Introduction ICANS remains a major cause of morbidity in CAR T-cell therapy recipients. Although early reports suggested safety of anakinra to treat severe or dexamethasone (dex)-refractory ICANS, outcomes in this patient population have not been characterized to date. To address this, we retrospectively analyzed a large cohort of patients (pts) uniformly treated with anakinra for severe and/or dex-refractory ICANS. Methods We retrospectively analyzed 101 adults treated with CAR T-cell therapy at Fred Hutch Cancer Center (FHCC; n=64) and Oregon Health & Science University (OHSU; n=37) between 2017-2025 receiving anakinra 200-300 mg intravenously every 8 hours for severe or dex-refractory ICANS. A significant neurologic improvement (SNI) was defined as a ≥2-grade improvement in ICANS from anakinra initiation in the absence of additional ICANS-directed therapy. ICANS-related treatment failure-free survival (TFFS) from anakinra initiation was defined as the probability of remaining free from subsequent ICANS-directed therapy, with patients censored at death. Results The most common diseases were large B-cell lymphoma (49%), mantle cell lymphoma (22%), and acute lymphoblastic leukemia (12%). Grade ≥3 ICANS occurred in 82% of pts. Anakinra was initiated at a median of 1 day after ICANS onset, including after dex failure in 89 pts (88%).We observed SNI at 24, 48, and 72 hours after anakinra initiation in 15%, 29%, and 42% of pts, respectively (Figure 1). The 28-day cumulative incidence of ICANS resolution was 86% (95% CI, 78–92%), with a median time to resolution of 8 days after anakinra initiation (Figure 2A). The 14-day ICANS-related TFFS after anakinra initiation was 74.8% (95% CI, 66.7-83.8) (Figure 2B). Twenty-six pts (26%) required additional therapies after anakinra initiation, including methylprednisolone (n = 21), intrathecal chemotherapy (n = 9), siltuximab (n = 2), and cetuximab (n = 1).Next, we evaluated factors associated with outcomes. Older age (OR 0.96, 95% CI 0.92–0.99; p=0.014) and multiple myeloma (OR 0.08, 95% CI 0.001–0.69; p=0.016) were associated with lower odds of 48-hour SNI. Elevated day +0 lactate dehydrogenase (HR 0.34 per log10 U/L, 95% CI, 0.15–0.78; p=0.011) and ferritin (HR 0.67 per log10 ng/mL, 95% CI, 0.49–0.91; p=0.010) were associated with longer time to ICANS resolution. In multivariable analysis adjusting for CAR T-cell product type and day 0 ferritin, longer time to anakinra initiation from ICANS onset was independently associated with inferior TFFS (HR 1.16 per day, 95% CI, 1.01–1.34; p=0.042). Conclusion In this large multicenter cohort, we benchmarked key outcomes in pts treated with anakinra for severe/dex-refractory ICANS: SNI at 72 hours, 42%; median time to ICANS resolution, 8 days; 14-day TFFS, 75%. Time to anakinra initiation independently impacted TFFS. Collectively, our findings warrant studying anakinra as frontline treatment of ICANS.

Abstract Anakinra is increasingly used for corticosteroid-refractory and/or severe immune effector cell–associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor (CAR) T-cell therapy; however, robust data on its efficacy and predictors of response are lacking. We evaluated the outcomes of 101 patients treated with anakinra for ICANS (corticosteroid-refractory, n = 90) and investigated factors associated with anakinra efficacy. The median time to ICANS resolution from anakinra initiation was 8 days, and the 28-day cumulative incidences of ICANS resolution and treatment-related mortality (TRM) were 86% and 13%, respectively. Anakinra treatment failure occurred in 28%. The day +28 antitumor response rate was 91% (complete response, 47%). Significant neurologic improvement (SNI; ≥2-grade improvement in ICANS) occurred in 43% of patients within 72 hours after anakinra initiation. Achieving 72-hour SNI was associated with faster time to ICANS resolution (median, 3 vs 9 days; P< .001) and hospital discharge (28-day cumulative incidence, 93% vs 53%; P< .001), lower 2-week cumulative exposure to dexamethasone (120 vs 190 mg; P = .029) and anakinra (3650 vs 6600 mg; P = .059), lower TRM (28-day cumulative incidence, 0% vs 21%; P = .011), and a trend toward superior overall survival (28 days, 98% vs 74%; P = .094). In multivariable analysis, older age, CAR T-cell product type, and higher day 0 C-reactive protein were independently associated with lower odds of 72-hour SNI. Our study benchmarks key clinical outcomes after anakinra treatment for ICANS; 72-hour SNI may provide a practical clinical decision point to identify patients who may require additional treatment strategies.

