Blood Cancer Discovery最新文献

Among patients with poly-refractory myeloma, autologous chimeric antigen receptor T-cell therapy offers exceptional promise. With the availability of bispecific antibodies, a total immunotherapeutic strategy in combination with chimeric antigen receptor T-cell therapy is now feasible. See related article by Fandrei et al., p. 38.

Significance: The acceptance of MRD-negative complete response as an endpoint that is reasonably likely to predict clinical benefit will allow for the design of streamlined clinical trials for accelerated approval, enabling significantly faster patient access to novel therapies. Cooperative efforts were required to obtain and analyze clinical trial data from multiple sponsors and to determine the best approach to analysis with a relatively limited number of available datasets. The process to evaluate MRD as an intermediate endpoint, undertaken jointly by myeloma researchers and industry, with feedback from the FDA, serves as a roadmap for other areas of oncology to develop intermediate endpoints.

Significance: Our study demonstrates the use of "IF-THEN" SynNotch-gated CAR-T cells targeting CD33 and CD123 in AML reduces off-tumor toxicity. This strategy enhances T-cell phenotype, improves expansion, preserves HSPCs, and mitigates cytokine release syndrome-addressing critical limitations of existing AML CAR-T therapies.

Recent advancements in clinical tools for blood cancers are highlighted in this article, adapted from the 14th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to the US Congress and the public.

Establishing a strategy for sequencing of T cell-redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunologic impact of bispecific T cell-engaging antibodies (BsAb) as bridging therapy (BT) to subsequent B-cell maturation antigen-directed chimeric antigen receptor T (CAR-T) cell therapies in 52 patients with RRMM. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared with chemotherapy, anti-CD38, or anti-SLAMF7 antibody-based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T-cell expansion in patients receiving BsAbs as BT. In vitro cytotoxicity of CAR-T cells was comparable among BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T-cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T cell infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM. Significance: CAR-T cell therapy and BsAbs have revolutionized treatment of triple-class refractory multiple myeloma; however, optimal sequencing is unknown. We demonstrate that BT with BsAb before B-cell maturation antigen-directed CAR-T cell therapy is safe and effective, which might have implications for other hematologic malignancies as well. See related commentary by Bal and Costa, p. 10.

T cell-redirecting bispecific antibodies (BsAb) induce significant responses in heavily pretreated multiple myeloma. BsAbs are currently administered in a dose-dense manner until disease progression. However, continuous therapy is associated with safety concerns, including a high risk of infections and high costs. In addition, chronic exposure to BsAbs, and thus long-term T-cell stimulation, induces T-cell exhaustion, which may contribute to relapse. There is increasing evidence that the strategy of induction treatment followed by maintenance with longer intervals between BsAb doses, or limited treatment duration with cessation of therapy in patients who achieve deep remission, improves the balance between toxicity and efficacy. Significance: There is increasing evidence that after initial debulking, less-frequent BsAb administration mitigates T-cell exhaustion and minimizes the potential for chronic or cumulative toxicity while maintaining durable clinical responses. In addition, specific patient subsets may experience an extended treatment-free period following fixed-duration treatment. Fixed-duration treatment may, therefore, decrease cumulative toxicities and the burden on patients and healthcare systems.

Combined tracking of clonal evolution and chimeric cell phenotypes could enable detection of the key cellular populations associated with response following therapy, including after allogeneic hematopoietic stem cell transplantation (HSCT). We demonstrate that mitochondrial DNA (mtDNA) mutations coevolve with somatic nuclear DNA mutations at relapse post-HSCT and provide a sensitive means to monitor these cellular populations. Furthermore, detection of mtDNA mutations via single-cell assay for transposase-accessible chromatin with select antigen profiling by sequencing (ASAP-seq) simultaneously determines not only donor and recipient cells but also their phenotype at frequencies of 0.1% to 1%. Finally, integration of mtDNA mutations, surface markers, and chromatin accessibility profiles enables the phenotypic resolution of leukemic populations from normal immune cells, thereby providing fresh insights into residual donor-derived engraftment and short-term clonal evolution following therapy for post-transplant leukemia relapse. As throughput evolves, we envision future development of single-cell sequencing-based post-transplant monitoring as a powerful approach for guiding clinical decision-making. Significance: mtDNA mutations enable single-cell tracking of leukemic clonal evolution and donor-recipient origin following allogeneic HSCT. This provides unprecedented insight into chimeric cellular phenotypes of early immune reconstitution, incipient relapse, and quality of donor engraftment with immediate translational potential for future clinical post-transplant monitoring and decision-making.

Diffuse large B-cell lymphoma (DLBCL) includes the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, which differ in cell of origin, genetics, and clinical response. By screening the subtype-specific activity of 211 drugs approved or in active clinical development for other diseases, we identified inhibitors of nicotinamide phosphoribosyl transferase (NAMPTi) as active in a subset of GCB-DLBCL in vitro and in vivo. We validated three chemically distinct NAMPTis for their on-target activity based on biochemical and genetic rescue approaches and found the ratio between NAMPT and PARP1 RNA levels was predictive of NAMPTi sensitivity across DLBCL subtypes. Notably, the NAMPT:PARP1 transcript ratio predicts higher antitumor activity in BCL2-translocated GCB-DLBCL. Accordingly, pharmacologic and genetic inhibition of BCL2 was potently synergistic with NAMPT blockade. These data support the inhibition of NAMPT as a therapeutically relevant strategy for BCL2-translocated DLBCLs. Significance: Targeted therapies have emerged for the ABC subtype of DLBCL, but not for the GCB subtype, despite the evidence of a significant subset of high-risk cases. We identify a drug that specifically targets a subset of GCB-DLBCL and provide preclinical evidence for BCL2 translocations as biomarkers for their identification.

In Blood Cancer Discovery, Thibaud and colleagues report the incidence of pathogenic germline variants (PGV) in patients with multiple myeloma and that these PGVs are associated with DNA repair pathway genes, including BRCA1 and BRCA2. They find an association of patients with PGVs and previous family or personal history of cancer, and that these patients are diagnosed slightly earlier than those without PGVs. Patients with PGVs had a longer progression-free survival than those without PGVs when they received high-dose melphalan and autologous stem cell transplant, providing a therapeutic rationale for diagnostic germline testing in myeloma. See related article by Thibaud et al., p. 428.