Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors

Bruno L. Cadilha; Mohamed Reda Benmebarek; Klara Dorman; Arman Oner; Theo Lorenzini; Hannah Obeck; Mira Vänttinen; Mauro Di Pilato; Jasper N. Pruessmann; Stefan Stoiber; Duc Huynh; Florian Märkl; Matthias Seifert; Katrin Manske; Javier Suarez-Gosalvez; Yi Zeng; Stefanie Lesch; Clara H. Karches; Constanze Heise; Adrian Gottschlich; Moritz Thomas; Carsten Marr; Jin Zhang; Dharmendra Pandey; Tobias Feuchtinger; Marion Subklewe; Thorsten R. Mempel; Stefan Endres; Sebastian Kobold

doi:10.1126/sciadv.abi5781

Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors

Bruno L. Cadilha^*, Mohamed Reda Benmebarek, Klara Dorman, Arman Oner, Theo Lorenzini, Hannah Obeck, Mira Vänttinen, Mauro Di Pilato, Jasper N. Pruessmann, Stefan Stoiber, Duc Huynh, Florian Märkl, Matthias Seifert, Katrin Manske, Javier Suarez-Gosalvez, Yi Zeng, Stefanie Lesch, Clara H. Karches, Constanze Heise, Adrian GottschlichMoritz Thomas, Carsten Marr, Jin Zhang, Dharmendra Pandey, Tobias Feuchtinger, Marion Subklewe, Thorsten R. Mempel, Stefan Endres, Sebastian Kobold

^*Corresponding author for this work

Department of Dermatology, Allergology and Venereology

96 Citations (Scopus)

Abstract

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (T_reg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). T_reg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8⁺ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

Original language	English
Article number	eabi5781
Journal	Science Advances
Volume	7
Issue number	24
DOIs	https://doi.org/10.1126/sciadv.abi5781
Publication status	Published - 06.2021

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Cadilha, B. L., Benmebarek, M. R., Dorman, K., Oner, A., Lorenzini, T., Obeck, H., Vänttinen, M., Pilato, M. D., Pruessmann, J. N., Stoiber, S., Huynh, D., Märkl, F., Seifert, M., Manske, K., Suarez-Gosalvez, J., Zeng, Y., Lesch, S., Karches, C. H., Heise, C., ... Kobold, S. (2021). Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors. Science Advances, 7(24), Article eabi5781. https://doi.org/10.1126/sciadv.abi5781

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title = "Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors",

abstract = "CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.",

author = "Cadilha, \{Bruno L.\} and Benmebarek, \{Mohamed Reda\} and Klara Dorman and Arman Oner and Theo Lorenzini and Hannah Obeck and Mira V{\"a}nttinen and Pilato, \{Mauro Di\} and Pruessmann, \{Jasper N.\} and Stefan Stoiber and Duc Huynh and Florian M{\"a}rkl and Matthias Seifert and Katrin Manske and Javier Suarez-Gosalvez and Yi Zeng and Stefanie Lesch and Karches, \{Clara H.\} and Constanze Heise and Adrian Gottschlich and Moritz Thomas and Carsten Marr and Jin Zhang and Dharmendra Pandey and Tobias Feuchtinger and Marion Subklewe and Mempel, \{Thorsten R.\} and Stefan Endres and Sebastian Kobold",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",

year = "2021",

month = jun,

doi = "10.1126/sciadv.abi5781",

language = "English",

volume = "7",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

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Cadilha, BL, Benmebarek, MR, Dorman, K, Oner, A, Lorenzini, T, Obeck, H, Vänttinen, M, Pilato, MD, Pruessmann, JN, Stoiber, S, Huynh, D, Märkl, F, Seifert, M, Manske, K, Suarez-Gosalvez, J, Zeng, Y, Lesch, S, Karches, CH, Heise, C, Gottschlich, A, Thomas, M, Marr, C, Zhang, J, Pandey, D, Feuchtinger, T, Subklewe, M, Mempel, TR, Endres, S & Kobold, S 2021, 'Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors', Science Advances, vol. 7, no. 24, eabi5781. https://doi.org/10.1126/sciadv.abi5781

TY - JOUR

T1 - Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors

AU - Cadilha, Bruno L.

AU - Benmebarek, Mohamed Reda

AU - Dorman, Klara

AU - Oner, Arman

AU - Lorenzini, Theo

AU - Obeck, Hannah

AU - Vänttinen, Mira

AU - Pilato, Mauro Di

AU - Pruessmann, Jasper N.

AU - Stoiber, Stefan

AU - Huynh, Duc

AU - Märkl, Florian

AU - Seifert, Matthias

AU - Manske, Katrin

AU - Suarez-Gosalvez, Javier

AU - Zeng, Yi

AU - Lesch, Stefanie

AU - Karches, Clara H.

AU - Heise, Constanze

AU - Gottschlich, Adrian

AU - Thomas, Moritz

AU - Marr, Carsten

AU - Zhang, Jin

AU - Pandey, Dharmendra

AU - Feuchtinger, Tobias

AU - Subklewe, Marion

AU - Mempel, Thorsten R.

AU - Endres, Stefan

AU - Kobold, Sebastian

N1 - Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2021/6

Y1 - 2021/6

N2 - CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

AB - CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

UR - https://www.scopus.com/pages/publications/85107474573

UR - https://www.mendeley.com/catalogue/95145d53-43e7-379a-b85a-37a04706eebe/

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DO - 10.1126/sciadv.abi5781

M3 - Journal articles

C2 - 34108220

AN - SCOPUS:85107474573

SN - 2375-2548

VL - 7

JO - Science Advances

JF - Science Advances

IS - 24

M1 - eabi5781

ER -

Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors

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