Citations

Abstract Translational large-animal models that can accommodate human-scale implantable devices are essential for advancing neuromodulation therapies in epilepsy. This study establishes a kainic acid (KA)-induced porcine model of mesial temporal lobe epilepsy (mTLE) using clinical imaging, stereotactic surgery, and a fully implantable neural stimulation and recording (INSR) device designed for humans. Seven pigs (six KA-treated and one saline control) underwent MRI-guided stereotactic implantation of electrodes targeting bilateral hippocampus (HPC) and anterior thalamus (ANT), followed by intra-hippocampal KA or saline infusion. Local field potentials (LFP) were recorded continuously with synchronized video monitoring. Seizures and LFP interictal epileptiform-like discharges (IEDs) were quantified using validated automated detectors. Histology was performed in the saline control and the longest surviving KA-treated pig. Intra-hippocampal KA infusion induced acute status epilepticus in all (6/6) treated pigs. Four animals survived to chronic monitoring with spontaneous seizures observed in three pigs (2,733 seizures; mean duration of 27.2 ± 17.6 seconds). IEDs were observed in bilateral HPC of all animals, including saline control, with higher rates in the lesioned HPC (p <0.0001). While the IED morphology is consistent with epileptiform activity; IEDs alone are not specific for epilepsy and physiological transients (e.g. sharp-wave ripples) and injury-related hyperexcitability or strain-specific hyperexcitability cannot be excluded. Histological analysis revealed patchy neuronal loss and cytoarchitectural changes in HPC. This porcine model reproduces electrophysiological features of human mTLE. This approach provides a powerful translational bridge for developing and testing next-generation INSR and neuromodulation strategies in freely behaving large animals.

Abstract Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post–CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell–associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.

OBJECTIVE This study aimed to evaluate local control (LC) of tumors, patient overall survival (OS), and the safety of stereotactic radiosurgery (SRS) for esophageal cancer brain metastases (EBMs). METHODS This retrospective cohort study used data from 15 International Radiosurgery Research Foundation facilities encompassing 67 patients with 185 EBMs managed using SRS between January 2000 and May 2022. The median patient age was 63 years, with a male predominance (92.5%). Most patients (64.2%) had a single brain metastasis, while 7.5% had more than 5 metastases. The median tumor volume was 0.9 cm 3 , and the median margin dose delivered to the tumor was 20 Gy. RESULTS The median OS post-SRS was 15.2 months, with 1- and 2-year OS rates of 65.7% and 32.3%, respectively. A significant inverse correlation was found between the number of EBMs and OS in the univariable analysis. LC rates at 1 and 2 years were 89% and 76%, respectively. Adverse radiation effects (AREs) were observed in 17.9% of patients, with 13.4% being mild and transient and 4.5% severely symptomatic (Common Terminology Criteria for Adverse Events grade 3). New intracranial disease developed in 58.2% of patients, with 1- and 2-year rates of 58% and 73%, respectively. CONCLUSIONS SRS for EBMs demonstrated high survival rates and effective tumor control, with a low incidence of severe AREs. These findings highlight the potential role of SRS in the multidisciplinary multimodality management paradigm of EBM.

