TY - JOUR
T1 - Clinical efficacy and tumor microenvironment influence in a dose-escalation study of anti-CD19 chimeric antigen receptor T cells in refractory B-cell non-Hodgkin's lymphoma
AU - Yan, Zi Xun
AU - Li, Li
AU - Wang, Wen
AU - OuYang, Bin Shen
AU - Cheng, Shu
AU - Wang, Li
AU - Wu, Wen
AU - Xu, Peng Peng
AU - Muftuoglu, Muharrem
AU - Hao, Ming
AU - Yang, Su
AU - Zhang, Mu Chen
AU - Zheng, Zhong
AU - Li, James
AU - Zhao, Wei Li
N1 - Publisher Copyright:
2019 American Association for Cancer Research.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Purpose: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains of great interest. Patients and Methods: A phase I, first-in-human, dose-escalation study of anti-CD19 JWCAR029 was conducted in refractory B-NHL (NCT03355859) and 10 patients received CAR T cells at an escalating dose of 2.5 107 (n ¼ 3), 5 107 (n ¼ 4), and 1 108 (n ¼ 3) cells. Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphoma patients on Day 6 (1 day before lymphodepletion) and on Day 11 after CAR T-cell infusion when adequate CAR T-cell expansion was detected. Results: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieving complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 cytokine release syndrome occurred in all patients and grade 3 neurotoxicity in 1 patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in 3 different dose levels, but CAR T cells were significantly higher in patients achieved complete remission on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients. Increased tumor-associated macrophage infiltration was negatively associated with remission status. Conclusions: JWCAR029 was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact in CAR T therapy response.
AB - Purpose: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains of great interest. Patients and Methods: A phase I, first-in-human, dose-escalation study of anti-CD19 JWCAR029 was conducted in refractory B-NHL (NCT03355859) and 10 patients received CAR T cells at an escalating dose of 2.5 107 (n ¼ 3), 5 107 (n ¼ 4), and 1 108 (n ¼ 3) cells. Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphoma patients on Day 6 (1 day before lymphodepletion) and on Day 11 after CAR T-cell infusion when adequate CAR T-cell expansion was detected. Results: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieving complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 cytokine release syndrome occurred in all patients and grade 3 neurotoxicity in 1 patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in 3 different dose levels, but CAR T cells were significantly higher in patients achieved complete remission on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients. Increased tumor-associated macrophage infiltration was negatively associated with remission status. Conclusions: JWCAR029 was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact in CAR T therapy response.
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U2 - 10.1158/1078-0432.CCR-19-0101
DO - 10.1158/1078-0432.CCR-19-0101
M3 - Article
C2 - 31444250
AN - SCOPUS:85075958120
SN - 1078-0432
VL - 25
SP - 6995
EP - 7003
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -