Blood最新文献

Abstract: The treatment landscape of B-cell non-Hodgkin lymphomas is rapidly evolving. However, few advances have occurred in marginal zone lymphoma (MZL), with a single US Food and Drug Administration-approved agent impacting the treatment landscape. Multiple factors are associated with this slower pace of progress, with a lower MZL incidence representing a significant factor. Pivotal randomized indolent lymphoma clinical trials analyzed MZL subsets without the appropriate power to capture differences between treatment arms. Furthermore, the current Lugano classification may not fully capture the presentation or treatment responses of some subtypes, preventing access to clinical trials and limiting an efficacy assessment across the disease spectrum. Thus, current MZL treatment is largely informed by single-arm studies with relatively empiric treatment sequencing among available agents. Although frontline strategies in early and advanced-stage MZL can achieve prolonged disease control, few options exist in the relapsed/refractory setting capable of achieving similar results. Emerging data demonstrate the encouraging efficacy of CD3×CD20 bispecific antibodies and antibody-drug conjugates in achieving deep responses, as well as the potential of circulating tumor DNA in risk stratification and molecular response monitoring. Compounding all these considerations, it is essential to recognize MZL as a heterogeneous group of diseases characterized by unique biology, clinical presentation, treatment response, toxicity, and survival. Nonetheless, a common characteristic across MZL subtypes is their general indolent disease course, emphasizing the need to incorporate patient-centered assessment in clinical trials to better inform the decision-making process.

Abstract: High-grade B-cell lymphoma with 11q aberration (HGBCL-11q) is a rare pediatric non-Hodgkin lymphoma. This study assessed outcome in 90 children with HGBCL-11q. With survival rates ≥95%, patients with HGBCL-11q and no predisposition are candidates for deescalated therapy in future prospective trials.

Abstract: Current therapies, including autologous chimeric antigen receptor (CAR) T-cell immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL), a disease characterized by frequent central nervous system involvement, poor treatment response, early relapse, and lineage switching. More effective treatment strategies, including the availability of off-the-shelf immunotherapies, is particularly relevant in infants. PROM1/CD133 is a direct target of KMT2A-fusion oncoproteins and is expressed on leukemic cells. Allogeneic invariant natural killer T (iNKT) cells, "innately" more powerful effectors than T cells, can be deployed off-the-shelf without risk of acute graft-versus-host disease. Here, we equip iNKT cells with CD19- and/or CD133-targeting CARs, and investigate their antileukemia activity against KMT2Ar-ALL in relevant in vitro and in vivo models. Compared with monospecific counterparts and dual, bispecific CAR T cells, bispecific CD19-CD133 CAR-iNKT cells have a more potent antileukemia activity, effectively targeting both CAR antigen-high and -low leukemia. Bispecific CAR-iNKT cells eradicate medullary and, notably, leptomeningeal leukemia, and induce sustained remissions without discernible hematologic toxicity. Mechanistically, the more potent antileukemia effect of CAR-iNKT cells over CAR T cells is mediated by a pronounced CAR-dependent and CAR antigen-dependent upregulation of the innate activating receptor NKG2D on CAR-iNKT cells, and its engagement by its corresponding ligands on KMT2Ar-ALL cells. This ensures effective leukemia targeting even with downregulation of CD133 or CD19. Thus, by engaging with 2 different types of leukemia-associated antigens, that is, CAR antigens and NKG2D ligands, CAR-iNKT cells provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement.

Organ transplantation is a pivotal treatment for patients with organ failure. ABO-incompatible (ABOi) transplantation, developed to expand the donor pool, presents significant clinical challenges due to pre-existing antibodies targeting ABO antigens on donor organs. Current therapies employing broad B-cell depletion, such as rituximab, effectively reduce antibody-mediated rejection but increase infection risks. Therefore, there is a critical need of targeted methods to specifically eliminate ABO-responsive B cells. Here, we developed a novel bispecific antibody-ligand conjugate (BiALC) platform designed to selectively target ABO-responsive B cells. Utilizing synthetic trisaccharide A antigens conjugated to T-cell-recruiting Fab fragments, our optimized hexameric construct, (A3-peg)2-αCD3, demonstrated enhanced affinity and potent cytotoxicity specifically against type A antigen-responsive B cells. Notably, BiALC maintained robust efficacy even in the presence of circulating anti-A antibodies. In murine models, (A3-peg)2-αCD3 selectively depleted A-responsive B cells without broadly affecting total IgM+ and IgG+ B cell populations, preserving overall immune competence. Similarly, the human-compatible BiALC, (A3-peg)2-αhCD3, effectively and selectively depleted type A-responsive B cells from human PBMCs, with potency comparable to rituximab, while sparing total antibody-secreting cells. Overall, the BiALC strategy offers a promising antigen-specific approach to reduce rejection risks in ABOi transplantation without inducing broad immunosuppression through nonspecific pan-B cell depletion, supporting its potential for clinical translation.