Blood Cancer Discovery最新文献

Genomic antigen loss is a recurring mechanism of resistance to chimeric antigen receptor T-cell (CAR-T) and T-cell engagers (TCE) in relapsed/refractory multiple myeloma (RRMM). Yet, it remains unclear whether these events are acquired under treatment or merely selected from preexisting, undetectable clones. By leveraging chemotherapy mutational signatures as temporal barcodes within whole-genome sequencing data, we could time genomic antigen escape in 4 of 11 patients with RRMM. In all cases, the biallelic loss was driven by genomic events acquired after exposure to BCMA- and GPCR5D-targeted CAR-T/TCE and not present at baseline. Longitudinal digital PCR analysis corroborated that resistance mutations were undetectable at therapy initiation but emerged preceding relapse. Among 752 newly diagnosed patients, only 2.7% and 9% had monoallelic inactivation of TNFRSF17 and GPCR5D, respectively, with no biallelic loss. Our findings suggest limited utility of mutational screening prior to CAR-T/TCE while underscoring the importance of dynamic surveillance during therapy.

Significance: Multiple myeloma has been demonstrated to recurrently develop resistance to T-cell redirection via genomic antigen escape. By leveraging chemotherapy mutational signatures, we demonstrate that somatic antigen-escape mechanisms are uniformly acquired following treatment initiation and not selected from among preexisting clones, emphasizing the importance of dynamic longitudinal surveillance for their emergence. See related commentary by Kauer et al., p. 532.

The real-world effectiveness of the bispecific antibody teclistamab seems to be lower than the efficacy observed in pivotal registration trials. Understanding the drivers of this effectiveness-efficacy gap is essential for guiding the rational selection of patients most likely to benefit, optimizing bispecific antibody therapy in high-risk populations and ultimately advancing more personalized treatment strategies while supporting sustainable models of care. See related article by Razzo et al., p. 561.

Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin.

Significance: T cell-engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542.

This commentary explores new challenges in the management of newly diagnosed multiple myeloma and strategies for sustaining improvements in patient outcomes. We highlight the need for risk-adapted approaches, the potential future incorporation of T cell-redirecting immunotherapies in first-line treatment, and the challenge of access to care.

In this issue of Blood Cancer Discovery, Kamiya and colleagues identify aberrant RNA splicing as a targetable vulnerability in multiple myeloma. Using the RBM39 degrader indisulam, they show that therapeutic modulation of RNA splicing factors is a potential treatment strategy for patients with therapy-resistant multiple myeloma. See related article by Kamiya et al., p. 602.

Current understanding of lymphoma cell-intrinsic mechanisms of relapse following chimeric antigen receptor (CAR) T-cell treatment of diffuse large B-cell lymphoma (DLBCL) include antigen loss and apoptosis resistance. Herein, CD19 CAR T-cell response and resistance were modeled, and it was identified that treatment-naïve CD19 expression does not correlate with CAR T-cell sensitivity, but resistance is frequently accompanied by reversible downregulation of CD19 that once restored is not paralleled with restored sensitivity to CAR T cell-mediated killing. Profiling a suite of DLBCL cell lines to CD19 CAR T-cell sensitivity reveals that DLBCL cells become nonresponsive to CAR T cell-killing, including to alternative antigen targeting of CD20 or CD22. Leveraging these resistant models, we identified gene signatures present in the CAR T cell-resistant DLBCL cell lines that correlate with patient response to CTL019 in two independent clinical trials. Finally, we show that combination strategies to overcome this resistance, including up-front dual-antigen targeting and combined treatment with an Mcl-1 inhibitor, improve CAR T-cell responses.

Significance: We demonstrate that DLBCL cells surviving CD19 CAR T-cell treatment develop a resistance phenotype with a "resistance signature" predictive of clinical CAR T-cell response, mediating cross-resistance between CAR T cells targeting different antigens. Our findings suggest that up-front dual-antigen targeting and combination therapies could improve clinical outcomes.

In this issue of Blood Cancer Discovery, Papadimitriou and colleagues implement a temporal workflow to monitor genomic antigen escape during BCMA- or GPRC5D-directed immunotherapy. Using chemotherapy-induced mutational signatures as barcodes, they provide evidence that these mutations are acquired during therapy rather than being preexisting in newly diagnosed patients. See related article by Papadimitriou et al., p. 572.

Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms.

Significance: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.

The molecular basis of therapy resistance in multiple myeloma remains poorly understood. In this study, we performed single-cell RNA sequencing coupled with VDJ-targeted sequencing of highly purified primary multiple myeloma cells from patient bone marrow. This approach uncovered cellular heterogeneity and phenotypic plasticity of multiple myeloma cells across a spectrum of CD138 expression, accompanied by drastic epigenetic alterations. Notably, therapy-resistant subpopulations were identified within a minor fraction of CD138- multiple myeloma cells, which were shown via CRISPR/Cas9 screening to be vulnerable to splicing pathway inhibition. Consistently, this fraction of CD138- multiple myeloma cells showed increased differential splicing associated with overexpression of SR protein family splicing factors. Among these splicing factors, RBM39 was overexpressed in therapy-resistant cells and involved in aberrant splicing. Both genetic and pharmacologic RBM39 inhibition exhibited a significant lethal effect on multiple myeloma cells. Collectively, our findings identify distinct therapy-resistant multiple myeloma subpopulations and highlight targeting the splicing pathway as a promising therapeutic strategy.

Significance: Single-cell RNA sequencing coupled with VDJ-targeted profiling identified distinct therapy-resistant subpopulations within the minor CD138- fraction of multiple myeloma cells. These subpopulations were characterized by increased differential splicing events associated with overexpression of splicing factors from the SR protein family, with CD138- cells showing selective vulnerability to pharmacologic targeting of the splicing factor RBM39. See related commentary by Maron and Abdel-Wahab, p. 535.

Menin inhibitors are targeted therapies for the treatment of genetically defined subsets of acute leukemia. The menin inhibitor revumenib is approved for the treatment of relapsed or refractory leukemia with rearrangement of KMT2A. In addition, multiple menin inhibitors are currently in clinical development aimed at targeting other additional subsets, such as NPM1 mutations, which form up to 30% of acute myeloid leukemia. However, as observed with other targeted therapies for cancer, on-target resistance mutations emerged in advanced cases following monotherapy. Therefore, combination strategies incorporating menin inhibitors are needed to improve durability and depth of remission.

Significance: Menin inhibitors have the potential to reshape treatment paradigms in acute leukemia. There are multiple promising preclinical combinations that require careful clinical trial design and implementation for a successful translation into the clinical setting.