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Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma

The prognosis for patients with metastatic melanoma is poor and treatment options are limited. Genetically-engineered T cell therapy targeting chondroitin sulfate proteoglycan 4 (CSPG4), however, represents a promising treatment option, especially as both primary melanoma cells as well as metastases...

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Autores principales: Teppert, Karin, Winter, Nora, Herbel, Vera, Brandes, Caroline, Lennartz, Simon, Engert, Fabian, Kaiser, Andrew, Schaser, Thomas, Lock, Dominik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603253/
https://www.ncbi.nlm.nih.gov/pubmed/37901209
http://dx.doi.org/10.3389/fimmu.2023.1178060
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author Teppert, Karin
Winter, Nora
Herbel, Vera
Brandes, Caroline
Lennartz, Simon
Engert, Fabian
Kaiser, Andrew
Schaser, Thomas
Lock, Dominik
author_facet Teppert, Karin
Winter, Nora
Herbel, Vera
Brandes, Caroline
Lennartz, Simon
Engert, Fabian
Kaiser, Andrew
Schaser, Thomas
Lock, Dominik
author_sort Teppert, Karin
collection PubMed
description The prognosis for patients with metastatic melanoma is poor and treatment options are limited. Genetically-engineered T cell therapy targeting chondroitin sulfate proteoglycan 4 (CSPG4), however, represents a promising treatment option, especially as both primary melanoma cells as well as metastases uniformly express CSPG4. Aiming to prevent off-tumor toxicity while maintaining a high cytolytic potential, we combined a chimeric co-stimulatory receptor (CCR) and a CSPG4-directed second-generation chimeric antigen receptor (CAR) with moderate potency. CCRs are artificial receptors similar to CARs, but lacking the CD3ζ activation element. Thus, T cells expressing solely a CCR, do not induce any cytolytic activity upon target cell binding, but are capable of boosting the CAR T cell response when both CAR and CCR engage their target antigens simultaneously. Here we demonstrate that co-expression of a CCR can significantly enhance the anti-tumor response of CSPG4-CAR T cells in vitro as well as in vivo. Importantly, this boosting effect was not dependent on co-expression of both CCR- and CAR-target on the very same tumor cell, but was also achieved upon trans activation. Finally, our data support the idea of using a CCR as a powerful tool to enhance the cytolytic potential of CAR T cells, which might open a novel therapeutic window for the treatment of metastatic melanoma.
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spelling pubmed-106032532023-10-28 Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma Teppert, Karin Winter, Nora Herbel, Vera Brandes, Caroline Lennartz, Simon Engert, Fabian Kaiser, Andrew Schaser, Thomas Lock, Dominik Front Immunol Immunology The prognosis for patients with metastatic melanoma is poor and treatment options are limited. Genetically-engineered T cell therapy targeting chondroitin sulfate proteoglycan 4 (CSPG4), however, represents a promising treatment option, especially as both primary melanoma cells as well as metastases uniformly express CSPG4. Aiming to prevent off-tumor toxicity while maintaining a high cytolytic potential, we combined a chimeric co-stimulatory receptor (CCR) and a CSPG4-directed second-generation chimeric antigen receptor (CAR) with moderate potency. CCRs are artificial receptors similar to CARs, but lacking the CD3ζ activation element. Thus, T cells expressing solely a CCR, do not induce any cytolytic activity upon target cell binding, but are capable of boosting the CAR T cell response when both CAR and CCR engage their target antigens simultaneously. Here we demonstrate that co-expression of a CCR can significantly enhance the anti-tumor response of CSPG4-CAR T cells in vitro as well as in vivo. Importantly, this boosting effect was not dependent on co-expression of both CCR- and CAR-target on the very same tumor cell, but was also achieved upon trans activation. Finally, our data support the idea of using a CCR as a powerful tool to enhance the cytolytic potential of CAR T cells, which might open a novel therapeutic window for the treatment of metastatic melanoma. Frontiers Media S.A. 2023-10-11 /pmc/articles/PMC10603253/ /pubmed/37901209 http://dx.doi.org/10.3389/fimmu.2023.1178060 Text en Copyright © 2023 Teppert, Winter, Herbel, Brandes, Lennartz, Engert, Kaiser, Schaser and Lock https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Teppert, Karin
Winter, Nora
Herbel, Vera
Brandes, Caroline
Lennartz, Simon
Engert, Fabian
Kaiser, Andrew
Schaser, Thomas
Lock, Dominik
Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma
title Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma
title_full Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma
title_fullStr Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma
title_full_unstemmed Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma
title_short Combining CSPG4-CAR and CD20-CCR for treatment of metastatic melanoma
title_sort combining cspg4-car and cd20-ccr for treatment of metastatic melanoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603253/
https://www.ncbi.nlm.nih.gov/pubmed/37901209
http://dx.doi.org/10.3389/fimmu.2023.1178060
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