Citations

8579 Background: LOH may provide a means to target tumor versus normal cells, to augment the efficacy and safety of MSLN-targeted programs (Hecht et al. JCO . 2022). A2B694 is an autologous, logic-gated, Tmod CAR T therapy designed to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR activator with an HLA-A*02 blocker (Hamburger et al. Mol Imm. 2020). Methods: The first-in-human, open-label, phase 1/2 EVEREST-2 (NCT06051695) study of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose. Results: As of 05 January 2026, 13 patients were enrolled: 8 women/5 men, median age 59 years, 11 non-Hispanic White/2 Hispanic with unknown race. Tumor types included colorectal (n = 4), ovarian (n = 3), pancreatic (n = 3), non–small cell lung adenocarcinoma (NSCLC), gastro-esophageal, and mesothelioma (n = 1 each). A2B694 dose level (DL) groups were: DL1: 1×10 8 cells (n = 3), DL2: 2×10 8 cells (n = 4), DL3: 4×10 8 cells (n = 5), and DL4: 6×10 8 cells plus low-dose IL-2 (n = 1). Lymphodepletion prior to administration of A2B694 was well-tolerated, with expected, transient cytopenias. The only adverse event reported in more than 1 patient was grade 3 neutropenia. One patient had grade 3 ICANS and 1 patient had grade 1 CRS. There were no dose-limiting toxicities or new safety signals after up to 17 months follow-up. All 13 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood. While A2B694 was not detected in tumor biopsies collected in patients treated at DL1 (0/2), all patients treated at DL2-DL4 with available biopsies (3/3) had detectable A2B694 in the tumor microenvironment. A patient with KRAS G12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion per RECIST 1.1 by central review and had a confirmed CR at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease. On D243, the patient had a CNS relapse, with an ongoing non-CNS CR per RANO-BM at D284. At M12, the patient's CT showed no new findings and persistence of A2B694 in the blood was confirmed by ddPCR. Conclusions: We report the first patient with NSCLC to have a CR after CAR T. Overall, A2B694 demonstrated manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The maximum tolerated dose has not been reached; dose-escalation continues. Clinical trial information: NCT06051695 .

Objective Identifying eligible patients for precision oncology clinical trials is challenging, particularly for rare molecular subpopulations. To address this challenge, A2 Biotherapeutics developed BASECAMP-1 ( NCT04981119 ), a non-interventional master screening study to identify patients eligible for interventional studies of logic-gated Tmod chimeric antigen receptor T-cell therapies. Eligible patients for these interventional trials have an advanced solid malignancy and are germline human leucocyte antigen (HLA)-A*02 heterozygous, with tumour-associated HLA-A loss of heterozygosity (LOH). HLA-A LOH occurs in ~16% of advanced solid malignancies; therefore, an efficient screening strategy is required. This report describes BASECAMP-1; compares the efficiency of two screening methods; and discusses the broader advantages of BASECAMP-1 beyond efficient enrolment. Methods and analysis Patients are identified for BASECAMP-1 using two approaches. In the traditional approach, common for clinical trials, investigators consent and screen all patients who might be good candidates for cell therapy trials, with no prior knowledge of patient HLA-A type or LOH status. To further optimise our approach, we co-developed with Tempus AI (Tempus) the bioinformatic programme Aware, which identifies potentially eligible patients with tumour-associated HLA-A*02 LOH within a clinico-genomic database that includes linked genomic and transcriptomic sequencing and clinical data collected during routine care. Results Over 42 months of using a traditional approach to identify eligible patients, 1918 patients at 13 study sites were consented and screened for BASECAMP-1; of these, 30 patients with tumour-associated HLA-A*02 LOH were enrolled (~0.7 participants per month). Over the last 30 months of that same period, Tempus Aware screening was implemented and 55 patients with tumour-associated HLA-A*02 LOH were enrolled (~1.8 participants per month). The bioinformatic approach identified more patients than the traditional approach and used sequencing results produced as part of the standard clinical tumour sequencing workflow, reducing resource use and study staff burden. Additional advantages of using a screening study, such as BASECAMP-1, include manufacturing efficiencies and collection of a large dataset of molecular and clinical parameters that can be used to supplement trial analyses. Conclusions The BASECAMP-1 study demonstrates a clinico-genomic screening approach can more efficiently identify patients for precision oncology trials. Furthermore, precision oncology can be enhanced through collaborative data-sharing. Trial registration number NCT04981119 .

