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Updated: May 30, 2025
A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells
Published on: October 16, 2018
Results From First-in-Human Phase I Study of a Novel CD19-1XX Chimeric Antigen Receptor With Calibrated Signaling in
Jae H Park1,2,3, M Lia Palomba1,2,4, Karlo Perica1,2,3
1Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Purpose:
We designed a CD19-targeted chimeric antigen receptor (CAR) comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3ζ and 4-1BB/CD3ζ CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities.
Methods:
In this first-in-human, phase I, dose escalation and expansion clinical trial, patients with relapsed or refractory large B-cell lymphoma received 19(T2)28z-1XX CAR T cells at four dose levels (DLs), ranging from 25 to 200 × 106.
Results:
Twenty-eight patients underwent apheresis and received CAR T cells. Sixteen and 12 patients were treated in the dose escalation and expansion cohorts, respectively. The overall response rate (ORR) was 82% and complete response (CR) rate was 71% in the entire cohort. The lowest dose of 25 × 106 was selected for dose expansion. In 16 patients treated at this DL, 88% achieved ORR and 75% CR. With the median follow-up of 24 months, the 1-year event-free survival was 61% (95% CI, 45 to 82) and 14 patients remain in continuous CR beyond 12 months. In all cohorts, grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome rates were low at 4% and 7%, respectively. 1XX CAR T-cell products contain a higher proportion of CD8 T cells with memory features, and CAR T-cell persistence has been detected beyond 1-2 years in patients with ongoing remission.
Conclusion:
The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profiles and may benefit the treatment of other hematologic malignancies, solid tumors, and autoimmunity.
Insights
A novel chimeric antigen receptor (CAR) with a calibrated 1XX signaling module demonstrated high efficacy in treating large B-cell lymphoma at low doses. This CAR T-cell therapy showed promising response rates and favorable safety, suggesting broader therapeutic potential.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy has revolutionized B-cell malignancies.
- Conventional CARs utilize CD28/CD3ζ or 4-1BB/CD3ζ signaling modules.
- Optimizing CAR signaling is crucial for balancing efficacy and safety.
Purpose of the Study:
- To evaluate a novel CD19-targeted CAR with a calibrated 1XX signaling module in a phase I clinical trial.
- To determine the safety and efficacy of 1XX CAR T cells in patients with relapsed or refractory large B-cell lymphoma.
- To assess the potential for low-dose CAR T-cell administration with the 1XX construct.
Main Methods:
- A first-in-human, dose escalation and expansion trial was conducted.
- Patients received 19(T2)28z-1XX CAR T cells at doses ranging from 25 to 200 × 10^6.
- Safety, efficacy, and CAR T-cell persistence were assessed.
Main Results:
- An overall response rate (ORR) of 82% and complete response (CR) rate of 71% were observed across all patients.
- The lowest dose (25 × 10^6) showed an 88% ORR and 75% CR in 16 patients.
- Grade ≥3 cytokine release syndrome and neurotoxicity were low (4% and 7%), with CAR T-cell persistence noted beyond 1-2 years in responders.
Conclusions:
- The 1XX CAR T-cell therapy achieves high efficacy at low cell doses with a favorable toxicity profile.
- This calibrated CAR design offers a promising therapeutic strategy for large B-cell lymphoma.
- The 1XX CAR may have potential applications in other hematologic malignancies, solid tumors, and autoimmune diseases.
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