Supplementary Figure S1. Immunophenotype of Patient’s T-LGL cells.

Supplementary Figure S2: The binding specificity of αVβ monoclonal antibodies.

Supplementary Figure 5. αVβ monoclonal antibodies induce target T-cell activation, characterized by down modulation of the TCR complex

Supplementary Figure 3: Vβ monoclonal antibodies induce antibody dependent cellular cytotoxicity of target cells.

BACKGROUND Our group (Gazeau et al., TCT 2023) and others showed the safety and potential efficacy of treatment with the recombinant IL-1 receptor antagonist anakinra in patients with refractory cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR) T-cell therapy. While anakinra is now routinely used, its efficacy has not been robustly investigated, and the optimal timing of anakinra initiation and factors associated with its efficacy are unknown. Here, we report the outcomes of a large multicenter cohort of patients treated with anakinra for refractory CRS and/or ICANS and analyze factors associated with the efficacy of anakinra to treat refractory ICANS. METHODS We included adults undergoing CAR T-cell therapy for hematologic malignancies at Fred Hutch Cancer Center (FHCC; n = 82) or Oregon Health & Science University (OHSU; n = 42) between 2017 to February 2025 who received anakinra for refractory CRS and/or ICANS per institutional guidelines (persistent or worsening despite corticosteroids; N = 124). Anakinra was initiated IV (n = 113) or SC (n = 11) at the dose of 8-10 mg/kg/day in 3 divided doses (FHCC) or 200 mg every 8 hours (OHSU). Cumulative incidence (CI) estimates of time to ICANS resolution were computed with death as the competing risk. RESULTS The most common disease types were large B-cell lymphoma (LBCL; n = 53, 43%), mantle cell lymphoma (n = 25, 20%), and multiple myeloma (n = 21, 17%). The most common CAR T-cell products were axicabtagene ciloleucel (n = 31, 25%), brexucabtagene autoleucel (n = 26, 21%), and tisagenlecleucel (n = 21, 17%). Complete or partial anti-tumor responses at day +28 occurred in 94 patients (89%). The CI of early death at 28 days was 7% (95% CI, 4-13%). Anakinra was initiated for persistent and/or severe ICANS in most patients (n = 106, 85%; grade ≥3: n = 82, 76%). Nearly all (n = 123; 99%) patients received concurrent dexamethasone (dex) with a median total dose of 234 mg (range, 30-690). More than half (n = 67; 54%) received concurrent methylprednisolone (MP) with a median total dose of 3,000 mg (range, 140-9,450). Anakinra was initiated after lack of response to dex in 106 patients (85%) and lack of response to both dex and MP in 14 patients (11%). In 21 patients (17%), anakinra and MP were initiated simultaneously after dex failure. Sixteen patients (13%) received additional therapies, including ruxolitinib (n = 1), siltuximab (n = 3), cetuximab (n = 1), intrathecal chemotherapy (n = 11), and dasatinib (n = 1). ICE scores significantly improved by 48 hours after anakinra initiation (Wilcoxon signed-rank p < 0.001). The median time to ICANS resolution from anakinra initiation was 10 days. In patients without ICANS resolution (n = 12), the most common cause of death was refractory toxicity (n = 6). Next, we used cause-specific Cox regression models to identify factors associated with the efficacy of anakinra to treat refractory ICANS. In univariate analyses, follicular lymphoma (FL; reference: LBCL, HR = 4.46, 95% CI, 1.61-12.3, p = 0.004) was associated with shorter time to ICANS resolution from anakinra initiation. We could not confirm associations between time from ICANS onset to anakinra initiation, daily/total MP or anakinra dose, or clinical scenarios (initiation after dex failure, after dex and MP failure, simultaneous initiation with MP after dex failure) and time to ICANS resolution from anakinra initiation. Higher daily dex dose was associated with shorter time to ICANS resolution from CAR T-cell infusion (time-dependent [td] HR = 1.19, 95% CI, 1.04-1.36, p = 0.013). In a multivariable model including daily dex dose, disease type, and CAR costimulatory domain, daily dex dose (tdHR = 1.25, 95% CI, 1.05-1.48, p = 0.014) and FL (HR = 3.88, 95% CI, 1.08-13.9, p = 0.038) remained independently associated with shorter time to ICANS resolution from CAR T-cell infusion. CONCLUSION To our knowledge, this is the largest study of CAR T-cell therapy recipients treated with anakinra for steroid-refractory CRS/ICANS. Anakinra was primarily administered for steroid-refractory ICANS with improved ICE scores by 48 hours and a median time to resolution of 10 days. Higher dex doses remained associated with shorter time to ICANS resolution, highlighting that corticosteroids remain the cornerstone of treating refractory ICANS. More effective strategies for anakinra-refractory ICANS are critically needed.

