CD19 CAR T Cell Product Exhibits High Remission Rate in Adult Relapsed and/or Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Ying Zhitao , Wang Wen , Wang Xiaopei , Zheng Wen , Lin Ningjing , Tu Meifeng , Xie Yan , Ping Lingyan , Zhang Chen , Liu Weiping , Deng Lijuan , Hao Ming , Yang Su , Zhou Yan , Li James , Song Yuqin , Zhu Jun 
Published: October 2019

Abstract
Background:
Relapsed and/or refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) has a poor prognosis after chemotherapy. We developed an anti-CD19 CAR T cell product, the first IND approved CD19-targeted CAR T cell product by China National Drug Administration (CNDA), to evaluate the safety and efficacy of administering escalating doses of the product (JWCAR029) in adult relapsed and/or refractory B-cell Non-Hodgkin lymphoma in the single arm, open-label and dose escalation Phase 1 trial (NCT03344367). Interim results based on the first 10 enrolled subjects are reported.
Design:
Eligible subjects undergo leukapheresis and T cells are transduced with a lentiviral vector encoding CD19-specific scFv CAR comprising 4-1 BB and CD3ζ signaling endodomains. Upon successful cell product generation, subjects begin lymphodepleting chemotherapy with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 on Days -4, -3, -2 followed by cell infusion on Day0. Flat dose escalation starts from 2.5 × 10^7 CAR+ T cells (dose level 1, DL1) to 5.0 × 10^7 CAR+ T cells (dose level 2, DL2) and to 1.0 × 10^8 CAR+ T cells (dose level 3, DL3) according to mTPI-2 algorithm. Safety data are collected and efficacy, PK data are detected by PET-CT/CT scanning, flow cytometry, and real-time quantitative polymerase chain reaction system (qPCR).
Results:
As of July 31st 2018, the first 10 subjects (9 male, 1 female) with relapsed and/or refractory diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, or indolent B-cell lymphoma were enrolled with median age of 53 years (range, 29-62 years). Three subjects were allocated to DL1, 4 were assigned to DL2, and the other 3 were allocated to DL3. Safety and efficacy data were evaluable in 7 subjects while 3 subjects in DL3 are still in DLT period. Cytokine Release Syndrome (CRS) was observed in 3 subjects, 2 subjects developed grade 1, 1 had grade 2. No ≧ grade 3 CRS was observed. Onset time of CRS shortened in a dose-dependent manner demonstrating that median onset time of CRS in DL1 was 11 days after infusion while median onset time of CRS in DL2 was 7 days after infusion. No subject received tocilizumab and dexamethasone to treat CRS. Only one subject in DL2 group had grade 1 NT of transient aphasia. No ≧ grade 3 events were observed. Other AEs included grade 1 fatigue, myalgia, headache, emesis, and cough etc. Clinical responses were evaluated on Day 28 after infusion. In total, six of 7 (86%) subjects achieved overall response while three of 7 subjects (43%) achieved a complete response. One subject had progressive disease (PD). At 3 months after infusion, for all 3 evaluable DL1 subjects, 1 subject remained in PR and improved to CR at 6 months after infusion.
Full PK data were examined showing detectable CAR+CD4+ and CAR+CD8+ T cells starting from Day 8 after infusion with peak expansion at Day 11-15 after infusion. CAR+CD4+ and CAR+CD8+ T cells were detected up to 180 days post-infusion. Median copy numbers in 1 microgram DNA were 3,912 (range: 43-5.2 × 10^4) in the first 3 subjects. Of 8 serum biomarkers that were examined, several biomarkers including interleukin-6 and TNF-alpha were significantly associated with CRS.
Conclusion:
Preliminary data from this Phase 1 trial demonstrate that JWCAR029 can provide significant clinical benefit with manageable AEs in relapsed or refractory adult B-NHL patients. Further data of efficacy, safety, subgroup, PK, serum biomarkers associated with safety and efficacy, anti-drug antibodies, and RNA-sequencing will be presented. Accrual is ongoing.

Disclosures
Hao: JW Therapeutics: Employment, Equity Ownership. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhu:Beijing Cancer Hospital: Employment.