On Wednesday 27 March 2019, Oral Session 20 (OS20)took place at the 45 thAnnual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE. During that session, Abstract OS20-2 was presented by Yongxian Hufrom Zhejiang University, Hangzhou, CN.
In an attempt to improve the response rates and lower the toxicity with chimeric antigen receptor T-cell (CAR-T) therapy in B-cell non-Hodgkin lymphoma (B-NHL), the preliminary clinical evaluation of a dual targeting CD19 and CD22 CAR-T construct was presented here. The primary aim of this study was to assess the safety of the dual CAR-T construct. The investigators also compared the efficacy of the dual CAR-T construct to a single-targeting CD19 CAR-T construct. The cytotoxicity of the dual CAR-T construct was assessed in vitroand in mouse models in vivoprior to this in-human preliminary trial.
Study design & baseline characteristics
- N = 20 heavily pre-treated patients with B-cell lymphoma infused with either:
- CD19/CD22 dual CAR-T construct: n = 11
- CD19 CAR-T construct: n = 9
- Dual CAR-T construct structure:
- CAR with antigen recognition domains of both CD19 (anti-CD19 ScFv) and CD20 (anti-CD22 ScFv)
- 4-1BB costimulatory domain
- CD3z signalling domain
- Lymphodepletion:
- Fludarabine (Flu): 30 mg/m 21−3 days prior to CAR-T infusion
- Cytoxan (CTX): 500 mg/m 22−3 days prior to CAR-T infusion
- Peripheral blood mononuclear cell (PBMC) collection for CAR-T engineering occurred approximately 11 days prior to infusion
- Computed tomography (CT) or positron emission tomography (PET)-CT was used for disease assessment every 30 days following CAR-T infusion
- No statistically significant differences in baseline characteristics between the single CD19 CART and the dual CD19/CD22 CAR-T groups:
|
Characteristic |
CD19 single CAR-T group
|
Dual CD19/CD22 CAR-T group
|
|---|---|---|
|
Median age (range) |
47.8 (27−65) years |
45.6 (25−65) years |
|
Male patients |
55.6% |
54.5% |
|
Disease type |
|
|
|
DLBCL |
88.9% |
81. 8% |
|
Burkitt lymphoma |
0% |
9.1% |
|
SLL/CLL |
11.1% |
0% |
|
Lymphoblastic lymphoma |
0% |
9.1% |
|
Prior lines of treatment |
|
|
|
2−3 |
22.2% |
27.2% |
|
4−5 |
33.3% |
36.3% |
|
> 5 |
44.4% |
36.3% |
|
Disease stage |
|
|
|
I−II |
22.2% |
18.2% |
|
III−IV |
77.8% |
81.8% |
|
Refractory status at study entry |
|
|
|
Primary refractory |
44.4% |
36.4% |
|
Refractory to ≥ 2 lines |
55.6% |
63.6% |
|
Relapse after auto-SCT |
22.2% |
18.2% |
Key results
- Average CAR-T cell infusion dose (range):
- CD19/CD22 dual CAR-T group: 5.2 x 10 6/kg (1.1−10 x 10 6/kg)
- CD19 CAR-T group: 5.8 x 10 6/kg (1.6−10 x 10 6/kg)
- Comparison: P> 0.05
- Average peak CAR-T cell expansion after infusion (10.1 ± 3.32 and 9.2 ± 2.25 days):
- CD19/CD22 dual CAR-T group: 68.7% (6.9−78.6% in CD3 +T cells)
- CD19 CAR-T group: 36.8% (3.6−60.9% in CD3 +T cells)
- Grade 3−5 cytokine release syndrome (CRS):
- CD19/CD22 dual CAR-T group: 10%
- CD19 CAR-T group: 33%
- Neurotoxicity occurred in one patient infused with the dual CD19/CD22 CAR-T construct
- No patient died due to CAR-T-related adverse events
- Overall response rates (ORR):
- CD19/CD22 dual CAR-T group: 90%
- CD19 CAR-T group: 75%
- CR rates:
- CD19/CD22 dual CAR-T group: 70%
- CD19 CAR-T group: 50%
- Overall survival rates at Day 90 post infusion:
- CD19/CD22 dual CAR-T group: 90.0 ± 9.5%
- CD19 CAR-T group: 55.6% ± 16.6%
- The OS rates remain stable at Day 250 post infusion
Conclusions
Promising preliminary in-human results for the dual CD19/CD22 CAR-T construct with B-NHL patients achieving higher CR and ORR, with low severe CRS rates, compared to the standard CD19 single CAR-T construct. More in-human studies and of a larger scale with extended observation periods are needed to further validate these preliminary results.