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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Bibliographic Details
Published in:Frontiers in immunology Vol. 14; p. 1178060
Main Authors: Teppert, Karin, Winter, Nora, Herbel, Vera, Brandes, Caroline, Lennartz, Simon, Engert, Fabian, Kaiser, Andrew, Schaser, Thomas, Lock, Dominik
Format: Journal Article
Language:English
Published: Frontiers Media S.A 11.10.2023
Subjects:
adoptive T cell therapy
chimeric antigen receptor
chimeric costimulatory receptor
Immunology
immunotherapy
melanoma
ISSN:1664-3224, 1664-3224
Online Access:Get full text
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Summary: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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Reviewed by: Simon Völkl, University Hospital Erlangen, Germany; Niels Schaft, University Hospital Erlangen, Germany; Theresa L. Whiteside, University of Pittsburgh, United States
Edited by: Steven Fiering, Dartmouth College, United States
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2023.1178060