Abstract Background: Despite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in breast cancer and other solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated [1]. While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy [2]. A2B395 is an allogeneic, logic-gated, EGFR-targeted, TmodTM CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells (with preserved HLA expression) while allowing activation against tumor cells (with HLA-A*02 loss of heterozygosity [LOH]). This approach is designed to avoid on-target, off-tumor toxicity, a significant limitation to CAR T treatment of solid tumors [3]. To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response [4]. Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy [5]. A2B395 represents a novel approach for targeting EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity. Methods: DENALI-1 is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity at any time in the course of their disease via next-generation sequencing. Key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including triple-negative breast, colorectal, non-small cell lung, squamous cell head and neck, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of the phase 1 portion is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm the RP2D and collect and analyze biomarker data. The Phase 2 portion will assess overall response rate per RECIST v1.1. As of 03 July 2025, the first patient dosed with A2B395, who has breast cancer, completed the 28-day safety review period. Dose-escalation is ongoing. Citation Format: J. M. Specht, S. R. Punekar, M. Ulrickson, D. J. Wong, J. R. Hecht, M. Maus, P. M. Grierson, J. B. Sunwoo, J. R. Molina, D. G. Maloney, K. Spencer, H. E. Fuentes Bayne, M. Davila, S. P. Patel, B. Creelan, D. B. Zhen, J. Niu, D. C. Prasad, R. L. Marar, N. A. Bagegni, G. Palluconi, J. Lee, A. Mardiros, W. Bretzlaff, W. J. Langeberg, J. S. Welch, E. Ng, W. Y. Go, K. Kirtane, R. A. Shatsky. Denali-1: a seamless phase 1/2 study of A2B395, a logic-gated, allogeneic, Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with triple-negative breast cancer and other EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity (LOH) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-03.

Abstract Background: Advantages of covalent Bruton Tyrosine Kinase inhibitor (cBTKi) treatment (tx), as compared to BCL2 inhibitor (BCL2i) containing regimens, include ease of initial administration without a requirement for frequent laboratory monitoring, even in patients (pts) with bulky disease. However, limitations of cBTKi monotherapy include acquired resistance, cumulative toxicity and the financial burden associated with continuous administration. CLL pts treated on the E1912 study who discontinued (dc) ibrutinib for reasons other than progression of disease (PD) had a median progression free survival (PFS) of ~2.7 years from ibrutinib dc, suggesting that a time-limited cBTKi strategy may be feasible for some pts(Shanafelt et al. Blood Advances 2025). We hypothesized that acalabrutinib (acala) and obinutuzumab (O) could be administered as a time-limited initial tx for CLL with duration guided by minimal residual disease (MRD). Methods: This is an ongoing phase II, multicenter, investigator-initiated study of acala and O for previously untx pts with CLL/small lymphocytic lymphoma (SLL) requiring tx per iwCLL 2018 criteria (NCT04722172). Pts with TP53 aberrancy are excluded. Pts receive acala 100 mg twice daily and O during 28-day cycles (C) 2-7. Undetectable MRD is defined with a 10-4 sensitivity in the peripheral blood (PB) by ClonoSeq next generation sequencing (uMRD4). Pts undergo MRD testing at C13; if uMRD4 at C13 with a complete response (CR) or partial response (PR), pts dc acala and enter tx free observation (TFO). If detectable MRD4 (dMRD4) at C13, pts continue acala until uMRD4, with repeat MRD testing occurring at C16, 19, 22 and 25. All pts dc acala after a maximum of 26C and enter TFO, even if dMRD4. If pts have PD meeting iwCLL criteria for tx during TFO, re-tx consists of acala + 6 cycles of O. Pts are followed for 13C of re-tx. Primary endpoint is 36-month PFS. Results: 55 pts initiated tx. Baseline characteristics include: median age 67, 64% male, 47% LN ≥ 5 cm, 73% IGHV unmutated. Best overall response rate (ORR) was 95% (CR: 4, PR: 48, SD: 0, PD: 1, unknown: 2). Best uMRD4 rate at any time during the study was 49% (n=27 pts, intention-to-treat, IIT). 5 pts dc tx prior to C13 MRD testing (2 pt decision, 2 AE, 1 due to PD after ~4C). At C13, 22 pts (40% of IIT) were uMRD4; 21 entered TFO after 13C and 1 pt had 19C tx prior to TFO. 28 pts had dMRD4 (51% ITT) at C13. Between C13 and 26, 2 pts became uMRD4 and entered TFO, 1 pt died (COVID-19), and 2 pts stopped acala for tx of other cancers. 21 pts completed 26C acala per protocol prior to entering TFO; 2 additional pts had PD at C25 and EOT. Median tx duration was 19C. In univariate analyses, age, del11q, del13q, IGHV mutational status and baseline LN ≥ 5 cm were not predictive of uMRD4 at C13. At a median follow-up of 38 months, the median PFS for the overall cohort is 42 months (95% confidence interval (CI): 37, not reached), with an estimated 36-month PFS of 69% (95% CI: 57%, 84%). At data cutoff, of 46 pts entering TFO, 29 pts remained in TFO without PD, 7 pts had PD during TFO but had not met iwCLL criteria for re-tx, and 10 pts had PD requiring tx (5 pts re-tx pe protocol, 5 came off study for non-protocol tx approach). The overall median TFO period (measured from acala dc to PD) was 25 months (95% CI: 21 – not reached, n=46 pts). 5 pts have initiated re-tx with acala + O (1 pt best response PR and uMRD4; 4 ongoing tx). Median time to re-tx was 18 months (range 6-34, n=5 pts). Conclusions: This study is proof-of-concept that cBTKi may be administered as a time-limited tx without the addition of a BCL2i. While the initial PFS is shorter than historical studies examining continuous cBTKi, of patients entering TFO after 1-2 years of acala, the median duration of TFO until PD is 25 months, and longer follow-up will provide re-tx outcomes. Potential advantages to MRD-guided, time-limited cBTKi tx include time off tx for pts, limiting acquired resistance, the ability to re-challenge with cBTKi at progression, and reserving BCL2i for third-line or later tx.

