A trispecific CAR targeting CD19, CD20, and CD22 with OX40 co-stimulatory domain with overall response rate was 50%, including complete responses in 83% of lymphoma patients, and one-year overall survival rate was 61%, with durable remissions observed in lymphoma.
Abstract
Disease recurrence is the main cause of treatment failure after CD19-directed CAR T cells, often due to CD19 antigen loss, stability and/or coverage. To overcome single-antigen escape, we evaluated a trispecific CAR targeting CD19, CD20, and CD22 with OX40 co-stimulatory domain. Preclinical studies demonstrated potent, antigen-specific cytotoxicity in in vitro and in vivo lymphoma models. We then conducted a first-in-human phase I trial in patients with relapsed/refractory B-cell malignancies. Sixteen patients received infusions at a median vein-to-vein time of 7 days, at doses of 0.5-2×10⁶ cells/kg. No severe cytokine release syndrome nor neurotoxicity occurred. Overall response rate was 50%, including complete responses in 83% of lymphoma patients. One-year overall survival rate was 61%, with durable remissions observed in lymphoma. CAR T expansion did not correlate with dose or response. T-cell exhaustion in apheresis cells correlated with progressive disease. Trispecific CAR T cells are safe and potentially active in lymphoma.
PURPOSE
This report presents long-term outcomes of third-generation anti-CD30 CAR T-cell therapy in relapsed/refractory (r/r) CD30+ lymphoma patients.
PATIENTS AND METHODS
In this single-arm, multicentre, phase 1/2 trial, patients received lymphodepletion regimen comprising fludarabine and cyclophosphamide, followed by infusion of anti-CD30 CAR-T cells. Primary endpoints included safety and overall response rate (ORR), while secondary endpoints were progression-free survival (PFS) and overall survival (OS).
RESULTS
Forty-four patients were enrolled, including 33 cases of Hodgkin lymphoma. Of 44 patients, 23 achieved complete response (CR) to CAR-T, and 19 achieved PR, resulting in a CR rate of 52.3% and an ORR of 95.5%. The most frequent toxicities were hematologic AEs of grade 3 or higher (68.2% of neutropenia). Cytokine release syndrome occurred in 18 patients (40.9%), with two cases (4.5%) being ≥ grade 3. In the follow-up period, 24 patients underwent auto-HSCT after CAR-T within a median of 3 months. The best ORR was 95.5%, with 27 patients (61.4%) achieving CR. The best CR rate was higher in patients receiving CAR-T followed by auto-HSCT compared to those receiving CAR-T alone (75% vs. 45%). 3-year OS and PFS rates for all patients were 79.0% (95%CI, 66.1%-91.9%) and 74.2% (95%CI, 60.3% -88.1%). Patients receiving consolidated auto-HSCT following CAR-T exhibited significantly longer OS and PFS compared to those treated with CAR-T alone.
CONCLUSION
Third-generation anti-CD30 CAR-T demonstrates high efficacy and a favorable safety profile in r/r CD30+ lymphoma patients. Addition of auto-HSCT following CAR T-cell therapy improves depth of remission and potentially enhances OS and PFS.
Xiangmin Wang, Qing Zhang, Dongmei Yan et al.· Clinical Cancer Research· 0 citations
CD19-directed chimeric antigen receptor-T cell (CAR-T) therapies have transformed treatment for relapsed/refractory large B-cell lymphoma (LBCL), yet heterogeneity in toxicity and efficacy persists. To address this, we developed a novel composite endpoint: severe toxicity-free and progression-free survival at 6 months (TPFS6), defined as absence of severe CRS, ICANS, progressive/stable disease (PD/SD), and non-relapse mortality (NRM) within 6 months of CAR-T therapy. In our cohort, 37% achieved TPFS6. Events contributing to TPFS6 failure included severe CRS (6.8%), ICANS (30.3%), NRM (1.7%), and PD/SD (61.2%). Multivariable analysis demonstrated female sex (p = 0.01), ECOG < 2 (p = 0.05), and lower LDH and CRP (both p = 0.004) predicted TPFS6. With a median follow-up of 36.2 months, the estimated 2-year OS and PFS were 54.5% and 39.6%, respectively. Landmark analysis showed TPFS6 was associated with improved OS (HR = 0.19; 95% CI: 0.11-0.35; p < 0.001) and PFS (HR = 0.33; 95% CI: 0.16-0.67; p = 0.002). CAR-T product type was not significantly associated with OS but was with PFS (HR = 3.09; 95% CI: 1.27-7.50; p = 0.013). TPFS6 remained prognostic for OS and PFS even after accounting for PD/SD, underscoring the impact of severe toxicity on subsequent survival. TPFS6 is a clinically meaningful endpoint integrating efficacy and safety and may predict long-term outcomes following CAR-T therapy.