Supplementary Table S1. (A) List of published datasets used to compile the distribution of TCRVB Gene Usage across T-cell NHL. (B) TCR Vβ usage in 314 patients with T-cell NHL by disease type. Note that both the IMGT and Wei et al nomenclature are listed.

While CD19-CAR-T cell therapy has revolutionized treatment for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), a substantial proportion of patients experience treatment failure. Previous studies demonstrated poor outcomes with conventional salvage therapies. However, the impact of novel treatments, particularly CD19-CD3 bispecific antibodies, on outcomes in this patient population remains unclear. Additionally, prognostic factors to predict outcomes after CAR-T failure have not been well characterized. MethodsWe conducted a single-center, retrospective analysis of all R/R LBCL patients who received CD19-CAR-T therapy at Oregon Health & Science University between 2016 and 2024. Patients with documented CAR-T failure were identified and analyzed for baseline characteristics, post-relapse features, and subsequent treatment outcomes. Primary endpoints included overall survival (OS), progression-free survival (PFS), and response rates. Prognostic factors were evaluated using univariate analysis, and prediction models were developed. ResultsOf 187 LBCL patients receiving CD19-CAR-T therapy, 100 experienced treatment failure. The median OS after CAR-T failure was 5.06 months. Sixty-eight patients (68%) received subsequent therapy, while 32% received best supportive care only. Patients receiving subsequent treatment showed a trend toward improved survival compared to those without further treatment with median OS of 9.95 months versus 0.76 months, respectively. Among patients receiving subsequent therapy, the most common treatments were polatuzumab vedotin-based regimens (18%), followed by bispecific antibodies (13%; glofitamab or epcoritamab), radiotherapy alone (13%), anti-CD19 therapies (6%; tafasitamab or loncastuximab), other targeted treatments (12%), and salvage chemotherapy ± rituximab (7%). The highest complete response (CR) rates were achieved with bispecific antibodies (38%), followed by anti-CD19 agents (33%) and polatuzumab-based regimens (27.8%). Salvage chemotherapy ± rituximab failed to induce CR in any patient. Overall response rates (ORR) were highest with polatuzumab-based regimens (55.6%), other targeted therapies (50.0%), and bispecific antibodies (46%). Radiotherapy alone achieved CR in 23% of patients with an ORR of 31%. No statistically significant differences in response rates, PFS, or OS were observed between treatment groups. Patients relapsing after 2022 showed no improvement in survival compared to those relapsing before 2022 (median OS 8.77 vs. 7.80 months, p=0.77). Univariate analysis identified prognostic factors of 1-year HR: shorter interval from CAR-T to relapse [HR 0.994 (95%CI 0.991, 0.998); p=0.002), ECOG performance status ≥2 at subsequent treatment initiation [HR 2.59 (95%CI 1.36, 4.95); p=0.006], and LDH >1.5 x upper normal limit [HR 3.41 (95%CI 1.81, 6.40); p=0.002]. Age at subsequent treatment ≥65 years showed a trend toward worse survival (HR 1.76 [95%CI 0.93, 3.32], p=0.079). Prediction models were developed to estimate 12-month overall survival at subsequent treatment using these prognostic factors. The apparent and optimism-corrected c-statistic of the best performing model was 0.78 and 0.76, respectively. ConclusionOutcomes for patients with LBCL after CD19-CAR-T failure remain poor despite the availability of novel therapies including bispecific antibodies. The identified prognostic factors and prediction model may assist clinicians in patient counseling. Further research is needed to optimize therapeutic strategies for these challenging patients.

