CSPG4 as Target for CAR-T-Cell Therapy of Various Tumor Entities–Merits and Challenges

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.

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

“…From the antigen-antibody targeting perspective, CSPG4 may promote chemoresistance by activation of integrin-dependent PI3K/Akt signaling in cell lines and patient samples [48]. However, CSPG4 has been suggested to be less prone to antigen loss during CAR-T-cell therapy [21], consistent with our findings that residual tumor cells remain susceptible to anti-CSPG4-PDD treatment. This may signify that our anti-CSPG4-(PDD) ADC might be less prone to resistance in relation to antigen down-regulation and payload efflux.…”

“…While highly-expressed in melanomas, its restricted and low normal tissue distribution may help limit on-target toxicities [20]. A neural crest marker, CSPG4 participates in melanoma pathogenesis and progression through activation of key signaling pathways (e.g., MAPK/ERK1,2) and through the promotion of sustained high-level activating signals required for malignant progression [20][21][22]. Hence, targeting antibodies and ADCs directly to melanoma cells with highly aggressive behavior could improve outcomes for a significant proportion of patients [23].…”

Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer

“…For example, expression of antigenic targets on both TNBC primary tumors and cells residing in the TME (e.g. MDSCs, TAMs, CAFs, Tregs), can facilitate CAR-T cell directed targeting of multiple cell types to overcome the immunosuppressive TME and enhance anti-tumor activity (69,76,94).…”

“…In TNBC, second-generation CSPG4-CAR-T cells have demonstrated in vitro anti-tumor activity in MDA-MB-231, Hs578T, MDA-MB-468 TNBC cells, resulting in pro-inflammatory cytokine release and cytotoxicity to tumor cells(77). A major advantage of CSPG4-CAR-T cell therapy is the ability to target both primary TNBC cells as well as CAFs because CSPG4 is highly expressed on stromal cells in the TNBC TME(76). To limit the potential of on-tumor/off-target toxicity due to low CSPG4 expression on normal tissue, the incorporation of suicide genes into CSPG4-CAR constructs has been proposed(77).…”

CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes

“…The TA chondroitin sulfate proteoglycan 4 (CSPG4), a cell surface proteoglycan that plays an important role in oncogenic pathways involved in cancer progression and metastatic spread (36)(37)(38)(39)(40)(41)(42), was selected as the target for the following reasons. CSPG4 is highly expressed with limited heterogeneity on both differentiated cancer cells and cancer initiating cells (CICs) in several types of cancer.…”