EBMT 2019 | Preliminary in-human evaluation of a CD19/CD22 dual CAR-T construct for B-NHL

On Wednesday 27 March 2019, Oral Session 20 (OS20) took place at the 45^th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE. During that session, Abstract OS20-2 was presented by Yongxian Hu from 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 vitro and in mouse models in vivo prior 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/m² 1−3 days prior to CAR-T infusion
  • Cytoxan (CTX): 500 mg/m² 2−3 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  (N = 9)	Dual CD19/CD22 CAR-T group (N = 11)
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 10⁶/kg (1.1−10 x 10⁶/kg)
  • CD19 CAR-T group: 5.8 x 10⁶/kg (1.6−10 x 10⁶/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.