Supplementary Figure 4. Target T-cells do not undergo complement dependentcytotoxicity (CDC).

Context Combining agents with different mechanisms of action may enhance treatment efficacy in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]) is an FDA-approved, CD19-directed, antibody–drug conjugate indicated for R/R diffuse large B-cell lymphoma after ≥2 systemic therapies. Objective LOTIS-7 will evaluate the safety and activity of Lonca + other agents in patients with R/R B-NHL. This phase 1b, open-label, multicenter, multiarm study (NCT04970901) will enroll ~200 patients with B-NHL in part 1 (dose escalation, 60 patients) and part 2 (dose expansion, 140 patients). Design Arms include Lonca + (1) Pola (arm C), (2) glofitamab (arm E), or (3) mosunetuzumab (arm F). Arm C enrollment is complete; arms E and F are enrolling. In part 1, arm C patients receive Lonca at escalating doses (90-150 μg/kg intravenously [IV]) and Pola (1.8 mg/kg IV) on day 1 of each 3-week cycle; patients in arms E or F will receive the same escalating doses of Lonca + glofitamab 30 mg (IV) or mosunetuzumab 45 mg (subcutaneously) after step-up dosing, respectively. Lonca treatment may continue for up to 1 year or until disease progression, unacceptable toxicity, or other discontinuation criteria. Primary endpoints frequency and severity of adverse events (AEs) and serious AEs; dose-limiting toxicities; AE-related dose modifications; and changes from baseline in safety parameters, vital signs, Eastern Cooperative Oncology Group performance status (ECOG PS), and 12-lead electrocardiograms. Secondary endpoints overall and complete response rates; duration of response; progression-free, relapse-free, and overall survival; Lonca concentrations; and antidrug antibody titers. Key eligibility criteria age ≥18 years, pathologic diagnosis of R/R B-NHL (2016 WHO classification), measurable disease (2014 Lugano classification), treatment failure/intolerance, ≥2 prior lines of therapy for part 1 (≥1 for part 2), and ECOG PS of 0-2. Patients previously receiving a study drug are excluded from the arm using that drug. Status The study opened in December 2021. As of December 2023, 23 patients were enrolled, with 12 patients treated in arm C, 6 in arm E, and 4 in arm F. Funding ADC Therapeutics SA and Sobi; medical writing: Citrus Health Group.