Introduction Patients (pts) with progressive disease after ≥2 prior lines of systemic therapy are unlikely to derive additional benefit from current salvage immunochemotherapies, and survival declines significantly with each subsequent treatment. Pts with refractory disease following second-line therapy have worse outcomes, with reported overall response rates (ORRs) of 1% to 14% and overall survival (OS) of 5 months (Blood. 2017;130[16]:1800-1808). While chimeric antigen receptor (CAR) T-cell therapy has become a preferred strategy in the second- and third-line settings, pts with R/R disease following CAR-T experience dismal survival, with progression-free survival (PFS) and OS as low as 3 and 5 months, respectively, and no agreed standard of care post CAR-T (Blood. 2022;140[24]:2527-2529). The randomized, global, phase 3 ECHELON-3 study (NCT04404283) was conducted in pts with R/R DLBCL after ≥2 prior therapies who were ineligible for hematopoietic stem cell transplant and/or CAR-T. Here, we present subgroup analyses in pts with 2 prior lines of therapy, refractory disease, or prior CAR-T. Methods In these subgroup analyses of ECHELON-3, eligible pts had 2 prior lines of systemic therapy, disease refractory to the last prior therapy, or prior exposure to CAR-T. Pts could qualify for ≥1 subgroup and were analyzed separately. Refractory disease was defined as stable or progressive disease as best overall response to last line of treatment or relapse ≤6 months from the end of treatment. Pts were randomized 1:1 to receive brentuximab vedotin (BV; 1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with rituximab (R; 375 mg/m2) q3w and lenalidomide (Len; 20 mg) once daily. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. P values are descriptive. Results In total, 230 pts were enrolled in ECHELON-3 from April 2021 to November 2023, with a median follow-up of 16.4 months (range, 0.1-31.5 months). Overall, 94 pts with 2 prior lines of systemic therapy were enrolled and randomized to BV+Len+R (n=48) or placebo+Len+R (n=46). Median OS was 16.3 months (95% CI, 12.6 months-not estimable) with BV+Len+R vs 8.5 months (95% CI, 4.1-15.8 months) with placebo+Len+R (hazard ratio [HR], 0.557; 95% CI, 0.317-0.977; P=.0388). Median PFS was 7.1 months (95% CI, 3.6-12.6 months) with BV+Len+R vs 2.7 months (95% CI, 1.4-4.0 months) with placebo+Len+R (HR, 0.462; 95% CI, 0.279-0.764; P=.0020). ORR was 68.8% (95% CI, 53.7%-81.3%) with BV+Len+R vs 43.5% with placebo+Len+R (95% CI, 28.9%-58.9%; P=.0216); complete response (CR) rate was 52.1% vs 13.0%, respectively. Additional data for pts by lines of therapy received will be presented. In total, 194 pts with disease refractory to the most recent systemic therapy were enrolled and randomized to BV+Len+R (n=98) and placebo+Len+R (n=96). Median OS was 11.7 months (95% CI, 8.8-16.3 months) with BV+Len+R vs 5.5 months (95% CI, 3.7-8.5 months) with placebo+Len+R (HR, 0.566; 95% CI, 0.396-0.808; P=.0015). Median PFS was 4.1 months (95% CI, 2.8-5.4 months) with BV+Len+R vs 1.5 months (95% CI, 1.4-2.6 months) with placebo+Len+R (HR, 0.508; 95% CI, 0.363-0.712; P&lt;.0001). ORR was 59.2% (95% CI, 48.8%-69.0%) with BV+Len+R vs 29.2% (95% CI, 20.3%-39.3%) with placebo+Len+R (P&lt;.0001); CR rate was 34.7% vs 11.5%, respectively. Overall, 67 pts who received prior CAR-T were enrolled and randomized to BV+Len+R (n=32) and placebo+Len+R (n=35). Median OS was 15.6 months with BV+Len+R vs 4.4 months with placebo+Len+R (HR, 0.38; 95% CI, 0.2-0.75). Median PFS was 3.0 months with BV+Len+R vs 1.4 months with placebo+Len+R (HR, 0.41; 95% CI, 0.22-0.76). ORR was 65.6% (95% CI, 46.8%-81.4%) with BV+Len+R vs 25.7% (95% CI, 12.5%-43.3%) with placebo+Len+R (P=.0014); CR rate was 37.5% vs 11.4%, respectively. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes, including CR and OS, in pts with 2 prior lines of therapy, disease refractory to prior treatment, or prior CAR-T. This treatment benefit was generally consistent with that observed in the overall ECHELON-3 study population. Therefore, BV+Len+R has the potential to address an unmet need for effective and tolerable therapy in heavily pretreated pts, as described above.

