Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery

Abstract

Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface–conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.

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Figure 1: Synthesis and characterization of TCR-signaling-responsive protein nanogels.
Figure 2: Nanogel anchoring to CD45 promotes prolonged cell surface retention.
Figure 3: IL-15Sa-NG backpacks promote T cell expansion in vitro.
Figure 4: IL-15Sa-NGs promote specific expansion of adoptively transferred T cells in tumors.
Figure 5: IL-15Sa-NG backpacks increase the therapeutic window for adjuvant cytokine delivery during ACT.
Figure 6: TCR signaling–responsive NG backpacks improve T cell therapies.

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Acknowledgements

We thank K.D. Wittrup (MIT) for the gift of the engineered IL-2-Fc constructs and the Koch Institute Swanson Biotechnology Center for technical support on flow cytometry, IVIS imaging and MALDI mass spectrometry. This work was supported in part by the Ragon Institute of MGH, MIT and Harvard (D.J.I.), the Melanoma Research Alliance (award 306833; D.J.I.), the NIH (Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute and CA172164; D.J.I.) and the Koch Institute Marble Center for Cancer Nanomedicine (D.J.I.). L.T. was funded by a Cancer Research Institute (CRI) Irvington Postdoctoral Fellowship, and Y.Z. was supported by a National Science fellowship from the Agency for Science, Technology and Research, Singapore. L.T. and Y.-Q.X. were supported by the ISREC Foundation with a donation from the Biltema Foundation and Swiss National Science Foundation (project grant 315230_173243). M.V.M. was supported by NIH grant CA K08166039. D.J.I. is an investigator of the Howard Hughes Medical Institute.

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L.T., Y.Z., M.B.M. and D.J.I. designed the in vitro and syngeneic mouse experiments; H.C.W. and E.K.J. provided ALT-803; L.T., Y.Z., D.J.I., A.P.C., S.B.K. and M.V.M. designed the studies with the humanized mice; L.T., Y.Z., L.M., M.B.M., Y.-Q.X., N.L., A.P.C. and S.B.K. performed the experiments; L.T., Y.Z., M.B.M. and D.J.I. analyzed the data and wrote the manuscript; and all authors edited the manuscript.

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Correspondence to Li Tang or Darrell J Irvine.

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Competing interests

D.J.I., L.T., and Y.Z. are inventors on licensed patents related to the technology described in this manuscript. D.J.I. is a co-founder of Torque Therapeutics, which licensed patents related to this technology.

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Tang, L., Zheng, Y., Melo, M. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat Biotechnol 36, 707–716 (2018). https://doi.org/10.1038/nbt.4181

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