Phase I/II Study of CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies

AbstractChimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.

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Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

BMJ Open ◽

10.1136/bmjopen-2019-034629 ◽

2020 ◽

Vol 10 (2) ◽

pp. e034629 ◽

Cited By ~ 3

Author(s):

Philip George ◽

Nathaniel Dasyam ◽

Giulia Giunti ◽

Brigitta Mester ◽

Evelyn Bauer ◽

...

Keyword(s):

T Cells ◽

Phase I ◽

B Cell ◽

Chimeric Antigen Receptor ◽

Dose Escalation ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Third Generation ◽

Car T Cells ◽

Car T

IntroductionAutologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.Methods and analysisEligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.Ethics and disseminationEthical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.Trial registration numberNCT04049513

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Efficacy and safety of the dual SYK/JAK inhibitor cerdulatinib in patients with relapsed or refractory B‐cell malignancies: Results of a phase I study

American Journal of Hematology ◽

10.1002/ajh.25387 ◽

2019 ◽

Vol 94 (4) ◽

Cited By ~ 4

Author(s):

Paul A. Hamlin ◽

Ian W. Flinn ◽

Nina Wagner‐Johnston ◽

Jan A. Burger ◽

Greg P. Coffey ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Phase I Study ◽

Jak Inhibitor ◽

Efficacy And Safety ◽

B Cell Malignancies

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The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies

Cytotherapy ◽

10.1016/j.jcyt.2019.04.005 ◽

2019 ◽

Vol 21 (7) ◽

pp. 769-781 ◽

Cited By ~ 6

Author(s):

Jun-Xia Cao ◽

Wei-Jian Gao ◽

Jia You ◽

Li-Hua Wu ◽

Jin-Long Liu ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

B Cell Malignancies

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Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies

Blood ◽

10.1182/blood.2020006770 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jordan Gauthier ◽

Evandro D. Bezerra ◽

Alexandre V. Hirayama ◽

Salvatore Fiorenza ◽

Alyssa Sheih ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Severe Toxicity ◽

B Cell Malignancies ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Grade 3

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose. The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

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