Addgene

Introduction: Chemo-free targeted therapies, which are safe and effective, are increasingly sought for older MCL patients. We investigated acalabrutinib with rituximab (AR) as an initial treatment for patients with MCL Methods: We enrolled 50 previously untreated patients in this single-institution, single-arm Phase 2 trial (NCT05214183). Patients received acalabrutinib 100 mg orally twice daily and rituximab weekly for four weeks, then monthly for 12 months, and every two months up to 24 months. Acalabrutinib was continued beyond 24 months. The primary objective was to evaluate the best overall response rate (ORR) after AR. ClonoSEQ-based MRD assessment and multiomic analysis were conducted on serial blood, plasma, and tissue samples Results: Among 50 pts, the median age was 69 years (range: 65–81). Forty-six pts had classic, 3 had blastoid, and 1 was pleomorphic morphology. TP53 aberration status (mutations or deletion) was available in 43/50 pts and 12 pts had aberrant TP53. High risk MCL in 20/50 pts (40%). One pt was not evaluable for response at 12 weeks. Best PET-CT response at 12 weeks was 93%, 78%, 16% and 7% for overall, CR, PR and NR. Early responder pts (CR at end of 12 weeks) were 80% (37/50), and late responders (PR), 20% (9/46). Best PET-CT based response rates were 94% ORR and 94% CR; 6% were non-responders. The study met its primary end point of 40% CR at end of 12 weeks. MRD assessments at 3, 6, 12, 18 and 24 months in evaluable patients, demonstrated an MRD negative rate of 30%, 54%, 87%, 92% and 93% respectively. With a median follow up of 38.7 months, the overall median PFS and OS were not reached (3-year PFS 84%, OS 94%). 3-year PFS in pts with aberrant TP53 was 71% and 86% in wile type TP53 (p = NS). Survival outcomes were not significantly different between various prognostic subgroups, however, ultra-high-risk pts (> 1 high risk factor) had significantly inferior PFS of 15.7 months compared to low and high-risk pts. Nineteen pts (38%) came off study (5 for disease progression). Overall, 3 pts died (2 with primary progression and another with unknown reason in remission). The most common all-grade toxicities were fatigue (86%), myalgia (70%), diarrhea (60%), infections (54%), headache (40%), 1% toxicities were grade 3 or higher. One pt had recurrence of grade 2 atrial fibrillation (2%), one pt had palpitations grade 2 and one pt had recurrence of grade 3 unstable angina. Early responders had significant amplification of PI3KCA and TBL1XR1 genes. Serial blood RNA-seq detected significant sustained reduction in SOX11 (p < 0.0001) and B-cell gene expression (p = 0.01). Paired sample single cell RNA sequencing in primary refractory case demonstrated high fraction of clonal B cells and exhausted CD8 T cells at progression. CD8 effector memory T cells were elevated in late responders and high-risk patients Conclusions: AR combination is highly effective, safe, and impacts the genomic and immune landscape in older MCL patients Research funding declaration: Astra Zeneca, Lymphoma research Foundation Carrier development award grant Keywords: genomics, epigenomics, and other -omics; aggressive b-cell non-Hodgkin lymphoma; combination therapies Potential sources of conflict of interest: P. Jain Employment or leadership position: NA Consultant or advisory role: Eli Lilly, Kite, Astra Zeneca, LOXO Oncology, Incyte, Janssen-PCYC, Kite, Expert perspectives Stock ownership: NA Honoraria: Aptitude Health, Pharmacy times, Dava Oncology, Adaptive biotech, Eli Lilly, Beigene, Genentech Educational grants: NA Other remuneration: NA

Abstract Background: Protein arginine methyltransferase 5 (PRMT5) is an enzyme that methylates substrates involved in cellular activities, including transcription, RNA splicing, DNA damage repair, apoptosis, and cell-cycle regulation, and may act as an oncogene in multiple tumor types. Overexpression of PRMT5 is associated with poor clinical outcomes in a variety of cancers, including lung, colon, pancreas, and bladder cancer, and glioblastoma multiforme. Homozygous loss of the methylthioadenosine phosphorylase (MTAP) gene occurs in 15% of all tumor types, leading to the accumulation of methylthioadenosine (MTA), which partially inhibits PRMT5 and increases the susceptibility of these tumor cells to additional PRMT5 inhibition. BGB-58067 is an oral, highly potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that selectively inhibits PRMT5 in tumors with MTAP deletion. Preclinical evidence has shown the effectiveness of BGB-58067 in inhibiting PRMT5-mediated signaling and in its in vivo antitumor activity. Methods: This study is a first-in-human, phase 1a/b, open-label, international, multicenter trial to evaluate the safety/tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of BGB-58067 in patients with advanced solid tumors with MTAP deficiency (NCT06589596). In the dose-escalation and safety-expansion phase (phase 1a), sequential cohorts of patients will receive increasing dose levels of BGB-58067 given orally as monotherapy. In the dose-expansion and optimization phase (phase 1b), patients with select tumor types will receive BGB-58067 at the recommended dose(s) for expansion (RDFE[s]). Eligible patients are ≥18 years of age with pathologically confirmed advanced, metastatic, or unresectable solid tumors who have previously received standard systemic therapy or for whom treatment is not available or tolerated and with evidence of homozygous loss of the MTAP gene or lost MTAP expression in the tumor tissue. For phase 1a, the primary objectives are to assess the safety/tolerability of BGB-58067 and to determine the maximum tolerated dose or maximum administered dose and RDFE(s); secondary objectives are to assess the preliminary antitumor activity (objective response rate [ORR], duration of response [DOR], and disease control rate [DCR], per investigator) and PK of BGB-58067. For phase 1b, the primary objectives are to determine the recommended phase 2 dose and to assess the antitumor activity (ORR per investigator); secondary objectives are to further assess antitumor activity (DOR, DCR and progression-free survival per investigator) and safety/tolerability of BGB-58067. As of December 2024, the trial is actively recruiting patients in Australia, China, and the United States. Citation Format: Brian A. Van Tine, Timothy Humphries, Sophie Postel-Vinay, Hui Gan, Ugonma Chuwueke, Tai Qin, Hayden Huang, Chunyu Wang, Yan Dong, Caicun Zhou. Trial in progress: A first-in-human phase 1a/b study of BGB-58067, an MTA-cooperative PRMT5 inhibitor, in patients with advanced solid tumors and MTAP deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT193.

Antibody-based research applications are critical for biological discovery. Yet there are no industry standards for comparing the performance of antibodies in various applications. We describe a knockout cell line-based antibody characterization platform, developed and approved jointly by industry and academic researchers, that enables the systematic comparison of antibody performance in western blot, immunoprecipitation and immunofluorescence. The scalable protocols, which require minimal technological resources, consist of (1) the identification of appropriate cell lines for antibody characterization studies, (2) development/contribution of isogenic knockout controls, and (3) a series of antibody characterization procedures focused on the most common applications of antibodies in research. We provide examples of expected outcomes to guide antibody users in evaluating antibody performance. Central to our approach is advocating for transparent and open data sharing, enabling a community effort to identify specific antibodies for all human proteins. Mid-level graduate students with training in biochemistry and prior experience in cell culture and microscopy can complete the protocols for a specific protein within 1 month while working part-time on this effort. Antibody characterization is needed to meet standards for resource validation and data reproducibility, which are increasingly required by journals and funding agencies.