dose cyclophosphamide in hard‐to‐treat patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma demonstrated a favorable safety and efficacy profile. This regimen could serve as a bridge to modern cellular therapy with CAR‐T cell. [ABSTRACT FROM AUTHOR]