Explore the vast range of titles available.

High-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL. This trial has completed accrual. The primary outcome was complete response rate (CRR). Secondary outcomes were objective response rate (ORR), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), assessment of safety, central nervous system (CNS) relapse and blood levels of CAR T cells and cytokines. The primary endpoint in efficacy-evaluable patients ( n  = 37) was met, with 78% CRR (95% confidence interval (CI), 62–90) and 89% ORR (95% CI, 75–97). As of 17 May 2021 (median follow-up, 15.9 months), 73% of patients remained in objective response; median DOR, EFS and PFS were not reached. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in three patients (8%) and nine patients (23%), respectively. There were no treatment-related grade 5 events. Robust CAR T-cell expansion occurred in all patients with a median time to peak of 8 days. We conclude that axi-cel is highly effective as part of first-line therapy for high-risk LBCL, with a manageable safety profile. In a phase 2 trial, first-line treatment with axicabtagene ciloleucel, an autologous CD19-targeting CAR T-cell therapy, exhibited a high complete response rate and a manageable safety profile in adults with high-risk large B-cell lymphoma.

In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015–2021) vs. CAR-T (2018–2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT ( n  = 281) or commercial CAR-T ( n  = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p  < 0.001), a lower 2-year cumulative incidence of relapse (27.8% vs. 48% ; p  < 0.001), and a superior 2-year OS (78.9% vs. 65.6%; p  = 0.037). In patients with early (within 12 months) treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3% ; p  < 0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9% ; p  < 0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p  = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio 1.83; p  = 0.0011) and lower incidence of relapse (hazard ratio 2.18; p  < 0.0001) compared to CAR-T. In patients with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with improved clinical outcomes compared to CAR-T. These data support the consideration of auto-HCT in select patients with LBCL achieving a CR in the relapsed setting.

ObjectiveIdentifying 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 analysisPatients 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.ResultsOver 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.ConclusionsThe 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 numberNCT04981119.

In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes. In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization. A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival. At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

Key Clinical Message Atypical hemolytic uremic syndrome (aHUS) patients treated with eculizumab may require higher doses to achieve and maintain optimal clinical response. Further studies are warranted to elucidate optimal dosing regimens of eculizumab in aHUS patients, and whether dosing regimens can be predicted based on mutational status, eculizumab levels, or other testing. Atypical hemolytic uremic syndrome (aHUS) patients treated with eculizumab may require higher doses to achieve and maintain optimal clinical response. Further studies are warranted to elucidate optimal dosing regimens of eculizumab in aHUS patients, and whether dosing regimens can be predicted based on mutational status, eculizumab levels, or other testing.

Seronegative myasthenia gravis is a rare, but potential adverse effect of immune checkpoint inhibition. There have been few but increasing number of cases reported in recent years, and early recognition is important for prompt diagnosis and management. Here, we describe the case of a 65-year-old male with metastatic renal cell carcinoma on pembrolizumab diagnosed with new-onset seronegative myasthenia gravis and review literature on its management.Seronegative myasthenia gravis is a rare, but potential adverse effect of immune checkpoint inhibition. There have been few but increasing number of cases reported in recent years, and early recognition is important for prompt diagnosis and management. Here, we describe the case of a 65-year-old male with metastatic renal cell carcinoma on pembrolizumab diagnosed with new-onset seronegative myasthenia gravis and review literature on its management.

BackgroundMesothelin (MSLN) is overexpressed in many cancer types. Loss of heterozygosity (LOH) may provide a means to target tumor versus normal cells1 and to augment the efficacy and safety of MSLN-targeted programs2–4. A2B694 is an autologous, logic-gated, Tmod CAR T therapy to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR T activator with a human leukocyte antigen (HLA)-A*02 blocker (figure 1)5 6.MethodsThe first-in-human, open-label, phase 1/2 EVEREST-2 study is evaluating safety and efficacy 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 (RP2D). Phase 2 primary objective: assess overall response rate.ResultsAs of May 23, 2025, 7 patients were enrolled: 5 women/2 men, median age 59y, 6 non-Hispanic White/1 Hispanic with unknown race. Tumor types included ovarian (n=3), pancreatic (n=2), non-small cell lung adenocarcinoma (NSCLC; n=1), and colorectal (n=1). A2B694 dose groups were 1×108 (n=3) and 2×108 (n=4) cells. Lymphodepletion was well-tolerated, with expected, transient cytopenias. All patients had ≥1 adverse event, most commonly chest pain (non-cardiac), fatigue, and neutropenia (each in 4 patients) and anemia, cough, decreased appetite (1 serious), leukopenia, and lymphopenia (each in 3 patients). One patient had Grade 3 ICANS and was treated with a prolonged course (41 days) of dexamethasone. There were no dose-limiting toxicities, cytokine release syndrome, or new safety signals after 9 months of follow-up.All 7 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood and in a tumor biopsy collected on Day (D) 42, demonstrating that A2B694 persists in the tumor microenvironment (figure 2). Six patients had progressive disease by D90. The patient with KRASG12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion and had a confirmed CR per RECIST 1.1 by central review at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease.ConclusionsA2B694 has manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. CR per RECIST 1.1 was observed in 1 patient with KRASG12V/STK11 co-mutated NSCLC. The maximum tolerated dose has not been reached and the dose-escalation phase to determine the RP2D continues.AcknowledgementsThe authors would like to thank the patients, their families, and their caregivers for participating in this trial; the screeners, clinical research coordinators, study nurses, data managers, and apheresis teams at each study site; and A2 Bio. Medical writing support was provided by Jennifer M. Kulak, PhD, of ApotheCom (Yardley, PA) and funded by A2 Bio.Trial RegistrationClinicalTrials.gov, NCT06051695ReferencesHecht J, et al. Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity. J Clin Oncol. 2022;40(suppl 4):190.Beatty GL, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology. 2018;155:29–32.Haas AR, et al. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells. Mol Ther. 2023;31:2309–2325.Hong D, et al. 959O Gavocabtagene autoleucel (gavo-cel, TC-210) dose escalation in refractory mesothelin-expressing solid tumors. Ann Oncol. 2021;32(suppl 5):S830.Hamburger AE, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.Punekar SR, et al. EVEREST-2: Initial data of the logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy A2B694 for patients with solid tumors associated with mesothelin (MSLN) expression and with human leukocyte antigen (HLA) loss of heterozygosity (LOH). J Clin Oncol. 2025;43(16 suppl):3040.Ethics ApprovalThis trial was approved by each site’s institutional review board.Abstract 535 Figure 1The structure of Tmod CAR T cells expressing a MSLN-targeted activator and an HAL-A*02-targeted blocker[Image Omitted. See PDF.]Abstract 535 Figure 2A2B694 levels over time[Image Omitted. See PDF.]

BackgroundDespite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in 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, Tmod 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, decreasing the risk for graft-vs-host disease (ie, on-target, off-tumor toxicity).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 (figure 1).MethodsDENALI-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 colorectal, non-small cell lung, squamous cell head and neck, triple-negative breast, 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 phase 1 is to evaluate safety, tolerability, and the recommended phase 2 dose using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm recommended phase 2 dose and collect biomarker data. Phase 2 will assess overall response rate per RECIST v1.1.ResultsThe first patient was enrolled on DENALI-1 in May 2025. Dose escalation is ongoing (figure 2).AcknowledgementsThe authors would like to thank the patients, their families, and their caregivers for participating in this trial; the screeners, clinical research coordinators, study nurses, data managers, and apheresis teams at each study site; and A2 Bio. Medical writing support was provided by Jennifer M. Kulak, PhD, of ApotheCom (Yardley, PA) and funded by A2 Bio.Trial RegistrationClinicalTrials.gov, NCT06682793ReferencesThe Cancer Genome Atlas (TCGA) Research Network. Accessed June 2021. https://www.cancer.gov/tcgaMacdonald JB, et al. Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol. 2015;72(2):203–218.Hamburger AE, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.DiAndreth B, et al. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030.Grierson PM, et al. 588 EVEREST-1: initial safety data from a seamless phase 1/2 study of A2B530, a logic-gated Tmod CAR T-cell therapy, in patients with solid tumors associated with CEA expression also exhibiting HLA-LOH. J ImmunoTher Cancer. 2024;12(Suppl_2):A670-A671.Kirtane K, et al. Logic-gated, allogeneic Tmod chimeric antigen receptor T-cell (CAR T) therapy targeting epidermal growth factor receptor (EGFR) in advanced solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH): DENALI-1 trial. J Clin Oncol. 2025;43(16 suppl): TPS2677.Ethics ApprovalThis trial was approved by each site’s institutional review board.Abstract 585 Figure 1Logic-Gated CAR T With the Goal to Reduce Toxicity: MSLN (Activator) and HLA-A*02 (Blocker) [6][Image Omitted. See PDF.]Abstract 585 Figure 2DENALI 1 dose escalation study design[Image Omitted. See PDF.]