CD19 Directed CAR T Cells(University of Colorado Denver)

Relapsed/refractory (R/R) B-cell non-Hodgkin lymphomas (NHL) present significant treatment challenges for both patients and clinicians. Despite advances in therapeutic approaches, including the approval of several chimeric antigen receptor (CAR) T-cell products in recent years, there remains a need for more effective options that improve upon existing therapies. To address this, we tested a CAR T-cell construct (UCD19) that incorporates a novel TNFRSF19 transmembrane domain alongside the FMC63 variable region and 4-1BB and CD3-zeta domains that have been used in approved CAR T-cell products manufactured in IL-7 and IL-15 in patients with R/R NHL. The primary aim of this phase 1 clinical trial was to evaluate the manufacturing feasibility and safety profile of the UCD19 product. The secondary aim was to evaluate preliminary efficacy. This trial was an open-label, single arm, single site, phase 1 study designed to assess the safety and feasibility of manufacturing and administration of UCD19 CAR T-cells. Ten patients ≥18 years with R/R B-cell NHL were infused with a fixed dose of UCD19 CAR T-cells (two dose levels) following standard lymphodepleting chemotherapy. Cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) were observed in 30% and 10% of subjects, respectively; all were grades 1 or 2. There were no grade 3 or higher CRS/ICANS. Overall response rate was 90% across the cohort, with a CR rate of 70% at 90 days, with 60% remaining in remission at 12 months. These results demonstrate favorable safety and preliminary efficacy, supporting further investigation of the novel UCD19 CAR T-cell therapy in larger clinical trials to confirm its safety and efficacy in patients with R/R B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT04240808.

Relapsed or refractory acute lymphoblastic leukemia (R/R ALL) remains a major therapeutic challenge with poor long-term survival outcomes. Although checkpoint inhibitors targeting PD-1/PD-L1 have shown efficacy in other hematologic malignancies, their role in ALL has not been fully defined. Combination strategies integrating PD-1/PD-L1 blockade with chemotherapy or CAR-T cells may enhance anti-leukemic responses and overcome immune resistance.

In this multicenter, open-label Phase II trial, 168 patients with R/R ALL were randomized to receive either FLAG chemotherapy plus nivolumab (Group A), CD19-directed CAR-T cells plus atezolizumab (Group B), or FLAG alone (Control). The primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival (OS), MRD negativity, and safety. Immune profiling assessed biomarkers like PD-L1, TIM-3, CD25 + , and cytokines.

MRD negativity rates were significantly higher in experimental arms compared to control (Group A: 19.5 %; Group B: 27.8 %; Control: 3 %; p < 0.001). Median PFS was 7.7 months in Group A, 11.7 months in Group B, and 4.1 months in the control group (p < 0.001). Median OS was 10.75, 13.5, and 5.65 months, respectively (p < 0.001). Higher baseline PD-L1 expression was independently associated with improved survival (HR 0.90 per 10 % increase; p = 0.002). The addition of checkpoint inhibitors did not significantly increase severe toxicities, and infection rates were lower in experimental groups compared to control. The swimmer plot analysis demonstrated prolonged remission in MRD-negative patients.

Adding PD-1 or PD-L1 blockade to either chemotherapy or CAR-T therapy improved clinical outcomes without excess toxicity in R/R ALL.