Editors' ChoiceImmunotherapy

CAR T Cells Advance to the Next Level

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Science Translational Medicine  05 Nov 2014:
Vol. 6, Issue 261, pp. 261ec190
DOI: 10.1126/scitranslmed.aaa1533

CAR T cells have been making headlines since 2011, when five patients with various B cell malignancies responded to this new form of cell therapy. CAR T cells are autologous T cells that are collected from patients and genetically modified with a viral vector to express a chimeric antigen receptor or “CAR.” Now, two new reports demonstrate that most patients with relapsed or refractory acute lymphoblastic leukemia benefit from treatment with CAR T cells. In these studies, the CAR redirects the T cells to the CD19 protein, which is expressed on B cells and on tumors derived from the B cell lineage.

The Lee et al. study reports the results of an intention-to-treat phase I dose-escalation trial. Over 2 years, 21 patients were enrolled and were infused with CD19 CAR T cells. All but two of these patients were able to receive the intended dose of T cells, which demonstrates the feasibility of making CAR T cells from patients with leukemia. Transient toxicities such as fever and low neutrophil counts were common; severe cytokine release syndrome occurred in 14% of the patients but could be treated and reversed. The complete response rate was 67%, and overall survival was over 50% at 10 months. Ten of the 12 patients who had no detectable disease after CAR T cell treatment went on to receive hematopoietic stem cell transplants.

Maude et al. report on 25 pediatric patients and 5 adult patients with the same disease. The complete response rate was 90%, and of these 27 patients, 19 had sustained remissions for a median follow-up time of 7 months. At 6 months, the overall survival rate was 78%. All patients had cytokine release syndrome, which was mild or moderate in 73% but severe enough to require intensive care in the other 27%. In all cases reported, this syndrome was reversible with administration of tocilizumab, a monoclonal antibody that blocks the IL-6 receptor. Three of the 30 patients went on to receive hematopoietic stem cell transplants.

The cell products used in the two studies were biologically different because of differences in the cell culture methods and viral vectors used and because of the different signaling domains built into the CARs. Yet, both cell treatments have similar mechanisms of action and both were effective. CAR T cells are changing the landscape in leukemia and in immunotherapy, and these two seminal reports are a real triumph of academic translational medicine.

D. W. Lee et al., T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet 10.1016/S0140-6736(14)61403-3 (2014). [Full Text]

S. L. Maude et al., Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014). [Full Text]

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