Bispecific Antibody Use in Patients With Lymphoma and Multiple Myeloma.

This article endeavors to navigate the clinical journey of bispecific antibodies (BsAbs), from elucidating common toxicities and management strategies to examining novel agents and broadening access in community health care. These drugs, commonly through T-cell activation, result in shared adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Variations in target antigens and designs, however, might introduce unique toxicities for different BsAbs, warranting specific management approaches. Recent US Food and Drug Administration approvals of BsAbs targeting CD3+ T cells linked to CD20 for non-Hodgkin lymphoma and to B-cell maturation antigen or GPRC5D for multiple myeloma have transformed the treatment landscape for hematologic malignancies. Emerging new agents promise further enhancement and safety, exploring novel antigen targets, innovative structures such as trispecific antibodies, and the engagement of diverse immune cells. Simultaneously, the expansion of BsAbs into community practices is underway, demanding a multifaceted strategy that encompasses educational initiatives, operational adaptations, and collaborative frameworks. This ensures comprehensive treatment access, allowing every patient, irrespective of geographical or socioeconomic status, to benefit from these advancements in cancer therapy.

SIRPα+ macrophages are increased in patients with FL who progress or relapse after frontline lenalidomide and rituximab.

Limited data exist regarding the outcome of patients with follicular lymphoma (FL) who relapse or progress after frontline lenalidomide and rituximab (R2). Moreover, mechanisms of resistance to R2 in FL remain unclear, with increased protumoral macrophages suspected as a major contributory culprit to this phenomenon. This retrospective study analyzed the outcome of patients with advanced-stage FL grade 1 to 3A who relapsed or progressed after frontline R2. A multiplex immunofluorescence macrophage panel, including CD47, CD14, CD68, CD115 (also known as colony-stimulating factor 1 receptor [CSF1R]), CD163, CD172a (also known as signal regulatory protein α [SIRPα]), and CD274 (also known as programmed cell death-ligand 1 [PDL1]), was used to stain tissue biopsy specimens collected before initiation of R2 and at the time of progression. Among 156 patients with advanced-stage FL treated with frontline R2, 33 (21%) relapsed or progressed and required second-line therapy, after a median of 33 months (range, 1-122 months). Second-line therapy was chemoimmunotherapy in 16 (48%) patients and other therapy in 17 (52%). The overall response rate was 78%, and complete response rate was 72%. Median progression-free survival was significantly longer in patients who received chemoimmunotherapy compared with other therapy (99 vs 25 months; P = .004). Three macrophage populations were significantly increased in tissue samples collected at progression compared with before frontline treatment: CD68+CD115+ (P = .02), CD68+CD115+CD172a+ (P = .02), and CD68+CD163+CD172a+ (P = .01). Chemoimmunotherapy is an effective treatment strategy for patients with FL who relapse after frontline R2. Therapies targeting specific macrophage populations may yield novel approaches for improving outcomes with frontline R2.

A multicenter retrospective study of polatuzumab vedotin in patients with large B-cell lymphoma after CAR T-cell therapy.

Polatuzumab vedotin (PV) is an antibody-drug conjugate targeting CD79b that is approved for patients with relapsed/refractory large B-cell lymphoma (LBCL). Patients who relapse after chimeric antigen receptor (CAR) T-cell therapy were not included in the registration study, and reports of PV use after CAR T cells are limited. This multicenter retrospective analysis included patients with LBCL who relapsed or progressed after CAR T-cell therapy and subsequently received PV with or without rituximab and bendamustine between July 2019 and May 2021. Response to treatment and progression were assessed based on the 2014 Lugano criteria. Fifty-seven patients were included in the study: 18 (32%) patients were primary refractory to CAR T-cell therapy, and 34 (60%) patients received PV-based therapy immediately after CAR T-cell therapy. PV was combined with rituximab in 54 (95%) patients and administered with bendamustine in 35 (61%) patients. A response was achieved in 25 (44%) patients, including complete remission in 8 (14%). No significant association between baseline characteristics and response was observed. After a median follow-up of 47 weeks (95% confidence interval [CI], 40-54), 46 (81%) patients had disease progression or died, and the median progression-free survival was 10 weeks (95% CI, 5-15). On a multivariate analysis, bone marrow involvement (hazard ratio, 5.2; 95% CI, 1.8-15; P = .003) and elevated lactate dehydrogenase levels (hazard ratio, 5.0; 95% CI, 1.4-16; P = .01) were associated with shorter progression-free survival. Studies aimed at better characterizing the intrinsic mechanism of resistance and identifying optimal consolidation strategies for these patients are warranted.

Statins enhance the chemosensitivity of R-CHOP in diffuse large B-cell lymphoma.

The beneficial effect of statins on the anti-lymphoma activity of the rituximab-based chemotherapy regimen is controversial. Here, we retrospectively reviewed patients with naïve-treated advanced diffuse large B-cell lymphoma (DLBCL) receiving frontline R-CHOP, and for whom data regarding differential statins use was available at the time of initiation of treatment. We observe that patients treated with statins and R-CHOP experienced a significantly higher CR rate as compared to those who received R-CHOP only. We further show that patients receiving medium or high intensity statins and R-CHOP experienced a significantly higher CR as compared to those treated with R-CHOP. Six-year progression free survival was higher for patients who received medium or higher intensity statins as compared to low or no statins. The potential contribution of cholesterol pathway in doxorubicin sensitivity was supported by in vitro/in vivo studies. Our study suggests that targeting cholesterol-using lovastatin could be a therapeutic strategy to enhance responses to R-CHOP in DLBCL patients.

Follicular lymphoma and macrophages: impact of approved and novel therapies.

The survival and proliferation of follicular lymphoma (FL) cells are strongly dependent on macrophages, because their presence is necessary for the propagation of FL cells in vitro. To this regard, as also shown for the majority of solid tumors, a high tissue content of tumor-associated macrophages (TAMs), particularly if showing a protumoral phenotype (also called M2), is strongly associated with a poor outcome among patients with FL treated with chemotherapy. The introduction of rituximab, an anti-CD20 antibody that can be used by TAMs to facilitate antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, has challenged this paradigm. In the rituximab era, clinical studies have yielded conflicting results in FL, showing variable outcomes based on the type of regimen used. This highlighted, for the first time, that the impact of TAMs on the prognosis of patients with FL may depend on the administered treatment, emphasizing the need to better understand how currently available therapies affect macrophage function in FL. We summarize the impact of approved and novel therapies for FL, including radiation therapy, chemotherapy, anti-CD20 monoclonal antibodies, lenalidomide, and targeted agents, on the biology of TAMs and describe their effects on macrophage phagocytosis, polarization, and function. Although novel agents targeting the CD47/SIRPα axis are being developed and show promising activity in FL, a deeper understanding of macrophage biology and their complex pathways will help to develop novel and safer therapeutic strategies for patients with this type of lymphoma.

Rate of Progression of Aortic Stenosis in Patients With Cancer.

Patients with cancer and aortic stenosis (AS) are exposed to several factors that could accelerate the progression of AS. This study aimed to determine the cumulative incidence of AS progression and associated factors in these patients. This retrospective cohort study included patients with cancer, mild or moderate AS and at least two echocardiograms 6 months apart between 1996 and 2016 at MD Anderson Cancer Center. AS progression was defined by an increase in mean gradient of 20 mmHg or peak velocity of 2 m/s by spectral Doppler echocardiography or as requiring aortic valve replacement. Univariate and multivariable Fine-Gray models to account for the competing risk of death were used. One hundred and two patients were included and median follow-up was 7.3 years. Overall, 30 patients (29%) developed AS progression, while 48 (47%) died without it. Yearly rate of mean gradient change was 4.9 ± 3.9 mmHg and yearly rate of peak velocity change was 0.23 ± 0.29 m/s for patients who developed AS progression. In the univariate analysis, coronary artery disease (CAD), dyspnea, prevalent cyclophosphamide and beta-blocker use were associated with AS progression. In multivariable analysis, CAD and prevalent cyclophosphamide use for the time interval of more than 3 years of follow-up remained significantly associated with increased cumulative incidence of AS progression. In conclusion, patients with mild or moderate AS and cancer are more likely to die before having AS progression. AS progression is associated with CAD and prevalent cyclophosphamide use.

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.

Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1ß and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1ß oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1ß and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.

PortEco: a resource for exploring bacterial biology through high-throughput data and analysis tools.

PortEco (http://porteco.org) aims to collect, curate and provide data and analysis tools to support basic biological research in Escherichia coli (and eventually other bacterial systems). PortEco is implemented as a 'virtual' model organism database that provides a single unified interface to the user, while integrating information from a variety of sources. The main focus of PortEco is to enable broad use of the growing number of high-throughput experiments available for E. coli, and to leverage community annotation through the EcoliWiki and GONUTS systems. Currently, PortEco includes curated data from hundreds of genome-wide RNA expression studies, from high-throughput phenotyping of single-gene knockouts under hundreds of annotated conditions, from chromatin immunoprecipitation experiments for tens of different DNA-binding factors and from ribosome profiling experiments that yield insights into protein expression. Conditions have been annotated with a consistent vocabulary, and data have been consistently normalized to enable users to find, compare and interpret relevant experiments. PortEco includes tools for data analysis, including clustering, enrichment analysis and exploration via genome browsers. PortEco search and data analysis tools are extensively linked to the curated gene, metabolic pathway and regulation content at its sister site, EcoCyc.