Background: Despite recent therapeutic advances, an unmet need exists for efficacious, well-tolerated, and convenient treatment (tx) options for patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL). In particular, pts with high-risk disease, including those refractory to both anti-CD20 tx and an alkylating agent (double refractory) and those with disease progression within 2 y of first-line (1L) immunochemotherapy (POD24), require more effective options. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was recently approved by the US FDA for the tx of adults with R/R diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic tx. Here we present initial results from the FL dose-expansion cohort of the EPCORE™ NHL-1 trial (NCT03625037; phase 1/2). Methods: Pts with CD20 + R/R FL (grade [G] 1-3A) who had received ≥2 prior lines of systemic tx received epcoritamab SC in step-up doses (SUD 1 and 2) in cycle (C) 1, followed by full doses of 48 mg in 28-d Cs: QW, C1-3; Q2W, C4-9; and Q4W, C≥10 until disease progression or unacceptable toxicity. The primary endpoint of overall response rate (ORR) was assessed per Lugano criteria by an independent review committee. As a secondary analysis, minimal residual disease (MRD) was assessed in peripheral blood using the clonoSEQ ® assay (Adaptive Biotechnologies, Seattle, WA). Results: Between Sep 2020 and Oct 2022, 128 pts with R/R FL G1-3A were enrolled to receive epcoritamab SC. As of Apr 21, 2023, the median follow-up was 17.4 mo. Median age was 65 y, 61% of pts had FLIPI 3-5, and 85% had stage III-IV disease. The median number of prior lines of tx was 3 (range, 2-9); 31% of pts had ≥4 prior lines of tx. Common prior therapies included anthracyclines (77%), lenalidomide (31%), and autologous stem cell transplant (19%). Most pts were primary refractory (54%), double refractory (70%), or refractory to their last prior tx (69%); 42% had POD24, and 52% progressed within 2 y of initiating any 1L tx. The ORR was 82%, with a complete response (CR) rate of 63% ( Figure). The median time to response and CR was 1.4 and 1.5 mo, respectively. ORRs/CR rates were generally consistent across prespecified high-risk subgroups: double refractory, 76%/56%; refractory to last prior tx, 74%/51%; POD24, 80%/61%; progression within 2 y of initiating any 1L tx, 79%/64%. High ORRs/CR rates were observed across lines of tx, with a trend of higher rates in earlier lines: 2 prior lines, 89%/72%; 3 prior lines, 88%/68%; ≥4 prior lines, 68%/45%. Median progression-free survival (PFS) was 15.4 mo; median duration of response, duration of CR, and overall survival were not reached. An estimated 85% and 74% of pts with CR remained in response at 12 and 18 mo, respectively. MRD negativity was correlated with improved PFS. The most common tx-emergent AEs (TEAEs) of any grade were CRS (66%), injection-site reaction (57%), COVID-19 (40%), fatigue (30%), neutropenia (28%), diarrhea (27%), and pyrexia (25%). TEAEs leading to tx discontinuation occurred in 19% of pts, the most common being COVID-19. CRS was mostly low grade (40% G1, 25% G2, 2% G3) and primarily occurred following the first full dose (median time to onset after first full dose, 15 h). No CRS events led to tx discontinuation. ICANS was reported in 8 pts (6% overall; 4% G1, 2% G2); all resolved without leading to tx discontinuation. Fatal TEAEs occurred in 13 pts (10%). In a separate R/R FL cohort evaluating an optimized SUD regimen in C1 to mitigate CRS risk, a clinically meaningful reduction in CRS incidence and severity was observed (data to be presented). Conclusions: Single-agent epcoritamab SC resulted in deep and durable responses with high ORR and CR rates in hard-to-treat, high-risk pts with R/R FL. Responses were consistent across subgroups. A correlation between MRD negativity and PFS was observed. The safety profile was manageable; CRS occurrence was predictable, and a reduction in CRS occurrence and severity was seen with an optimized SUD regimen. Overall, no new safety signals were detected. Epcoritamab is currently being investigated in several FL trials across lines of tx, including an ongoing phase 3 trial (NCT05409066) in R/R FL.

Background A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 x CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. Methods EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ + follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 016-mg priming dose on day 1 and a 080-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. Findings Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 174 months [IQR 91-209]). The overall response rate was 820% (105 of 128 patients; 95% CI 743-883), with a complete response rate of 625% (80 of 128; 95% CI 535-709). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. Interpretation Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile.

Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).

AbstractPurpose: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone that expresses one of 48 TCR variable beta (Vβ) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vβ would eliminate the malignant clone while having minimal effects on healthy T cells. Experimental Design: We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vβ13.3. We developed a panel of anti-Vβ13.3 antibodies to test for binding and elimination of the malignant T-cell clone. Results: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vβ13.3 by antibody-dependent cellular cytotoxicity and TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T cells in combination with exogenous natural killer cells. EL4 cells expressing the patient's TCR Vβ13.3 were also killed by antibody administration in an in vivo murine model. Conclusions: This approach serves as an outline for development of therapeutics that can treat clonal T-cell–based malignancies and potentially other T-cell–mediated diseases. See related commentary by Varma and Diefenbach, p. 4024