Major finding: CD19-specific chimeric antigen receptor T cells induced remission in patients with advanced CLL.
Impact: Second-generation chimeric antigen receptor overcame in vivo limitations of modified T cells.
Controversy: Activation of T cells by chimeric antigen receptors may induce toxicity.
A recent approach in tumor immunotherapy has been to genetically engineer a patient's own T cells to express a chimeric antigen receptor consisting of a tumor-specific antigen-recognition domain and a T-cell intercellular signaling domain. The success of this strategy has been impeded by the limited ability of chimeric antigen receptor T cells to expand in vivo and persist in the blood long enough to have clinical benefit. In 2 recent papers, June and colleagues surmounted this obstacle by adding a T-cell–specific costimulatory domain to first-generation chimeric antigen receptors. Their clinical trial focused on chronic lymphocytic leukemia (CLL), a B-cell malignancy that is an ideal candidate for chimeric antigen receptor-mediated T-cell immunotherapy due to expression of the cell surface antigen CD19 by B cells. Three patients with advanced, chemotherapy-resistant CLL were immunodepleted and infused with chimeric antigen receptor T cells targeted to CD19 (CART19 cells). CART19 cells trafficked to the bone marrow, expanded, and persisted in the blood for at least 6 months in all 3 patients. This immunotherapy induced a complete remission in 2 of the patients lasting over 10 months to date and a partial response in the third. However, the authors cannot exclude the possibility that previous courses of chemotherapy potentiated CART19 cell activity, or that the CART19 cells flourished because the immunodepleted patients could not reject them. Additionally, unexpected consequences of T-cell responses in other organs or release of high levels of cytokines due to rapid tumor lysis could lead to life-threatening toxicity. Although this approach may not be applicable to tumor types that lack well-defined, specific antigens, these encouraging results suggest that chimeric antigen receptor-modified T cells capable of expansion and long-term persistence in vivo could be a viable strategy for sustained control of certain cancers.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.
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