Multiple myeloma (MM), an incurable hematologic malignancy, presents significant challenges in managing its recurrence. The bone marrow tumor microenvironment (BM-TME) is critical to MM progression. However, classical immune checkpoint blockade (ICB) therapies, like anti-PD1, have shown limited efficacy in MM. Therefore, elucidating the compositional features and regulatory mechanisms of the TIME in MM is crucial for developing novel immunotherapeutic targets. Tissue-resident memory CD8+ T cells (CD8+ TRMs) reside indefinitely at multiple anatomical locations like the skin, intestine, and bone marrow, functioning as frontline responders against reencountered pathogens and tumors. Whether CD8+ TRMs within BM-TME are involved in the MM cell immune escape and pathogenesis has not been systematically elucidated. Firstly, we leverage single-cell RNA sequencing (scRNA-seq) to dissect the BM CD8+ T cells across patients at different stages of MM, and identify that CD69+CD8+ T subsets were BM residents, and the proportion of BM CD8+ TRMs between health donors and MM patients was comparable. Moreover, our findings indicated that BM CD8+ TRMs exhibit exhausted features and enrichment of NK genes with MM progresses. Importantly, we observed a considerable elevation of the NK gene KLRB1 and its encoded protein CD161 in BM CD8+ TRMs in MM patients. Immunofluorescence labeling of BM biopsy samples from MM patients confirmed the infiltration of the BM-TME with CD3+CD8+CD69+CD161+ cells. Then, we found that KLRB1 expression in BM CD8+ TRMs was higher than that of other classical inhibitory receptor genes (e.g., PDCD1, CTLA4, LAG3), and CLEC2D (encodes the ligand of CD161) was also markedly expressed in patients' MM cells, exhibiting considerably higher than classical immunosuppressive receptor ligand genes (e.g., PDL1, CD80, CD86). Moreover, patients with higher CLEC2D expression had unfavorable overall survival. We further found that the CD161 expression was higher in CD69+CD8+ TRMs compared to circulating CD69-CD8+ T cells, and the percentage of BM CD161+CD8+ TRMs in MM patients was significantly higher than in healthy donors, while there was no difference for PD-1, LAG3, and TIM3 expression. Notably, only a small fraction of BM CD8+ TRMs have mucosal-associated invariant T cell phenotypes (identified by CD161+TCR-Vα7.2+). Additionally, the CLEC2D expression of BM cells was analyzed, and the highest level of CLEC2D expression was observed in B cells from MM patients, followed by plasma cells. Importantly, CLEC2D expression in MM patients was significantly higher than in plasma cells from healthy donors. Next, to investigate whether the blockade of CD161 could restore the function of CD8+ TRMs, the primary BM cells from MM patients were isolated and stimulated ex vivo. Compared to the anti-PD-1 and isotype group, CD161 blocking presents enhanced CD8+ TRMs proliferation and cytokine secretion levels (TNF-α, IFN-γ, IL2), increasing MM cells apoptosis. Chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in treating relapsed/refractory MM. How to prevent CAR-T cell exhaustion and enhance function remains a significant challenge. Therefore, we next set out to investigate the impact of CD161 on CAR-T cells. Our results demonstrated that CD161 was highly expressed in early peripheral blood (PB) CAR-T cells after infusion in MM patients but decreased with time. Moreover, the CD161 expression of CAR-T cells was considerably higher than endogenous T cells. Notably, BM-derived CAR-T cells have higher CD161 expression than PB counterparts for the same patient, suggesting CD161 may have BM-specific expression enrichment. After co-culturing MM and CAR-T cells in vitro for 24 hours, we found that blocking CD161 led to an augmented proportion of CAR-T cells, increased IFN-γ secretion, and a notable elevation in tumor cell apoptosis compared to the anti-PD-1 and isotype groups. Taken together, we demonstrated that CD8+ TRMs constitute a vital anti-tumor cell subset in the MM BM-TME, which exhibits a high expression of the inhibitory CD161 receptor, binding to the CLEC2D expressed by MM cells, thereby mediating the dysfunction of CD8+ TRMs. Blocking the CD161-CLEC2D pathway is expected to become a novel target for MM immunotherapy. The combination of CD161 inhibitors and CAR-T cell therapy can potentially enhance the anti-myeloma function of CAR-T cells.

