Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells.
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.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA. cturtle@fhcrc.org.
Cameron J
CJ
Turtle
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Laïla-Aïcha
LA
Hanafi
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA.
Carolina
C
Berger
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Michael
M
Hudecek
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Barbara
B
Pender
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Emily
E
Robinson
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Reed
R
Hawkins
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Colette
C
Chaney
Department of Laboratory Medicine, University of Washington, Seattle, WA 98109, USA.
Sindhu
S
Cherian
Department of Laboratory Medicine, University of Washington, Seattle, WA 98109, USA.
Xueyan
X
Chen
Department of Laboratory Medicine, University of Washington, Seattle, WA 98109, USA.
Lorinda
L
Soma
Department of Laboratory Medicine, University of Washington, Seattle, WA 98109, USA.
Brent
B
Wood
Juno Therapeutics, Seattle, WA 98109, USA.
Daniel
D
Li
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Shelly
S
Heimfeld
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA.
Stanley R
SR
Riddell
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA.
David G
DG
Maloney
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013577:Syndrome; D019076:Transgenes; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
D014408:Biomarkers, Tumor; C000605956:CD19-specific chimeric antigen receptor; D011948:Receptors, Antigen, T-Cell; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine