Editors' ChoiceCancer

Committing CAR T cells to memory

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Science Translational Medicine  21 Dec 2016:
Vol. 8, Issue 370, pp. 370ec205
DOI: 10.1126/scitranslmed.aal3704

Adoptive cell therapy using T cells engineered to express chimeric antigen receptors (CARs) can achieve durable complete responses in a subset of cancer patients. Positive outcomes with CAR T cell therapy are generally associated with high levels of engraftment and long-term persistence of transferred cells. Accordingly, specific cell types with the highest potential for longevity, such as certain memory T cell subpopulations, have demonstrated the highest therapeutic potential. Strategies favoring the generation and preservation of such cells may therefore potentiate the therapeutic effects of CAR T cell–based cancer therapy.

Interleukin-15 (IL-15) is important for homeostatic maintenance of long-lived CD8 memory T cells, reversal of T cell anergy, and enhanced antitumor activity. To leverage the therapeutic potential of IL-15 for CAR T cell therapy but avoid the limitations associated with direct infusion of IL-15, which has a short serum half-life, Hurton et al. implemented a recombinant, cell membrane–tethered variant of IL-15 that mimics physiological IL-15 presentation by T cell surface-expressed receptors with CD19-specific CAR in order to improve the survival and longevity, as well as memory potential of infused T cells. Using immunodeficient mouse hosts, the team found the long-term persistence and antitumor activity of transferred human CAR T cells to be enhanced as the result of membrane-bound IL-15. Strikingly, this mode of presentation of IL-15 prolonged persistence without proliferation. As a result, a higher frequency of infused cells retained memory potential with a phenotype of T memory stem cells, which persist even in the absence of antigen stimulation and are thought to mediate T cell immunological memory after antigen clearance. Correspondingly, the beneficial effects conferred by membrane-bound IL-15 were independent of antigenic stimulation.

This study suggests that leveraging membrane-bound IL-15 to improve CAR T cell therapy could be useful in not only treating disease and preventing relapse but also under conditions of low tumor burden. It also suggests that cellular engineering approaches enhancing the T memory stem cell phenotype can significantly augment the longevity of the anticancer effects of adoptive cell therapy using CAR T cells, though the potential negative effects on existing treatment-associated toxicities remain unknown.

L. V. Hurton et al., Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc. Natl. Acad. Sci. U.S.A. 113, E7788–E7797 (2016). [Full Text]

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