Abstract BACKGROUND Bevacizumab, an anti-VEGF monoclonal antibody, has become a mainstay in the management of malignant gliomas. Multiple bevacizumab biosimilars have been approved since initial FDA approval of the reference agent and have seen widespread use due to reduced cost. However, real-world data evaluating comparability between reference and biosimilar agents have remained limited. METHODS We performed a retrospective analysis of patients treated with reference bevacizumab (Avastin) versus those receiving bevacizumab-bvzr, a widely used biosimilar agent (Zirabev) for the management of malignant glioma at our institution between 2019 and 2022. RESULTS A total of 161 patients were included in our final analysis; 97 received reference drug (Avastin) while 64 received the biosimilar agent (Zirabev). Demographics and baseline clinical characteristics between the two groups were similar. We performed survival analysis with post-progression survival (PPS) to ensure against lead-time bias. PPS was similar between the Avastin (median PPS 496 days) and Zirabev (median PPS 513 days) groups on univariate analysis (p=0.7654). Similarly, on multivariate Cox regression, there were no differences in PPS when comparing Avastin and Zirabev (HR 1.0673, p=0.6986). MGMT promoter methylation (HR 0.5709, p=0.0238), age at cancer diagnosis (HR 1.0356, p=0.0009), total dose of bevacizumab received (HR 0.9975, p=0.0087) and treatment with anticoagulation (HR 1.8086, p=0.0372) were significantly associated with PPS. Rates of therapy-related adverse effects were also similar between those receiving the reference drug and biosimilar agent (OR 0.9043, p=0.7824). However, concomitant treatment with antiplatelet therapy (OR 3.1447, p=0.0150) or anticoagulant therapy (OR 4.9069, p=0.0010) were significantly associated with increased risk for adverse effects. CONCLUSIONS Bevacizumab-bvzr demonstrated similar clinical efficacy and safety profile compared to reference bevacizumab in our institutional cohort. Concomitant treatment with antiplatelet therapy (OR 3.1447, p=0.0150) or anticoagulation (OR 4.9069, p=0.0010) were significantly associated with increased risk for adverse effects.

Purpose of review The rapid growth and integration of artificial intelligence in healthcare has the potential to revolutionize all fields of medicine, including anesthesiology. This review summarizes the role of artificial intelligence in anesthesiology, highlighting how it can enhance patient safety, workflow efficiency, and research capabilities, while also examining the potential risks and ethical issues of introducing this new technology. Recent findings Evolving applications in anesthesiology include closed-loop anesthetic delivery, risk stratification, intraoperative monitoring, natural language processing for literature synthesis, and predictive modeling for adverse events. While these tools offer significant promise for improving efficiency and safety, emerging risks, such as algorithmic bias, lack of transparency, hallucinations, and automation complacency – must be carefully addressed. Regulatory frameworks, clinician education, and transparent model development are necessary to ensure responsible integration. Summary Artificial intelligence is poised to transform anesthetic care, but it must be developed and deployed with caution. Clinician oversight, robust validation, and ethical safeguards are essential to ensure artificial intelligence enhances, rather than replaces, clinical judgment. Strategic adoption can improve patient outcomes, reduce preventable harm, and streamline perioperative workflows.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of postthymic T cell neoplasms, with ~40% classified as PTCL–not otherwise specified (PTCL-NOS). PTCL-GATA3, a molecularly defined subtype, associated with T helper 2 (T H 2)–like differentiation and poor prognosis, has frequent co-occurrence of TP53 loss/mutation and heterozygous PTEN loss. CD4+ T cell conditional mouse models with Trp53 mutation/deletion and Pten loss demonstrated mature T cell lymphomas (mTCLs) with T H 2-like transcriptomic and immunophenotypic profiles. Molecular studies revealed that codeletion of Trp53/Pten induced T cell receptor and Janus kinase–signal transducer and activator of transcription signaling, promoting T H 2 differentiation while inhibiting T H 1 differentiation. These findings were validated by CRISPR editing of TP53/PTEN loss in human CD4+ T cells and mechanistically evaluated the p53 binding region in intron-3 of GATA3, resulting in transcriptional repression. Transcriptomic profiles of m-TCLs recapitulated human-PTCL-GATA3 transcriptome and distinguished PTCL-NOS subtypes. Preclinical assessment of m-TCLs with PI3Kγ/δ inhibitors significantly improved survival, supporting a therapeutic approach for the p53-aberrant PTCL-GATA3.