Expert Opinion on Biological Therapy最新文献

Introduction: Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are aggressive hematologic malignancies with poor outcomes, particularly in relapsed/refractory settings. CD123, the interleukin-3 receptor alpha chain, is highly expressed on leukemic blasts and leukemia stem cells, making it an attractive therapeutic target with limited expression on normal hematopoietic cells. CD123-directed therapies - including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and CAR T-cell therapies - are under active investigation.

Areas covered: This review details the preclinical rationale, clinical development, efficacy, and toxicity of CD123-targeted therapies. It discusses completed and ongoing clinical trials for agents such as tagraxofusp, pivekimab sunirine, flotetuzumab, vibecotamab, and investigational CAR T-cell therapies (e.g. MB-102, UCART123v1.2). Toxicities, including myelosuppression, cytokine release syndrome (CRS), and hepatotoxicity - are characterized in detail, with attention to mitigation strategies. Future directions highlight combination regimens, switchable CAR designs, and biomarker-driven personalization.

Expert opinion: CD123-targeted therapy represents a promising yet challenging frontier in treating high-risk leukemias. While clinical activity has been demonstrated, especially in BPDCN, therapeutic durability and safety remain hurdles. Precision in antigen targeting, combination strategies, and toxicity management will be critical for successful integration of CD123-directed therapies into standard clinical practice.

Introduction: Small-cell lung cancer (SCLC) is a rapidly progressive form of cancer often expressing DLL3. Tarlatamab is a bispecific antibody which blocks DLL3-related downstream pathways and activates antitumor host immunity. It is currently authorized in the U.S.A. for the treatment of extensive SCLC.

Areas covered: This is a review evaluating the basic pharmacology and clinical data regarding tarlatamab. Most data come from SCLC; in the other two diseases, tarlatamab is in early clinical development.

Expert opinion: Tarlatamab is an effective therapy mainly in relapsed/progressed SCLC, and its assessment in limited SCLC alone or combined with other therapies is supported by the existing data.

Introduction: Talquetamab is a GPRC5DxCD3 T-cell-engaging bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma. GPRC5D represents a novel and emerging target in antimyeloma therapy, and there is substantial drug development for new therapies targeting this antigen.

Areas covered: Herein, we review the efficacy, safety, and future development directions of talquetamab, including emerging talquetamab-based combination regimens and ongoing clinical trials. We will also review the growing landscape of GPRC5D-targeting immunotherapies in development for multiple myeloma, including CAR-T and trispecific antibodies.

Expert opinion: Talquetamab, a GPRC5D-targeting bispecific antibody, was FDA-approved in 2023 for relapsed/refractory multiple myeloma after 4 or more prior lines of therapy. In contrast to the historic overall response rate (ORR) of 29.5%, talquetamab monotherapy achieved a promising ORR of ~70% in a triple-class-exposed population. Real-world evidence supports talquetamab as a bridging therapy to CAR-T. Notable adverse drug reactions include CRS, dysgeusia, nail/skin toxicities, and infections, which are often manageable but can be persistent. Sequencing studies suggest talquetamab retains efficacy before or after BCMA-directed therapies without diminishing effectiveness. Potential future directions for talquetamab include combination regimens with other antimyeloma therapies. Additional GPRC5D-directed therapies are also under development, including trispecific antibodies and CAR-T.

Introduction: Bispecific antibodies (BsAbs) are a novel class of immunotherapy agents that engage endogenous T cells to target and eradicate malignant B cells by simultaneously binding CD3 and CD20. BsAbs such as epcoritamab, glofitamab, and mosunetuzumab have demonstrated substantial efficacy across both aggressive and indolent B-cell non-Hodgkin lymphomas (B-NHL), with largely manageable safety profiles. Their off-the-shelf administration offers a practical alternative to CAR T-cell therapy, particularly for patients who are transplant-ineligible or lack access to cellular approaches.

Areas covered: This review provides a comprehensive overview of BsAbs in B-NHL. We detail pivotal studies in relapsed/refractory (R/R) DLBCL, FL, and MCL, highlighting single-agent outcomes and emerging combination strategies. Approaches incorporating BsAbs into cytotoxic backbones and antibody-drug conjugates, as well as chemotherapy-free regimens such as BsAbs combined with lenalidomide, are discussed. We also examine their potential to address poor-risk disease features and historically refractory subsets.

Expert opinion: BsAbs represent a major advance in B-NHL, offering high rates of deep remission with predictable safety and outpatient feasibility. As trial data continues to mature, BsAb-based regimens are poised to become foundational across multiple lines of therapy, reshaping expectations for patients with both aggressive and indolent lymphomas.