Title |
Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells
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Published in |
Science Translational Medicine, September 2016
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DOI | 10.1126/scitranslmed.aaf8621 |
Pubmed ID | |
Authors |
Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Michael Hudecek, Barbara Pender, Emily Robinson, Reed Hawkins, Colette Chaney, Sindhu Cherian, Xueyan Chen, Lorinda Soma, Brent Wood, Daniel Li, Shelly Heimfeld, Stanley R Riddell, David G Maloney |
Abstract |
CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4(+)/CD8(+) ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival. |
X Demographics
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Country | Count | As % |
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France | 3 | 6% |
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Spain | 3 | 6% |
Russia | 2 | 4% |
Comoros | 1 | 2% |
Trinidad and Tobago | 1 | 2% |
Romania | 1 | 2% |
Netherlands | 1 | 2% |
Other | 5 | 10% |
Unknown | 19 | 38% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 37 | 74% |
Scientists | 10 | 20% |
Science communicators (journalists, bloggers, editors) | 2 | 4% |
Unknown | 1 | 2% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Chile | 1 | <1% |
United States | 1 | <1% |
Germany | 1 | <1% |
Unknown | 675 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 119 | 18% |
Researcher | 107 | 16% |
Student > Bachelor | 61 | 9% |
Student > Master | 53 | 8% |
Other | 51 | 8% |
Other | 116 | 17% |
Unknown | 171 | 25% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 141 | 21% |
Biochemistry, Genetics and Molecular Biology | 110 | 16% |
Immunology and Microbiology | 88 | 13% |
Agricultural and Biological Sciences | 65 | 10% |
Engineering | 22 | 3% |
Other | 64 | 9% |
Unknown | 188 | 28% |