Editors' ChoiceCancer

Nanoparticles improve economic mileage for CARs

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Science Translational Medicine  26 Apr 2017:
Vol. 9, Issue 387, eaan2784
DOI: 10.1126/scitranslmed.aan2784

Abstract

Targeted nanoparticles deliver chimeric antigen receptor genes to T cells in situ.

Targeted T cell therapies have shown promise in clinical trials for treating a variety of malignancies. One major strategy involves genetically modifying T cells to express chimeric antigen receptor (CAR) genes, which bind tumor antigens and subsequently stimulate cytolytic activity, T cell proliferation, and cytokine release. CAR-T cell therapy has been most successful in treating blood cancers, although its applications to other malignancies are being tested using strategies such as combination with immune checkpoint blockade. Unfortunately, current manufacturing of CAR-T cells involves substantial cost and complexity related to the isolation, genetic manipulation, selective expansion, and adoptive transfer of a patient’s T cells. Should engineered T cell therapy reach its promise of extending to diverse patient populations across a variety of cancer types, the challenges of economics and manufacturing will likely grow.

Smith et al. report one potential solution to these issues, using a T cell targeted nanoparticle for CAR gene delivery. Their approach combines several features: nanoparticles that target T cells using an antibody fragment for binding the T cell coreceptor CD3e; biodegradable polymer functionalized with nuclear localization signals and microtubule-associated sequences for efficient nuclear delivery; and the piggyBac transposon system, which facilitates stable chromosomal integration. Furthermore, the particle synthesis is relatively simple, and the product can be lyophilized for extended storage.

The authors demonstrate that their nanoparticle is as effective as lentiviral-based methods using in vitro assays for tumor-specific cytolytic activity and cytokine production. Furthermore, in a mouse model of CD19+ leukemia, the intravenously infused anti-CD19 CAR nanoparticle performed as well as a model adoptive cell therapy, which involved ex vivo T cell activation, lentiviral transduction, and intravenous injection after several days in culture. Safety and selectivity have been recurring issues for many nucleic acid nanoparticle strategies. Although no major toxicities were observed in mice, the material used here required a high dose (>1012 particles compared with the 106 T cells in the adoptive cell therapy comparator), showed that nearly 40% of the splenic nanoparticle uptake was due to phagocytes rather than lymphocytes, and induced some minor changes in circulating cytokines. Nonetheless, Smith et al. present a practical alternative to current clinical implementations, with the potential to help drive CARs into broader use.

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