A. Saha, Junmin Whiting, Razan Mohty et al.· Bone Marrow Transplantation· 0 citations
PURPOSE
This single-center, open-label, Phase 1 trial evaluated the safety and tolerability of chimeric antigen receptor (CAR)-T cells targeting interleukin-13 receptor α2 (IL13Rα2) in patients with malignant gliomas.
PATIENTS AND METHODS
Adults with World Health Organization Grade 3-4 gliomas, recurrent after standard treatment and expressing IL13Rα2 (confirmed by immunohistochemistry), received a single intravenous infusion of autologous CAR-T cells. Primary objectives were to measure the maximum-tolerated dose (MTD) and recommended Phase 2 dose. Secondary objectives included assessment of pharmacokinetics, objective response rate, progression-free survival (PFS), and overall survival (OS).
RESULTS
Ten patients were sequentially assigned to three dosing cohorts (1.0×107, 3.0×107, 1.0×108 cells/kg). The MTD was not reached, as no dose-limiting toxicities were observed, and all adverse events (AEs) were Grade ≤3 without irreversible sequelae. The most common treatment-related AEs were pyrexia (70%) and elevated transaminase (70%). CAR-T cell levels in blood reached peak concentrations at a median of 7 days (range 3-14), and the transgene was detected in cerebrospinal fluid from five of six patients treated at the higher two doses. Nine patients were evaluable for survival analysis, among whom six were available for response assessment at 3 months; best response was stable disease in three cases. Median PFS was 2.6 months (95% confidence interval [CI]: 0.95-5.75), and median OS was 10.9 months (95% CI: 8.2-26.6).
CONCLUSIONS
Intravenous IL13Rα2-targeted CAR-T therapy was well tolerated and demonstrated preliminary safety. Further studies are warranted to optimize dosing and preconditioning regimens and identify exploratory biomarkers for efficacy evaluation.
Kiwan Kim, Seong-Won Song, Y. Jeon et al.· Clinical Cancer Research· 0 citations
PURPOSE
Advanced sarcomas lack effective maintenance therapies after first-line chemotherapy. We present long-term phase 1 results evaluating multi-antigen stimulated cell therapy-I (MASCT-I), a novel immunotherapy integrating dendritic cell vaccination with adoptive T-cell transfer, as maintenance treatment (NCT03034304).
PATIENTS AND METHODS
Thirty-one patients with disease control after chemotherapy received MASCT-I alone (n = 17) or with ifosfamide (n = 14). The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), overall survival (OS), time to progression (TTP), objective response rate (ORR), and disease control rate (DCR). Exploratory objective comprised evaluation of the relationship between clinical efficacy and antigen-specific immune responses.
RESULTS
Treatment was well tolerated with no treatment-related deaths. After a median follow-up of 63.6 months, median PFS from maintenance initiation (PFS1) was 9.5 months, and from first-line chemotherapy start (PFS2) was 16.2 months; median OS was 33.8 months. The combination with ifosfamide numerically improved survival outcomes compared to monotherapy. Patients with high antigen-specific immunity were significantly positively associated with prolonged survival. Notably, six of the seven patients who maintained progression-free status for over 4 years exhibited robust immune activation.
CONCLUSIONS
Our findings establish MASCT-I alone or combined with chemotherapy as maintenance treatment that elicits sustained antigen-specific immunity and encouraging survival in advanced sarcoma.
Xing Zhang, Bushu Xu, Q. Pan et al.· Clinical Cancer Research· 0 citations
This first-in-human study demonstrated the feasibility of an "off-the-shelf" base-edited CAR T cell approach and informs future multiantigen strategies against AML.
C. Georgiadis, Robert Chiesa, Hebatalla Rashed et al.· Science Translational Medici...· 0 citations