Editors' ChoiceCancer Immunology

An Armored CAR for Leukemia Treatment

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Science Translational Medicine  10 Dec 2014:
Vol. 6, Issue 266, pp. 266ec209
DOI: 10.1126/scitranslmed.aaa3455

For decades, cancer immunotherapy efforts have proven disappointing. With few exceptions—such as intravesical bacillus Calmette Guerin for bladder cancer, allogeneic stem cell transplantion for hematologic malignancies, and cytokine therapies for melanoma and renal cell carcinoma—cancer vaccines and other immunomodulatory agents yielded either disappointing efficacy or unacceptable toxicity, or both.

This losing streak ended in 2010, with FDA approval of Sipuleucel-T, a dendritic cell-based vaccine for prostate cancer. Following on the heels of this success was the emergence of so-called checkpoint inhibitors, such as the anti-cytotoxic T lymphocyte antigen-4 (CTLA4) antibody ipilimumab and the anti-programmed death 1 (PD1) antibody pembrolizumab, both of which have been approved for melanoma. Perhaps most encouraging, some checkpoint inhibitors have demonstrated clear efficacy against tumors historically considered resistant to immunotherapies, such as nonsmall cell lung cancer.

Now,another immunomodulatory approach has joined the cancer therapeutic armamentarium: chimeric antigen receptor (CAR) T cells, specifically anti-CD19 CAR T cells for acute leukemia. With this technique, autologous T cells may be engineered to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and costimulatory signaling domains. In a phase 1 dose-escalation trial of this approach, Lee et al. treated 20 pediatric or young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL), and 70% achieved a complete response. The principal toxicity was a potentially severe but transient cytokine-release syndrome. In a separate trial by Maude et al., 5 adults and 25 children with refractory B-cell ALL (of whom 15 had previously undergone transplantation) received single infusions of autologous T cells transduced with a CD19-directed CAR lentiviral vector. The complete response rate was 90%, the 6-month event-free survival rate was 67%, and the 6-month overall survival rate was 78%.

The future looks even brighter for this new technology. Treatment results in generation of tumor-specific T cells and appears to convey little risk of autoimmunity or graft-versus-host disease. Furthermore, CAR T-cell therapy has human leukocyte antigen (HLA)-independent antigen recognition with potential for very broad application, including lymphomas and even solid tumors.

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

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). [Abstract]

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