Cardiac fibroblasts (CFs) are key mediators of heart repair following myocardial infarction (MI). A specific CF subpopulation, termed Reparative Cardiac Fibroblasts (RCFs), has been shown to orchestrate scar formation and prevent ventricular rupture after MI. However, the timing of RCF appearance and the molecular events underlying this transition remain largely undefined. Here, we present a multi-modal dataset capturing the transcriptional dynamics of CFs during the early phase post-MI. Our integrative dataset combines bulk RNA sequencing, RNAscope in situ hybridization, and spatial transcriptomics to anatomically and temporally map the gene expression changes associated with the transition into RCFs. The dataset provides resources to characterize the distinct molecular programs that guide the emergence of RCFs from Periostin (Postn)+ activated CFs. This dataset provides a valuable resource for investigating CF heterogeneity and reparative pathways following MI. All raw and processed data, along with detailed metadata and annotations, are made available to facilitate reuse by the cardiovascular and single-cell biology communities.
B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.
6096 Background: Treatment intensification with antiPD-(L)1 agents given concurrently to definitive CRT in LA-HNSCC have failed to improve survival. Beyond radiation sensitization, PARP inhibition is predicted to trigger immune responses via STING pathway activation and synergize with anti-PD-(L)1 agents. TTCC-2022-01 RADIAN Trial evaluates niraparib and dostarlimab in LA-HNSCC patients (pts) treated with CRT (cohort A) or RT alone (Cohort B-cisplatin ineligible) (Oliva M et al ASCO 2024). Results of cohort A are presented. Methods: Investigator-initiated, non-randomized phase 1b/II study of niraparib and dostarlimab in LA-HNSCC pts candidates for definitive CRT or RT alone conducted in 7 Spanish sites. In cohort A, pts received 500 mg dostarlimab intravenously on week (w)-3 prior to RT and 200-300 mg/day niraparib from w-2 until 48h before start of CRT (70Gy/35 fractions plus cisplatin 100mg/m 2 w1,4 and 7). Maintenance dostarlimab (500 mg/3w) plus daily niraparib started 4w post-CRT for up to 14 cycles. Eligibility criteria: newly-diagnosed stage III-IVA-IVB HPV-negative oro-hipopharyngeal or laryngeal SCC and stage III HPV-related oropharyngeal, ECOG 0-1, centrally-confirmed PD-L1 CPS≥1, and with no cisplatin/dostarlimab/niraparib contraindications. Primary endpoint was 1-year disease-free survival (1y-DFS). Secondary objectives include safety; overall response rate (ORR) and ctDNA dynamics. 17 pts per cohort were planned. Experimental treatment was expected to increase 1y-DFS up to 75.9 % vs 65% historical control. Results: From Dec 23 to Jun 25, 17 pts were enrolled: median age 65 y (41-68); 71% male; 88% smokers; larynx/hypopharynx/oropharynx (HPV-related)= 53/6/41% (43%); stage III/IVA/IVB=29/53/18%. All pts completed dostarlimab and niraparib pre-CRT with no serious or Grade(G) 3-4 treatment-related adverse events (TRAEs); 15/17 completed CRT: 2 pts died during this phase (1 G5 febrile neutropenia cisplatin-niraparib-related; 1 unknown cause); 14/17 pts started maintenance: 2 completed, 7 ongoing and 5 (36%) discontinued due to TRAEs. The most common grade ≥3 TRAEs were neutropenia (71%), lymphopenia and dysphagia (29% each). Niraparib dose reductions/interruptions occurred in 12 (71%) pts. Most common TRAEs leading to dostarlimab+niraparib maintenance discontinuation were immune-mediated pneumonitis (18%) and respiratory tract edema (12%). ORR was 100% (14 complete+1 partial response) in 15 evaluable pts. With a median follow-up of 8.5 months (95% CI: 8.3-11.1), 15/17 were alive with no disease recurrence or progression. Intention-to-treat 1y-DFS was 88% (95% CI:74.1-100). Conclusions: Dostarlimab and niraparib with CRT showed promising efficacy results in this preliminary analysis. Maintenance post-CRT was poorly tolerated leading to high rate of discontinuation. Clinical trial information: NCT05784012 .
Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the pro-apoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics-based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.
