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Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control

Nature Biomedical Engineering volume 5, pages 1348–1359 (2021)Cite this article

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Abstract

Treating solid malignancies with chimeric antigen receptor (CAR) T cells typically results in poor responses. Immunomodulatory biologics delivered systemically can augment the cells’ activity, but off-target toxicity narrows the therapeutic window. Here we show that the activity of intratumoural CAR T cells can be controlled photothermally via synthetic gene switches that trigger the expression of transgenes in response to mild temperature elevations (to 40–42 °C). In vitro, heating engineered primary human T cells for 15–30 min led to over 60-fold-higher expression of a reporter transgene without affecting the cells’ proliferation, migration and cytotoxicity. In mice, CAR T cells photothermally heated via gold nanorods produced a transgene only within the tumours. In mouse models of adoptive transfer, the systemic delivery of CAR T cells followed by intratumoural production, under photothermal control, of an interleukin-15 superagonist or a bispecific T cell engager bearing an NKG2D receptor redirecting T cells against NKG2D ligands enhanced antitumour activity and mitigated antigen escape. Localized photothermal control of the activity of engineered T cells may enhance their safety and efficacy.

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Fig. 1: Constructing thermal-specific gene switches.
Fig. 2: Thermal treatments are well-tolerated by primary human T cells.
Fig. 3: Photothermal activation of engineered T cells in vivo.
Fig. 4: Photothermal control of IL-15 SA enhances adoptive T cell transfer and overall survival in mice.
Fig. 5: Expanding CAR T cell targeting via heat-triggered BiTEs.
Fig. 6: Photothermal control of TS-BiTE αHER2 CAR T cells mitigates outgrowth of antigen-negative tumours.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The data generated and analysed during the study are available from the corresponding author on reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank J. M. Brockman for their helpful insights during planning and experiments; K. Roy (Georgia Institute of Technology) for the constitutive αCD19 CAR (US9499629B2), wild-type K562s and Raji cells; and Y. Chen for the CD19+ K562. This work was funded by the NIH Director’s New Innovator Award (DP2HD091793), the National Centre for Advancing Translational Sciences (UL1TR000454) and the Shurl and Kay Curci Foundation. I.C.M. was supported by the Georgia Tech TI:GER programme. L.G. was supported by the Alfred P. Sloan Foundation, the National Institutes of Health GT BioMAT Training Grant under Award No. 5T32EB006343 and the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1451512. G.A.K. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. This work was performed in part at the Georgia Tech Institute for Electronics and Nanotechnology, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (Grant ECCS-1542174). S.J.P. was supported by a STOP Cancer Foundation/Disrupt Seed and the Borstein Family Foundation for this work. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. These authors contributed equally: Ian C. Miller, Ali Zamat.

Authors and Affiliations

  1. The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, USA

    Ian C. Miller, Ali Zamat, Lee-Kai Sun, Hathaichanok Phuengkham, Adrian M. Harris, Lena Gamboa & Gabriel A. Kwong

  2. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA

    Jason Yang, John P. Murad & Saul J. Priceman

  3. Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Saul J. Priceman

  4. Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  5. Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  6. Integrated Cancer Research Center, Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  7. Georgia Immunoengineering Consortium, Emory University and Georgia Institute of Technology, Atlanta, GA, USA

    Gabriel A. Kwong

  8. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Gabriel A. Kwong

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  1. Ian C. Miller
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Contributions

I.C.M. and G.A.K. conceived the idea. I.C.M., A.Z., L.K.S., H.P., L.G., J.P.M., S.J.P. and G.A.K. designed the experiments. I.C.M., A.Z., L.K.S., L.G., H.P., J.P.M., J.Y., S.J.P. and G.A.K interpreted the results. I.C.M., A.Z., L.K.S., H.P., A.M.H., J.P.M. and J.Y. performed the experiments. I.C.M., A.Z. and G.A.K. wrote the manuscript.

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Correspondence to Gabriel A. Kwong.

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I.C.M., L.G., A.Z. and G.A.K. are listed as inventors on a patent application pertaining to the results of this paper (US20200299686A1 and application no. 63/214,761). G.A.K. is co-founder and consultant at Glympse Bio and consults for Satellite Bio. This study could affect his personal financial status. S.J.P. is a scientific advisor to and receives royalties from Mustang Bio and Imugene Ltd. The terms of this arrangement have been reviewed and approved by Georgia Tech in accordance with its conflict-of-interest policies.

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Peer review information Nature Biomedical Engineering thanks Sebastian Kobold and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended data Fig. 1 Engineered Pmel-1 T cells enhance adoptive cell therapy in a high tumour burden setting.

a, Schematic representation of large tumour B16-F10 bearing C57BL/6 J mice upon systemic T cell transfer. b, Tumour-growth curves following inoculation of B16F10 following transfer of engineered murine T cells on day 0 and heat treatments on days 1, 3, and 5 (*P = 0.0489 between untreated and cohorts which received cells only on day 8. *P = 0.0295 between cohorts receiving cells and heat versus cells only on day 12, **P = 0.0043 between cohorts receiving cells and heat versus cells only on day 14, two-way ANOVA and Tukey post-test and correction, mean ± SEM is depicted, n = 6-7 biologically independent mice).

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Source data for tumour burden.

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Miller, I.C., Zamat, A., Sun, LK. et al. Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control. Nat Biomed Eng 5, 1348–1359 (2021). https://doi.org/10.1038/s41551-021-00781-2

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