Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice

Publication Date:
2018-08-16
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
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autor Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
beschreibung Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, -CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro . Gene expression data indicated a distinct activity profile for the -CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR .
citation_standardnr 6319719
datenlieferant ipn_articles
feed_id 9363
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-08-16
journaleissn 1557-3265
journalissn 1078-0432
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Clinical Cancer Research
relation http://clincancerres.aacrjournals.org/cgi/content/short/24/16/3981?rss=1
search_space articles
shingle_author_1 Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
shingle_author_2 Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
shingle_author_3 Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
shingle_author_4 Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
shingle_catch_all_1 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, -CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro . Gene expression data indicated a distinct activity profile for the -CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR .
Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_2 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, -CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro . Gene expression data indicated a distinct activity profile for the -CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR .
Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_3 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, -CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro . Gene expression data indicated a distinct activity profile for the -CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR .
Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_4 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, -CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro . Gene expression data indicated a distinct activity profile for the -CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR .
Gulati, P., Rühl, J., Kannan, A., Pircher, M., Schuberth, P., Nytko, K. J., Pruschy, M., Sulser, S., Haefner, M., Jensen, S., Soltermann, A., Jungraithmayr, W., Eisenring, M., Winder, T., Samaras, P., Tabor, A., Stenger, R., Stupp, R., Weder, W., Renner, C., Münz, C., Petrausch, U.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_title_1 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
shingle_title_2 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
shingle_title_3 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
shingle_title_4 Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
timestamp 2025-07-31T23:46:24.399Z
titel Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
titel_suche Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
topic WW-YZ
uid ipn_articles_6319719