B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells.

Abstract

We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients. Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFNγ and TNF. The severity of acute toxicities experienced by the patients correlated with serum IFNγ and TNF levels. The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFNγ ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions. Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+) cells in vivo; however, reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions.

• Authors: James N Kochenderfer, Mark E Dudley, Steven A Feldman, Wyndham H Wilson, David E Spaner, Irina Maric, Maryalice Stetler-Stevenson, Giao Q Phan, Marybeth S Hughes, Richard M Sherry, James C Yang, Udai S Kammula, Laura Devillier, Robert Carpenter, Debbie-Ann N Nathan, Richard A Morgan, Carolyn Laurencot, Steven A Rosenberg
• Journal: Blood (Blood) Vol. 119 Issue 12 Pg. 2709-20 (Mar 22 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22160384 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antigens, CD19
• Cytokines
• Recombinant Fusion Proteins

Topics

• Antigens, CD19 (immunology)
• B-Lymphocytes (immunology)
• Cytokines (adverse effects, immunology)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Humans
• Immunohistochemistry
• Immunotherapy, Adoptive (adverse effects, methods)
• Leukemia, Lymphocytic, Chronic, B-Cell (immunology, therapy)
• Lymphoma, B-Cell (immunology, therapy)
• Middle Aged
• Real-Time Polymerase Chain Reaction
• Recombinant Fusion Proteins (immunology, therapeutic use)
• Remission Induction
• T-Lymphocytes (immunology, transplantation)
• Transduction, Genetic