Introduction E1910 randomized pts with ALL aged 30-70 years who were measurable residual disease negative (MRD-) by multi-color flow cytometry (FC) after intensification to conventional chemotherapy (chemo) with or without blinatumomab (blina). The addition of blina resulted in improved overall survival (OS) (Litzow, NEJM 2024) and led to a new standard of care. Older ALL pts have inferior outcomes when compared to younger pts in part due to increased treatment toxicity. In E1910, exposure to dexamethasone and pegasparagase was reduced for older pts (age &gt;55 years). We present results of subgroup analyses describing outcomes of older pts enrolled in E1910. Methods Details of the E1910 protocol remission induction (step 1), high dose methotrexate with pegaspargase intensification (step 2), blina randomization (step 3), and maintenance (step 4) or allogeneic hematopoietic stem cell transplant (HCT) were previously presented (Litzow, NEJM 2024). MRD status was determined after step 2 centrally with 6-color FC with MRD- defined as &lt;0.01% in the bone marrow (BM). Following approval of blina in the US for MRD positive (MRD+) disease in 2018, MRD+ pts were assigned to the blina arm and no longer randomized. The primary objective was to compare the OS and relapse free survival (RFS) among older pts aged &gt;55 years (pre-specified stratification factor) who received chemo + blina to that of pts who received chemo alone (step 3 treatment). Estimates of OS and RFS were calculated using the Kaplan-Meier method. Comparison of OS and RFS between treatment arms was conducted using the two-sided stratified log-rank test and Cox model with CD20 status, rituximab use, and whether pts intended to receive HCT or not as stratification factors. Stratified Multivariate Cox models of OS and RFS were used to further evaluate the effect of step 3 treatment, adjusted by gender, white blood cell count (WBC), platelets, hemoglobin, peripheral blood blasts, BM blasts, performance status and combined molecular risk category. Results Among the 488 enrolled pts, 211 were ≥55 years old with median age of 61 (range 55-70). Among older pts, 49.3% were female and 83.4% were white, 17 (8.1%) pts had WBC &gt;30.000/uL at the time of diagnosis. 156 (73.9%) pts had CD10+ early B-ALL and 46 (21.8%) had CD10- B-ALL immunophenotype. The most common genetic subgroups were low hypodiploid (n=58, 27.5%), BCR::ABL1-like (n=34, 16.1%) and KMT2A rearranged (n=26, 12.3%). 8.1% of pts had low, 9.0% intermediate, 63.5% high combined molecular risk disease and in 19.4% of pts risk could not be assigned. Baseline characteristics were not significantly different in chemo + blina and chemo only pts. The median follow-up for this analysis from step 1 registration was 54.6 months. Complete response with (CR) or without (CRi) count recovery after induction was observed in 174 (82.5%) pts (167 CR, 7 CRi). 93 (44%) pts were MRD-. 32 (15.1%) pts received HCT on study and 24 (11.4%) pts received it off study. Among MRD- pts (n=93), 46 were randomized to and 45 received blina: 6 (13.3%) pts had 1, 14 (31.1%) had 2, 2 (4.4%) had 3 and 23 (51.1%) had 4 cycles. 3-year OS were 71% and 67% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.37-1.50; multivariate model: HR 0.56, 95% CI: 0.25-1.27). 3-year RFS were 69% and 59% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.39-1.45; multivariate model: HR 0.67, 95% CI: 0.32-1.42). Among MRD+ pts (n=25), 14 were randomized to and 11 received blina: 7 (63.6%) pts had 2, and 4 (36.4%) had 4 cycles. 3-year OS were 66% and 44% for the blina vs the chemo only arm (univariate model: HR 0.66, 95% CI: 0.12-3.64). 3-year RFS were 64% and 31% for the blina vs the chemo only arm (univariate model: HR 0.64, 95% CI: 0.15-2.74). Frequency of treatment-related toxicities among older pts during different study phases and treatment assignments will be presented. Conclusion Despite evidence of improved outcomes in the whole study cohort, the addition of blina to consolidation chemo for older pts with ALL was not associated with statistically significant improvement of OS or RFS in this exploratory analysis not powered to detect the difference in subgroups. This is possibly due to sample size but may be due to biologic differences in the older adult population. Further studies are needed to definitively determine tolerance and benefit of blina addition to consolidation for older pts with ALL.

Background: Epcoritamab (epcor) is a first-in-class CD3xCD20 bispecific antibody (bsAb) approved for the treatment of 3L+ LBCL and follicular lymphoma. In the single-arm, phase 1/2, EPCORE NHL-1 trial (NCT03625037), epcor given until disease progression or unacceptable toxicity, demonstrated deep and durable responses, a median overall survival (OS) of 18.5 months, and a manageable safety profile in R/R LBCL. A second CD3xCD20 bsAb given as fixed-treatment duration, glofitamab (glofit), also demonstrated durable responses, conferring a median OS of 11.5 months in the pivotal study. Understanding how long-term outcomes compare among bsAb agents remains an important knowledge gap. With over 2 years of follow-up, in the absence of a head-to-head study, it is now relevant to compare the efficacy of these agents via indirect comparison. This study evaluated OS, progression-free survival (PFS), and duration of complete response (DoCR) of epcor vs glofit in R/R LBCL using data from the respective pivotal trials. Methods: Two analyses were conducted to compare the efficacy of epcor and glofit. First, a matching-adjusted indirect treatment comparison (MAIC) was conducted using published OS and PFS data from the full cohort of the glofit pivotal trial (12.6 months of follow-up, Dickinson et al, 2022) and the epcor pivotal trial (EPCORE NHL-1). Piece-wise hazard ratios (HRs) were calculated when proportional hazards assumptions were not met. Baseline characteristic prognostic variables were selected based on literature, clinical judgement, and empirical statistical testing and were adjusted between epcor and glofit cohorts. Second, in sensitivity analyses, indirect comparisons were conducted using an updated analysis of glofit with longer follow-up that included DoCR, together with OS and PFS data starting at cycle (C) 3 with 32 months of follow-up (Hutchings et al, ASH 2023). Sensitivity analyses with longer follow-up could not be adjusted because glofit pt baseline characteristics were not presented. Aggregate OS and PFS curves for glofit were derived from subgroups of pts with complete response/partial response/no response (CR/PR/NR) at C3 (Hutchings et al, ASH 2023). Aggregate epcor OS and PFS curves were similarly derived for pts with CR/PR/NR at C3 without prior disease progression. Weighted Cox proportional-hazards models were used to estimate the OS and PFS HRs between the 2 comparators. The DoCR comparison included all glofit and epcor pts achieving CR. All comparisons used EPCORE NHL-1 data with a median of 37.1 months of follow-up. Results: Pts enrolled into the pivotal trials of epcor and glofit were comparable by several key baseline characteristics before adjustment: age ≥65 y; male gender; Ann Arbor disease stage III-IV; primary refractory disease; refractory to most recent anti-CD20 therapy; previous chimeric antigen receptor T-cell therapy (CAR T); refractory to CAR T; and previous autologous stem cell transplant (ASCT). MAIC analysis revealed no significant difference in OS benefit from C1 until month 6 (HR 1.08, 95% CI 0.71, 1.64; P=0.72), but a demonstrable OS advantage from 6 months onward (HR 0.60, 95% CI 0.37, 0.98; P=0.04) in favor of epcor. An OS comparison starting at C3 with longer glofit follow-up demonstrated a consistent survival advantage in favor of epcor (HR 0.68, 95% CI 0.46, 1.01; P=0.05). The proportion of pts who received CAR T or ASCT subsequent therapy were similar for epcor and glofit (CAR T: 7.0% vs 8.9%; ASCT: 6.4% vs 6.3%) (National Institute for Health and Care Excellence Glofit Single Technology Appraisal, 2023). The MAIC analysis showed comparable PFS between epcor and glofit (HR 1.06, 95% CI 0.79, 1.41; P=0.71), although there was substantial censoring in the glofit PFS curve due to immature follow-up. With longer follow-up in the analysis starting at C3, with less censoring, the glofit PFS curve remained similar to the epcor PFS curve from C3 until month 6 (HR 0.67, 95% CI 0.42, 1.07; P=0.10), where separation of the PFS curves were observed favoring epcor (HR 0.56, 95% CI 0.33, 0.97; P=0.04). Median DoCR was longer for epcor (36.1 months) vs glofit (26.9 months). Conclusion: These indirect treatment comparisons suggest that epcor may provide an overall survival benefit over glofit through longer PFS with more mature follow-up, potentially driven by longer DoCR. Survival data with longer follow-up in the full glofit cohort are needed to confirm these findings.