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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Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. / Turtle, Cameron J; Hanafi, Laïla-Aïcha; Berger, Carolina; Hudecek, Michael; Pender, Barbara; Robinson, Emily; Hawkins, Reed; Chaney, Colette; Cherian, Sindhu; Chen, Xueyan; Soma, Lorinda; Wood, Brent; Li, Daniel; Heimfeld, Shelly; Riddell, Stanley R; Maloney, David G.
in: SCI TRANSL MED, Jahrgang 8, Nr. 355, 07.09.2016, S. 355ra116.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells
AU - Turtle, Cameron J
AU - Hanafi, Laïla-Aïcha
AU - Berger, Carolina
AU - Hudecek, Michael
AU - Pender, Barbara
AU - Robinson, Emily
AU - Hawkins, Reed
AU - Chaney, Colette
AU - Cherian, Sindhu
AU - Chen, Xueyan
AU - Soma, Lorinda
AU - Wood, Brent
AU - Li, Daniel
AU - Heimfeld, Shelly
AU - Riddell, Stanley R
AU - Maloney, David G
N1 - Copyright © 2016, American Association for the Advancement of Science.
PY - 2016/9/7
Y1 - 2016/9/7
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Biomarkers, Tumor/metabolism
KW - CD4-Positive T-Lymphocytes/immunology
KW - CD8-Positive T-Lymphocytes/immunology
KW - Cell Proliferation
KW - Cyclophosphamide/pharmacology
KW - Female
KW - Humans
KW - Immunotherapy/adverse effects
KW - Lymphocyte Depletion
KW - Lymphocyte Subsets/immunology
KW - Lymphoma, Non-Hodgkin/drug therapy
KW - Male
KW - Middle Aged
KW - Receptors, Antigen, T-Cell/immunology
KW - Syndrome
KW - Transgenes
KW - Treatment Outcome
KW - Vidarabine/analogs & derivatives
KW - Young Adult
U2 - 10.1126/scitranslmed.aaf8621
DO - 10.1126/scitranslmed.aaf8621
M3 - SCORING: Journal article
C2 - 27605551
VL - 8
SP - 355ra116
JO - SCI TRANSL MED
JF - SCI TRANSL MED
SN - 1946-6234
IS - 355
ER -
