Abstract
Targeting cancer cells using chimeric-antigen-receptor (CAR-)T cells has propelled adoptive T-cell therapy (ATT) to the next level. A plentitude of durable complete responses using CD19-specific CAR-T cells in patients suffering from various lymphoid malignancies resulted in the approval by the food and drug administration (FDA) of CD19-directed CAR-T cells for the treatment of acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). A substantial portion of this success in hematological malignancies can be traced back to the beneficial properties of the target antigen CD19, which combines a universal presence on target cells with no detectable expression on indispensable host cells. Hence, to replicate response rates achieved in ALL and DLBCL in the realm of solid tumors, where ideal target antigens are scant and CAR-T cells are still lagging behind expectations, the quest for appropriate target antigens represents a crucial task to expedite the next steps in the evolution of CAR-T-cell therapy. In this review, we want to highlight the potential of chondroitin sulfate proteoglycan 4 (CSPG4) as a CAR-target antigen for a variety of different cancer entities. In particular, we discuss merits and challenges associated with CSPG4-CAR-T cells for the ATT of melanoma, leukemia, glioblastoma, and triple-negative breast cancer.
Highlights
T cells redirected to malignant cells via chimeric antigen receptors (CARs) have induced spectacular responses in patients suffering from relapsed and refractory hematological malignancies [1,2,3]
The proteoglycan chondroitin sulfate proteoglycan 4 (CSPG4) has been found on the surface of melanoma cells, mixed lineage leukemias (MLL)-rearranged leukemia cells, glioblastoma cells, and triple-negative breast cancer
CSPG4 acts as an oncogenic driver, supporting growth and survival of melanoma cells, which reduces the risk of antigen-loss
Summary
T cells redirected to malignant cells via chimeric antigen receptors (CARs) have induced spectacular responses in patients suffering from relapsed and refractory hematological malignancies [1,2,3]. CARs are created by assembling an antibody-derived single chain Fv (scFv) and the intracellular part of the CD3ζ chain linked in cis with a co-stimulatory domain [5] This modular composition allows for T-cell activation in response to antigens located on the surface of malignant cells by binding of the single chain Fv and subsequent signaling through the CD3ζ chain and the co-stimulatory domain [5]. The large D2 domain is composed of 15 CSPG4-specific repeats and harbors CS attachments sites, integrin-binding sites, collagen-binding sites and it is supposed to act as a growth factor repository, presenting those to adjacent receptor tyrosine kinases (RTK) [18]. Direct association of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) with CSPG4 via a D-domain has been confirmed [18]. We discuss merits and challenges that CSPG4-CAR-T cells may entail on the ATT of those ill-fated malignancies
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